Patent Publication Number: US-2022218883-A1

Title: Implantable Device Coated by a Self-Assembled Monolayer and Therapeutic Agent

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application claims priority to U.S. Provisional Patent Application No. 62/838,548 filed Apr. 25, 2019, entitled “Implantable Device Coated by a Self-Assembled Monolayer and Therapeutic Agent,” the disclosure of which is hereby incorporated by reference in its entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     Field of the Invention 
     The present disclosure is generally directed to an implantable device and, more particularly, to an implantable device at least partially coated by a self-assembled monolayer and therapeutic agent covalently bonded to portions of the self-assembled monolayer. 
     Description of Related Art 
     Implantable devices, such as endovascular devices and/or blood-contacting devices, are used for a variety of therapies, as are known in the art. For example, a common method for treating stenosed or aneurysmal vessels or other blocked passageways is to utilize an implantable expandable prosthesis or stent device. The prosthesis or stent device is an expandable structure configured to be deployed in a vessel or passageway in an expanded state to maintain patency or continuity of the vessel or passageway. Conventional stents are often formed from a framework of interconnecting members or struts, which can be arranged to form closed or open cells. Many stent designs are known and can include combinations of different types of framing structures, such as helical coils, meshes, lattices, or interconnected rings. Such framing structures can be made from, for example, stainless steel and/or cobalt chromium. Conventional stents can be covered or uncovered. The cover can be constructed from a biocompatible material, such as expanded polytetrafluoroethylene (ePFTE). In one common design, a stent can include a series of cylindrical rings aligned in a series along a central longitudinal axis. The rings can be fixedly secured to one another by a plurality of interconnecting members, such as longitudinally extending struts. 
     Placement of endovascular devices, such as stents, in the vascular system of a patient is known to cause a physiological response, such as thrombosis and local inflammation. For example, the blood-contacting surface of a metal stent can increase platelet aggregation and blood clot formation compared to a native, non-instrumented vessel wall (e.g., endothelium). Additionally, local trauma and vascular inflammation caused by stent implantation can result in vascular cell proliferation (also referred to as neointimal hyperplasia) into a lumen of the stent, resulting in restenosis and reduced blood flow. Various therapeutic agents can be provided to patients to reduce the immune response and/or to inhibit platelet aggregation and blood clot formation. For example, antiplatelet agents, such as ticagrelor, can be prescribed as antiplatelet therapies. Ticagrelor is taken orally and, therefore, must be taken in sufficient concentrations systemically to effect platelet inhibition at local stent site(s). This results in high systemic levels of ticagrelor and an associated bleeding risk. 
     Drug eluting stents formed from degradable biomaterials can be used for preventing neointimal hyperplasia. Current drug eluting stent systems can comprise a slowly degrading polymer, which allows a drug to seep into underlying tissues over a predetermined time period, such as a number of hours or days. Some drug eluting stents may also comprise a micro-textured surface that promotes direct adsorption of the drugs. 
     SUMMARY OF THE INVENTION 
     Current methods for providing therapies for implantable devices, such as antiplatelet therapies, suffer from a number of deficiencies, as described herein. For example, providing medication orally or by injection does not target specific tissues or regions of the body, such as a wound site caused by deployment of an implantable device. Instead, in order to ensure that target tissues are exposed to a therapeutically effective concentration of a drug, the drug must be provided in sufficient amounts to provide system-wide efficacy. Accordingly, the patient may be exposed to systemic effects of the drug even when only targeted treatment is needed. 
     Drug eluting stents also may not provide targeted therapy when the implantable device is provided in proximity to dynamic tissues, such as flowing blood. In particular, the flowing blood carries away the drug eluted from the implantable device, meaning that the eluted drug does not collect in sufficiently-high concentrations in proximity to the implanted device. In order to account for drug carried away by blood flow, the implanted device may be configured to elute a sufficient amount of drug for system-wide efficacy. 
     The implantable medical devices and coatings disclosed herein are configured to address these issues by immobilizing therapeutic agents to surfaces of implantable devices. The immobilized therapeutic agents are configured to provide targeted therapies, such as antiplatelet therapies, directly to the tissues surrounding the implantable device for extended periods, such as for an entire useful life of the implantable device. 
     Beneficially, by immobilizing the therapeutic agent(s) on the implanted device, a level of therapeutic efficacy for tissues surrounding the implantable device can be achieved without needing to provide a sufficient amount of the drug for achieving system-wide efficacy to the patient. Accordingly, in one example, the medical devices and coatings disclosed herein avoid the need for antiplatelet therapy in order to prevent vascular interventions. Instead, the therapeutic agent(s) bonded and immobilized on the implantable medical device provide antiplatelet effects for tissues surrounding the implanted device, thereby avoiding the need to provide antiplatelet therapy with system-wide efficacy. 
     According to an aspect of the disclosure, an implantable device comprises a body configured to be implanted within a body of a patient and a self-assembled monolayer. The self-assembled monolayer comprises molecules comprising a first portion (moiety) bonded to a surface of the body, a second portion (moiety) opposite the first portion, and a linkage portion (moiety) extending between the first portion and the second portion. The implantable device further comprises a therapeutic agent comprising at least one therapeutic molecule covalently bonded to the second portion of the molecules of the self-assembled monolayer. 
     According to another aspect of the disclosure, a method of deploying an implantable device comprises advancing an implantable device through a vascular system of the patient to a preselected deployment site through a delivery catheter; and extending the implantable device from a distal end of the delivery catheter, thereby causing the implantable device to expand from a contracted state to a deployed state. The implanted device comprises a body configured to be implanted within a body of a patient and a self-assembled monolayer. The self-assembled monolayer comprises molecules comprising a first portion (moiety) bonded to a surface of the body, a second portion (moiety) opposite the first portion, and a linkage portion (moiety) extending between the first portion and the second portion. The implanted device further comprises a therapeutic agent comprising at least one therapeutic molecule covalently bonded to the second portion of the molecules of the self-assembled monolayer. 
     According to another aspect of the disclosure, a method of preparing an implantable device coated by a therapeutic agent comprises: preparing a body portion of an implantable device, which is configured to be blood contacting when implanted; exposing surfaces of the body of the implantable device to a solution containing molecules configured to form a self-assembled monolayer on the surfaces of the implantable device; and immersing the coated device comprising the self-assembled monolayer in a solution containing a therapeutic agent comprising at least one site configured to covalently bond to the at least one site of the self-assembled monolayer layer. 
     According to another aspect of the disclosure a method of deploying an implantable device comprises advancing an implantable device formed according to the previously described method through a vascular system of the patient to a preselected deployment site through a delivery catheter; and extending the implantable device from a distal end of the delivery catheter, thereby causing the implantable device to expand from a contracted state to a deployed state. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       These and other features and characteristics of the present disclosure, as well as the methods of operation and functions of the related elements of structures and the combination of parts and economies of manufacture, will become more apparent upon consideration of the following description and the appended claims with reference to the accompanying drawings, all of which form a part of this specification, wherein like reference numerals designate corresponding parts in the various figures. It is to be expressly understood, however, that the drawings are for the purpose of illustration and description only and are not intended as a definition of the limit of the invention. 
         FIG. 1A  is a perspective view of an implantable device, according to an aspect of the present disclosure; 
         FIG. 1B  is a cross sectional view of a portion of an elongated tine of the implantable device of  FIG. 1A ; 
         FIG. 1C  is a perspective view of another embodiment of an implantable device in a deployed position, according to an aspect of the present disclosure; 
         FIG. 2A  is a schematic drawing showing a coating comprising a self-assembled monolayer on a surface of an implantable device, according to an aspect of the disclosure; 
         FIG. 2B  is a schematic drawing showing a coating comprising a self-assembled monolayer on a surface of an implantable device comprising two therapeutic agents, according to an aspect of the disclosure; 
         FIGS. 2C and 2D  are schematic drawings showing coatings comprising mixed self-assembled monolayers on a surface of an implantable device, according to an aspect of the disclosure; 
         FIG. 3  is a flow chart of steps for forming a coating comprising a self-assembled monolayer and/or mixed self-assembled monolayer on a surface of an implantable device, according to an aspect of the disclosure; 
         FIG. 4  is a reaction scheme for immobilization of ticagrelor on a monolayer of 16-carboxylhexadecylphosphonic acid, according to an aspect of the disclosure; 
         FIG. 5  shows a comparison of a chemical structure of 2-phenoxyethanol and ticagrelor; 
         FIG. 6A  is a reaction scheme for a Mitsunobu reaction for immobilization of 2-phenoxyethanol, according to an aspect of the disclosure; 
         FIG. 6B  is a reaction scheme for a Mitsunobu reaction for immobilization of ticagrelor, according to an aspect of the disclosure; 
         FIG. 7  is a spectral graph obtained by DRIFT spectroscopy for a mixed monolayer comprising 16-carboxyhexadecylphosphonic acid and tetradecylphosphonic acid; 
         FIG. 8  is a spectral graph obtained by DRIFT spectroscopy for a self-assembled 12-aminododecylphosphonic acid monolayer after immobilization of 2-phenoxyethanol to the monolayer; 
         FIG. 9  is a spectral graph obtained by DRIFT spectroscopy for a self-assembled 12-aminododecylphosphonic acid monolayer after immobilization of ticagrelor to the monolayer; 
         FIGS. 10A-10C  are AFM images of coated substrates; 
         FIGS. 11A-11C  are SEM images of bare and coated stents showing platelet adhesion for different surfaces; 
         FIGS. 12A and 12B  are spectral graphs obtained by DRIFT spectroscopy showing spectra obtained by DRIFT spectroscopy for a 12-amino-dodecylphosphonic acid (ADPA) monolayer; 
         FIG. 13  is a spectral graph obtained by DRIFT spectroscopy for pure ticagrelor overlaid with a spectral graph for ticagrelor immobilized to an ADPA monolayer on a SS316L stainless steel stent; 
         FIGS. 14A-14C  are SEM images of surfaces of stainless steel (SS316L) stents, some of which are coated by monolayers and immobilized ticagrelor, exposed to platelet rich plasma (PRP) for one hour; 
         FIG. 15  are graphs showing flow cytometric platelet populations for a control stent, a bare metal stent, a stent coated by an ADPA self-assembled monolayer, and a stent with ticagrelor immobilized to the monolayer; 
         FIG. 16  is a bar graph showing adenosine diphosphate (ADP) Enzyme-linked immunosorbent assay (ELISA) results for the coated stents in nmol/L; 
         FIG. 17  is a spectral graph obtained by DRIFT spectroscopy showing immobilized ticagrelor on CoCr substrate compared to solid ticagrelor; and 
         FIG. 18  is a bar graph showing platelet coverage of stents surfaces for a bare metal stent and a ticagrelor coated stent. 
     
    
    
     DESCRIPTION OF THE INVENTION 
     The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges are both preceded by the word “about”. In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. Also, unless indicated otherwise, the disclosure of these ranges is intended as a continuous range including every value between the minimum and maximum values. 
     As used herein, the terms “comprising,” “comprise” or “comprised,” and variations thereof, are meant to be open ended. The terms “a” and “an” are intended to refer to one or more. 
     As used herein, the “treatment” or “treating” of a condition, wound, or defect means administration to a patient by any suitable dosage regimen, procedure, and/or administration route of a composition, device, or structure, with the object of achieving a desirable clinical/medical end-point, including repair and/or replacement of a tricuspid or mitral valve. 
     As used herein, the term “patient” or “subject” refers to members of the animal kingdom including but not limited to human beings. 
     A material is “biocompatible” in that the material and, where applicable, degradation products thereof, are substantially non-toxic to cells or organisms within acceptable tolerances, including substantially non-carcinogenic and substantially non-immunogenic, and are cleared or otherwise degraded in a biological system, such as an organism (patient), without substantial toxic effect. Non-limiting examples of degradation mechanisms within a biological system include chemical reactions, hydrolysis reactions, and enzymatic cleavage. 
     By “biodegradable” or “bioerodable,” it is meant that a material that once implanted and placed in contact with bodily fluids and tissues will degrade either partially or completely through chemical reactions with the bodily fluids and/or tissues, typically and often preferably over a time period of hours, days, weeks or months. Non-limiting examples of such chemical reactions include acid/base reactions, hydrolysis reactions, and enzymatic cleavage. The biodegradation rate of the material may be manipulated, optimized or otherwise adjusted so that the matrix degrades over a useful time period. 
     With reference to  FIGS. 1A-2B , the present disclosure is generally directed to an implantable device  10  comprising a coating  12  comprising a therapeutic agent  14 . As used herein, an “implantable device” can refer to various devices and structures configured to be implanted in a body of a patient. In some examples, the implantable device  10  is an endovascular device, such as a tubular stent (e.g., a venous or arterial stent), blood filter, defect or shunt closure device, intra-cardiac repair device, or fixation device that can be implanted into the vascular system of a patient through a vascular access site using a delivery catheter. A defect or shunt closure device may comprise, for example, devices configured for closing septal defects (e.g., a patent foramen ovale, atrial septal defect, or a ventricular septal defect). In other examples, the implantable device  10  can be a ventricular assist device. In other examples, the implantable device  10  can be a joint replacement device, orthopedic implant, or another blood-contacting implantable device, as are known in the art. 
     In some examples, the coating  12  is configured to immobilize the therapeutic agent  14  to the implantable device  10 . The immobilized therapeutic agents  14  can be used to provide therapies to targeted locations surrounding the implantable device  10 . Use of immobilized therapeutic agents  14 , rather than materials that can be eluted from the implantable device  10 , avoids potential complications and negative physiological effects of systemic delivery of antiplatelet and/or anticoagulant agents. 
     The implantable devices  10  and methods disclosed herein provide substantial benefits over presently available stents and treatment methods, especially relating to avoiding formation and/or treatment of stent thromboses. As discussed previously, antiplatelet drugs and antiplatelet therapies are currently used to prevent stent thrombosis. Such antiplatelet drugs can be delivered orally in sufficient concentration to provide systemic antiplatelet activity. Systemic antiplatelet therapy is non-targeted and affects an entire host platelet population. Consequently, systematic antiplatelet activity may increase bleeding. In contrast, the implantable devices  10  disclosed herein provide covalent linkages between the implantable device  10  and therapeutic agent  14 , which effectively trap the antiplatelet agent to the implantable device  10 . 
     Self-Assembled Monolayer Examples 
     With reference to  FIGS. 2A and 2B , the coating  12  of the implantable device  10  is formed from and/or comprises a self-assembled monolayer  16  binding the therapeutic agent  14  to a surface  42  of a body  20  (e.g., bulk material) of the implantable device  10 . The body  20  is generally an elongated tubular structure. Portions of the body  20  may be formed from a suitable metal, plastic, or ceramic materials depending on the intended use of the implantable device  10 . The body  20  may formed from stainless steel, for example 316L stainless steel. In other examples, portions of the body  20  may be formed from metals including titanium and/or nickel titanium alloys. The body  20  may also be formed from silicone, as is used in standard medical tubing. Silicone may be oxidized to provide bonding sites for the self-assembled monolayer  16 . As described in further detail herein, the coating  12  may be formed by conventional deposition processes, such as aerosol spraying and/or immersion in a solution containing material(s) of the coating  12 . 
     Generally, a “therapeutic agent” refers to a compound that provides a certain beneficial effect for a patient when provided to the patient in a sufficient concentration or dose. For example, the therapeutic agent  14  of the present disclosure may provide an antiplatelet therapy, such as preventing platelets from adhering to surfaces of the implantable device  10  and preventing formation of blood clots in proximity to the device  10 . In other examples, the therapeutic agent  14  provides anticoagulation and/or cytotoxic properties. In some examples, as described in detail in connection with  FIGS. 2B-2D , different types of therapeutic agents  14 ,  214  such as, for example, therapeutic agents  14 ,  214  having both antiplatelet and cytotoxic properties, are bonded to surfaces  42  of an implantable medical device  10 . Such an implantable device  10  may be used in coronary and/or endovascular stenting to provide antiplatelet effects while simultaneously preventing neointimal hyperplasia, which may be another major mode of stent failure. 
     The therapeutic agent  14  may comprise ticagrelor. Ticagrelor is an antiplatelet therapy recommended by the American College of Cardiologists. As described in further detail herein, an ethanol group of a ticagrelor molecule  34  can be bonded to a tail portion  30  of a molecule  26  of the self-assembled monolayer  16 . The tail portion  30  may comprise a terminal amine. As used herein, “amine” or “amino” refers to a chemical group having the indicated number of carbon atoms, where indicated, and terminating in a —NH 2  group, thus having the structure —R—NH 2 , where R is an unsubstituted or substituted divalent organic group that, e.g., includes linear, branched, or cyclic hydrocarbons, and optionally comprises one or more heteroatoms. 
     The ticagrelor molecule(s)  34  may be bonded to the molecules  26  of the self-assembled monolayer  16  by a Mitsunobu reaction. While not intending to be bound by theory, it is believed that this Mitsunobu reaction method may be preferable because the resultant amide bond between the self-assembled monolayer  16  and ticagrelor molecules  34  are not susceptible to esterases, which would be the case when using, for example, bonds formed by ethylene diamine coupling between carboxylic acids and alcohols. The therapeutic agent  14  may comprise an anticoagulant, such as enoxaparin and fondaparinux. The therapeutic agent  14  may also comprise certain cytotoxic and/or anti-stenosis drugs designed to prevent initial hyperplasia and restenosis, as are used in conventional drug eluting stents. For example, the therapeutic agent  14  may comprise one or more of sirolimus, tacrolimus, and everolimus. In other examples, the therapeutic agent  14  can comprise a blood thinning agent, such as prasugrel. In some examples, multiple types of therapeutic agents  14  can be bonded to the self-assembled monolayer  16  to provide a variety of therapeutic effects. 
     With continued reference to  FIG. 2A , the self-assembled monolayer  16  comprises molecules  26  that provide a linkage between a surface  42  of the implantable device  10  and the therapeutic agent  14 . The self-assembled monolayer  16  may be a film or surface formed from, for example, a single layer of the molecules  26 , which are vertically aligned and arranged side by side to form a substantially continuous layer. 
     The molecules  26  may comprise a first portion, moiety, or end (referred to hereinafter as “a head portion  28 ”) that spontaneously bonds to a surface of a substrate, such as a surface  42  of the body  20  of implantable device  10 . As used herein, a “moiety” generally refers to a part of a molecule, and may refer to a part of a molecule that remains substantially identifiable or intact when the molecule is bonded with other compound(s) or molecule(s) to form a larger molecule, such as a polymer chain. A moiety may be a nucleotide as-incorporated into a nucleic acid or an amino acid as-incorporated into a polypeptide or protein. As used herein, “non-reactive”, in the context of a chemical constituent, such as a molecule, compound, composition, group, moiety, ion, etc., can mean that the constituent does not react with other chemical constituents in its intended use to any substantial extent. The non-reactive constituent is selected to not interfere, or to interfere insignificantly, with the intended use of the constituent, moiety, or group as a recognition reagent. 
     The head portion  28  may comprise an organic acid, such as phosphoric acid, carboxylic acid, bromic acid, or other organic acids capable of binding to oxygen molecules on the surface  42  of the body  20  of the implantable device  10 . As used herein, an “organic acid” refers generally to an organic compound having acidic properties, which is capable of forming a covalent bond with, for example, the oxygen molecules on the surface  42 . Organic acids are generally weak acids that do no dissociate in water. “Carboxyl” or “carboxylic” refers to a group having an indicated number of carbon atoms, where indicated, and terminating in a —C(O)OH group, thus having the structure —R—C(O)OH, where R is an unsubstituted or substituted divalent organic group that can include linear, branched, or cyclic hydrocarbons. Non-limiting examples of these include: C 1-8  carboxylic groups, such as ethanoic, propanoic, 2-methylpropanoic, butanoic, 2,2-dimethylpropanoic, pentanoic, etc. “Phosphonic” refers to a compound or molecule terminating in a —H 3 PO 3  group. “Bromic” refers to a compound or molecule terminating in a —HBrO 3  group. 
     In one example, the molecule  26  of the self-assembled monolayer  16  is a phosphonic acid, such as 12-aminododecylphosphonic acid. In that case, the head portion  28  of the molecule  26  comprises a chemical group (e.g., a phosphonic acid group) configured to bind to the oxygen molecules on the surface  42  of the implantable device body  20 . In order to ensure that the molecules  26  align in a desired orientation, the head portion  28  may be non-reactive with other surfaces and/or surfaces containing primarily other available atoms or functional groups. 
     In some examples, the surface  42  is used “as is” meaning that no surface preparation techniques or processes are performed on the surface  42  before the molecules  26  are bonded to the surface  42 . For example, the monolayer  16  may be formed on stents provided from a manufacturer and without initial surface processing. In other examples, surfaces  42  of metal alloys can be sanded and polished using various mechanical or electrochemical techniques in order to improve surface uniformity and thus optimize binding of monolayer head portions  28 , which improves surface coverage. In some examples, in order to promote spontaneous bonding with the organic acid, the surface  42  may comprise an oxidized surface and/or a surface material comprising oxygen atoms that are available for covalent bonding to the head portion  28 . For example, an oxygen plasma spray preparation may be applied to the surface  42 . 
     To provide a linkage for the therapeutic agent(s)  14 , the molecules  26  of the self-assembled monolayer  16  further comprise a second portion, moiety, or end (referred to hereinafter as “the tail portion  30 ”) comprising one or more sites capable of reacting with reactive groups of the therapeutic agent  14  to form a suitable and sufficient covalent linkage between the molecules  26  and the therapeutic agent  14 . The tail portion  30  may be non-reactive with other agents, compounds, and/or molecules during conjugation to a therapeutic agent  14  to ensure that formed monolayers  16  include a sufficient concentration of the therapeutic agent  14 . The composition of the tail portion  30  may be selected based on available and/or reactive groups or moieties, such as amine, carboxyl, or thiol groups, of the therapeutic agent  14  being immobilized on the implantable device  10 . The tail portion  30  may be, for example, an amine group. In other examples, the tail portion  30  may comprise a carboxyl group. 
     The molecule  26  of the self-assembled monolayer  16  further comprises a linker or linkage portion  32  extending between the head portion  28  and the tail portion  30  of the molecule  26 . In the context of the linker moieties or linkage portions described herein, the constituents of the linkage portion  32  may be non-reactive in that they do not interfere with the binding of the head portion  28  and tail portion  30  of the molecule  26 . 
     The linkage portion  32  may comprise an alkyl chain comprising a sufficient number of carbon atoms to provide separation between the surface  42  of the body  20  and the therapeutic agent  14 , so that, for example, ticagrelor molecules  34  of the therapeutic agent  14  have sufficient space to bind to the tail portions  30  of the self-assembled monolayer  16 . The linkage portion  32  is generally non-bulky in order to avoid sterically hindering or otherwise interfering, to any substantial extent, with the binding of the therapeutic agent  14  to the tail portion  30  of the molecules  26 , and/or with binding of the head portion  28  to the surface  42 . Further, the linkage portions  32  may be configured to adopt a particular configuration, such as a trans configuration, so that molecules  26  can be aligned and closely packed on the surface  42 . 
     The alkyl chain of the linkage portion  32  may have from about 12 to about 18 carbon atoms, such as 16 carbons atoms. When shorter carbon chains are used, some carbon atoms may adopt a gauche configuration, causing the linkage portions  32  not to pack as well on the surface  42 . The linkage portions  32  of all molecules  26  of the self-assembled monolayer  16  may be the same length. Alternatively, the length of the alkyl chains may vary to provide additional separation between the molecules  26 ,  34  and/or binding sites for the therapeutic agent  14 . The alkyl chain may be linear and/or saturated hydrocarbyl, e.g., linear alkane. 
     As discussed previously, the linkage portion  32  may comprise an alkyl chain comprising a selected number of carbon atoms. As used herein, “alkyl” refers to straight, branched chain, or cyclic hydrocarbon groups including, for example, from 1 to about 20 carbon atoms, for example and without limitation C 1-3 , C 1-6 , C 1-10  groups, for example and without limitation, straight, branched chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like. An alkyl group may be, for example, a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50  group that is substituted or unsubstituted, for example, hydrocarbyl. Alkyl groups may be monovalent, divalent, or multivalent moieties. 
     Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl moieties. Branched alkyl groups comprise any straight alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups comprise isopropyl, isobutyl, sec-butyl, and t-butyl. Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also comprise fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group may be substituted with any number of straight, branched, or cyclic alkyl groups. 
     With reference to  FIG. 2B , a coating  12  comprising a self-assembled monolayer  16  comprises the head portion  28  and linkage portion  32 , as in previous examples. However, the monolayer  16  in  FIG. 2B  comprises a tail portion  30  configured to bind to different therapeutic agents, such as molecules  234  of a first therapeutic agent and molecules  244  of a second therapeutic agent. In order for both molecules  234 ,  244  to bind with sites of the tail portion  30 , molecules  234 ,  244  may have similar chemistries and binding capabilities. In other examples, as described in detail in connection with  FIGS. 2C and 2D , a self-assembled monolayer may be a mixed monolayer comprising monolayer molecules with different tail portions  30  that bind to different therapeutic agents. 
     Exemplary Frame Structures 
     Having described features of the coating  12  and self-assembled monolayers  16 , structural features of exemplary implantable devices  10  that can be coated with the coating  12  will now be described. As discussed previously, the coatings  12  and self-assembled monolayers  16  can be used with a variety of different types of implantable medical devices formed from a variety of materials. Accordingly, the implantable devices  10  described in connection with  FIGS. 1A-1C  are merely examples of types of devices to which the coatings  12  could be applied, and are not meant to limit the scope of the present disclosure. 
     With specific reference to  FIGS. 1A and 1B , the implantable device  10  may be a coronary/endovascular stent. The body  20  of the stent comprises a frame  22  formed from interconnected elongated tines  24 , such as bent pieces of wire or filament. Tines  24  may be formed from any material that can be drawn, such as metals or plastics. For example, the elongated tines  24  may be formed from, stainless steel, cobalt chromium, titanium oxide, nickel titanium oxide, and other alloys. The tines  24  may also be formed from high performance or engineered alloys, such as a super-elastic shape-memory material, such as nickel-titanium alloys (e.g., Nitinol). In some examples, the body  20  may further comprise a cover (not shown) formed from, for example, a mesh, film, or flexible sheet, extending over portions of the body  20 . The coating  12  may cover all surfaces of the body  20  and/or cover of the implantable device  10 . For example, as shown in  FIG. 1B , both inwardly and outwardly facing surfaces of the elongated tines  24  may be covered by the coating  12 . In other examples, only selected portions or surfaces of the body  20  may be coated by the self-assembled monolayer  16  and/or therapeutic agent  14 . 
     The implantable device  10  may be configured to transition between a contracted state for delivery to a deployment location of a patient&#39;s vascular system by, for example, a delivery catheter, and a deployed state (shown in  FIG. 1A ). In the deployed state, the body  20  of the stent may expand radially outwardly to contact a wall of a vessel to anchor the body  20  in the deployment location. The body  20  may also expand longitudinally during deployment, thereby extending a length Li of the body  20  by a predetermined distance. When deployed, the body  20  contacts vessel walls to maintain patency of the vessels and to permit blood flow through a central lumen  36  of the body  20 . 
     The elongated members or tines  24  may be arranged in a variety of patterns within the scope of the present disclosure. For example, the elongated members  24  may be arranged to form open cells, closed cells, expandable rings, or coils. As shown in  FIG. 1A , in some examples, the body  20  may comprise a plurality of radially expandable annular rings  38  arranged or aligned in series along the longitudinal axis A 1  of the body  20 . The rings  38  may be connected to each other at connection points  40 , thereby forming the elongated tubular structure. The rings  38  may be replaced by one or more helical coils. Portions of the body  20  may be covered by a suitable sheet or film, such as a metal mesh or fabric cover. In other examples, no covering or sheet is provided. In that case, the self-assembled monolayer  16  and therapeutic agent  14  may be directly deposited to the tines  24  of the frame  22 . 
     Coated Inferior Vena Cava Blood Filler 
     As discussed previously, the coating  12  and self-assembled monolayers  16  of the present disclosure may be applied to a variety of different types of implantable devices, in addition to the stent shown in  FIGS. 1A and 1B . 
     With reference to  FIG. 1C , in another example, the implantable device  10  may comprises an inferior vena cava (IVC) blood filter  110 . As in previous examples, surfaces of the blood filter  110  may be coated by the coating  12  comprising the self-assembled monolayer  16 . The coating  12  may be applied to all surfaces of the blood filter  110 . Alternatively, some portions of the filter  110  may be coated with the coating  12  and other portions of the blood filter  110  may be bare or can be coated with self-assembled monolayers comprising different types of therapeutic agents and/or different types of coatings. 
     A blood filter  110  is a vascular filter configured to be deployed in the inferior vena cava to prevent, for example, pulmonary emboli from passing through the vascular system of a patient. The depicted blood filter  110  comprises support members  112 , such as metallic tines. The support members  112  comprise a proximal end  114 , enclosed within a collar  116 , and a distal end  118 . As shown in  FIG. 1C , the support members  112  extend axially and radially outward from the collar  116 , thereby forming an umbrella shaped structure. The distal end  118  of the support members  112  may comprise or may be bent to form hooks  120 . The depicted hooks  120  are configured to engage a wall of a vessel, such as a wall of the inferior vena cava, to retain the filter  110  at a desired location in the inferior vena cava. The depicted filter  110  further comprises bent members  122  extending from the collar  116  and bent to form loops or arcs around the support members  112 . The bent member  122  may be thinner and more flexible than the support member  112 . As shown in  FIG. 1C , the bent members  122  may extend axially and radially from the collar  116  and comprise a portion  124  that wraps around the support members  112 . The blood filter  110 , as shown, further comprises a hook  126  extending proximally from the collar  116 , for retrieval and removal of the blood filer  110 . 
     As with the previously-described stents, the blood filter  110  may be initially provided in a contracted configuration, in which the support members  112  and bent members  112  are closely compressed about the longitudinal axis A 2  of the filter  110 . In the contracted configuration, the blood filter  110  may be delivered to a deployed location through, for example, a delivery catheter, as are known in the art. Once deployed from the delivery catheter, the members  112 ,  122  of the filter  110  may be configured to extend radially outward from the longitudinal axis A 2 , to the deployed configuration shown in  FIG. 1C . 
     As discussed previously, the coating  12  may be applied to some or all portions of the filter  110 . For example, molecules  26  of the self-assembled monolayer  16  may be deposited on portions of the structural members  112 , bent members  122 , and/or collar  116 , using the processes and techniques disclosed herein. 
     Mixed Self-Assembled Monolayers 
     As discussed previously, in some examples, the coating  12  may comprise multiple therapeutic agents  214  that provide different therapeutic effects and treatments for the patient. In order to provide binding sites for different therapeutic agents  214  (shown in  FIG. 2D ), the self-assembled monolayer may be a mixed self-assembled monolayer  216  comprising multiple types of molecules. For example, as shown in  FIGS. 2C and 2D , the mixed self-assembled monolayer  216  may comprise a first type of molecules (referred to herein as “first molecules  226 ”) and a second type of molecules (referred to herein as “second molecules  236 ”). The first molecules  226  and the second molecules  236  may be randomly dispersed on the surface  42  of the implantable device body  20 . In some examples, the mixed monolayer  216  may comprise an equal amount of the first molecules  226  and the second molecules  236 . In other examples, the molecules  226 ,  236  may be provided in different concentrations to achieve a particular therapeutic result. 
     Both the first molecules  226  and second molecules  226  comprise head portions  228 ,  238  bonded to the surface  42  of the implantable device body  20 . The head portions  228 ,  238  often comprise the same functional or chemical groups for competition reasons, though first and second molecules  226 ,  236  with different head portions  228 ,  238  may also be used in some examples. For example, the head portions  228 ,  238  may comprise different types of organic acids. 
     The first molecules  226  and the second molecules  236  may further comprise tail portions  230 ,  240 . Unlike in previous examples, the tail portions  230 ,  240  may be configured to bind to different types of therapeutic agents  214  (shown in  FIG. 2D ). For example, the tail portion  230  of the first molecule  226  may be configured to bind to a first therapeutic agent molecule  234 , such as ticagrelor. The tail portion  240  of the second molecule  236  may be configured to bind to a second therapeutic agent molecule  244 , such as, for example, a cytotoxic or anti-stenosis drug. In other examples, the second molecule  236  may be a spacer molecule configured to separate the first molecules  226  to improve bonding between the first molecules  226  and the first therapeutic agent molecule  234 . In that case, the tail portion  240  of the second molecule  236  may be non-reactive or, at least, incapable of binding to therapeutic agent molecules  230 ,  240 . 
     The first and second molecules  226 ,  236  may further comprise linkage portions  232 ,  242  extending between the head portions  228 ,  238  and the tail portions  230 ,  240 . The first and second molecules  226 ,  236  may comprise similar or identical linkage portions  232 ,  242 . For example, the linkage portions  232 ,  242  may be the same length and/or comprise a same number of carbon atoms, so that the tail portions  230 ,  240  are easily accessible for bonding with the therapeutic agent molecules  234 ,  244 . 
     Method of Forming a Coated Implantable Device 
     Having described embodiments of the implantable device  10  and coating  12 , methods of forming such devices  10  will now be described in detail. As shown in  FIG. 3 , the method may comprise a step  310  of forming and/or preparing a body  20  of an implantable device  10 , such as the stent (shown in  FIGS. 1A and 1B ) or the IVC filter (shown in  FIG. 1C ). As discussed previously, the body  20  comprises material(s) that react with and act as a substrate for the self-assembled monolayer  16  or mixed monolayer  216 . For example, an implantable device  10  may be formed from interconnected metal tines  24  formed from stainless steel and comprising an oxidized outer surface. The tines  24  may be connected together by various processes, as are known in the art, such as welding. In other examples, a stent body  20  may be cut from a single tube of flexible metal. For example, various automated laser cutting techniques may be used to cut a stent body  20  including features, such as rings, helices, and longitudinally extending struts. Preparing the body  20  of the implantable device  10  may also comprise preparing a surface of the body  20  to bond with the self-assembled monolayers  16 ,  216 . For example, portions of the body  20  may be oxidized to ensure that a sufficient concentration of oxygen atoms is available to bond with the self-assembled monolayer  16 . Surfaces of the body  20  may also be sanded or cleaned to prepare for formation of the self-assembled monolayer  16 . 
     At step  312 , the method may further comprises applying a solution comprising molecules that form the self-assembled monolayer layer  16  or mixed monolayer  216  on surfaces of the body  20  of the implantable device  10 . The solution may be applied by, for example, aerosol spraying. Alternatively, the body  20  of the implantable device  10  may be immersed in the solution containing molecules  26 ,  226 ,  236  of the self-assembled monolayers  16 ,  216  for a sufficient period of time to allow the self-assembled monolayers  16 ,  216  to form. As discussed previously, the body  20  may comprise elongated members or tines  24  formed from, for example, stainless steel. Molecules  26 ,  226 ,  236  in the solution may bind to oxygen molecules on surfaces of the body  20  of the implantable device  10  to form the self-assembled monolayers  16 ,  216 . 
     Following formation of the monolayers  16 ,  216 , at step  314 , the therapeutic agent  14  may be bonded to the self-assembled monolayer  16 ,  216 . For example, the device  10  coated by the self-assembled monolayer  16 ,  216  may be immersed in a solution containing molecules  34 ,  234 ,  244  of the therapeutic agent  14 ,  214  for a sufficient time and under suitable conditions to allow the therapeutic agent  14 ,  214  to bind to sites on the self-assembled monolayer  16 ,  216 . Specifically, the therapeutic agent  14 ,  214  may be selected to include at least one site configured to covalently bond to the at least one site of the self-assembled monolayer  16 ,  216 . 
     As discussed previously, in one example, the body  20  comprises 316L stainless steel, the self-assembled monolayer  16 ,  216  is formed from phosphonic acid (e.g., 12-aminododecylphosphonic acid), and the therapeutic agent  14 ,  214  comprises ticagrelor. In such an arrangement, the self-assembled monolayer  16 ,  216  connects to molecules  34  of the ticagrelor by an amide bond, as shown schematically in  FIGS. 2A-2D  and  FIG. 6B . It is believed that this amide bond formation reaction provides a strong linkage between the drug to be delivered and the monolayer  16 ,  216 . In particular, it is believed, without any intent to be bound thereby, that the monolayer  16 ,  216  is strongly adhered to the surface through the phosphonic acid head group. Therefore, the entire system is strongly adhered to the 316L stainless steel substrate. 
     EXAMPLES 
     Example 1 
     Monolayers composed of various phosphonic acids were synthesized on substrates to model effects of the coatings of the present disclosure on implantable devices. The monolayers all had a phosphonic acid head group and varying tail groups to allow for different organic reactions for immobilization of a therapeutic agent, such as ticagrelor, at an interface between the self-assembled monolayer and the ticagrelor. 
     Preparation of Planar Substrates 
     Initially, planar substrates of 316L stainless steel produced by Goodfellow Inc., were prepared. Specifically, substrates were cut into 1 cm×1 cm coupons. The coupons were mechanically sanded with 1200 grit sandpaper on a standard metal polisher. Progressively finer grit sandpaper was used until the substrates were polished with a 1 micron diamond suspension. The coupons were also rinsed in methanol to remove silicon carbide paper. 
     Formation of Self-Assembled Monolayers and Deposition of Therapeutic Agents 
     Once the substrate coupons were prepared, a monolayer composed entirely of 16-carboxyhexadecylphosphonic acid, with carboxylic acid at the interface, was synthesized and deposited on the substrate. The monolayer was deposited by aerosol spraying a 1 mM solution of 16-carboxyhexadecylphosphonic acid in tetrahydrofuran. A schematic drawing of the proposed reaction scheme using the 16-carboxyhexadecylphosphonic acid is shown in  FIG. 4 . 
     It was expected that a therapeutic agent, such as ticagrelor, could be immobilized on the monolayer formed from the 16-carboxyhexadecylphosphonic acid (“PHDA”) using ester bond formation. However, after many (&gt;100) attempts under varying conditions, it was determined that the tail groups of the monolayer were too strongly hydrogen bonded together to react with the coupling agents effectively. 
     In order to address the strong hydrogen bonding between the tail groups, in a second example, spacer molecules of tetradecylphosphonic acid were placed in the monolayer at a ratio of 9:1 (16-carboxyphosphonic acid:tetradecylphosphonic acid) to form a mixed self-assembled monolayer. The self-assembled monolayers comprising the 9:1 ratio formed easily by aerosol spraying. Specifically, aerosol spraying was performed using a room temperature solution of 0.9 mM solution of 16-carboxyhexadecylphosphonic acid and 0.1 mM tetracedylphosphonic acid. The solution was sprayed onto the 316L stainless steel coupons and dried for 2 hours. 
     A model compound of 2-phenoxyethanol was used for ticagrelor. The 2-phenoxyethanol molecule was deemed to be an appropriate substitute because it has an identical synthetic target, specifically an ethanol tail on a ring species. A comparison of a chemical structure of tricagrelor and 2-phenoxyethanol is shown in  FIG. 5 . A number of different coupling reagents have been utilized, including thionyl chloride, carbodiimide cross-linking chemistry with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (“EDC”) and N-hydroxysuccinimide (“NHS”), carbodiimide cross-linking chemistry with -dicycloexylcarbodiimde (“DCC”) and NHS, and carbodiimide cross-linking chemistry with DCC and 4-dimethylaminopyridine (“DMAP”). Example conditions can be found in the following Table. It was determined that none of the reactions worked with the carboxylic acid terminated monolayer. 
     
       
         
           
               
             
               
                 TABLE 
               
             
            
               
                   
               
               
                 Attempted immobilization conditions for 2-Phenoxyethanol 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Target 
                 Crosslinking  
                 Time  
                   
                   
                   
               
               
                 SAM 
                 molecule 
                 Agents 
                 in soln 
                 Dry 
                 Rinse 
                 Solvent 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 PHDA 
                 1 mM  
                 20 mM EDC/50  
                 1  
                 Hr 
                 Vac 
                 EtOH 
                 Dry THF 
               
               
                   
                 2-Phen 
                 mMNHS 
                   
                   
                 Line 
                   
                   
               
               
                 PHDA 
                 1 mM  
                 20 mM EDC/50  
                 1.5  
                 Hr 
                 Vac 
                 EtOH 
                 Dry THF 
               
               
                   
                 2-Phen 
                 mMNHS 
                   
                   
                 Line 
                   
                   
               
               
                 PHDA 
                 2 mM  
                 2 mM EDC/2  
                 24  
                 Hr 
                 Vac 
                 EtOH 
                 2- 
               
               
                   
                 2-Phen 
                 mMNHS 
                   
                   
                 Line 
                   
                 Propanol 
               
               
                 PHDA 
                 2 mM  
                 2 mM DCC/2 
                 24  
                 Hr 
                 Vac 
                 EtOH 
                 2- 
               
               
                   
                 2-Phen 
                 mMNHS 
                   
                   
                 Line 
                   
                 Propanol 
               
               
                 PHDA 
                 2 mM  
                 2 mM DCC/2  
                 24  
                 Hr 
                 Vac 
                 EtOH 
                 2- 
               
               
                   
                 2-Phen 
                 mM DMAP 
                   
                   
                 Line 
                   
                 Propanol 
               
               
                 PHDA 
                 5 mM  
                 5 mM EDC/5  
                 1.5  
                 Hr 
                 Vac 
                 EtOH 
                 2- 
               
               
                   
                 2-Phen 
                 mMNHS 
                   
                   
                 Line 
                   
                 Propanol 
               
               
                 PHDA 
                 5 mM  
                 5 mM DCC/5  
                 1.5  
                 Hr 
                 Vac 
                 EtOH 
                 2- 
               
               
                   
                 2-Phen 
                 mM DMAP 
                   
                   
                 Line 
                   
                 Propanol 
               
               
                   
               
            
           
         
       
     
     In view of the difficulties in using carboxylic acid, the self-assembled monolayer was then changed from presenting a carboxylic acid terminated group at the interface to an amine. In this way, the Mitsunobu reaction, which is shown schematically in  FIG. 6A , could be used to link the 2-phenoxyethanol to the surface in an amide bond. The amide bond is not subject to the esterase issues in the previous approach. Therefore, as described herein, an amine terminated monolayer was formed using 12-aminododecylphosphonic acid in tetrahydrofuran. The 12-aminododecylphosphonic acid self-assembled monolayer was formed by solution deposition, where the prepared SS316L coupons were submersed in a 1 mM solution for 30 min, followed by drying at 60° C. The amine tail group was used to react with 2-phenoxyethanol through a Mitsunobu reaction. 
     In order to perform the reaction, the stainless steel coupon containing the 12-aminododecylphosphonic acid self-assembled monolayer was placed in a room temperature solution of tetrahydrofuran with 50 mM 2-phenoxyethanol, 50 mM triphenylphosphine, and 50 mM diethyl azdodicarboxalate. The solution was stirred for 18 hours. Following the 18 hour period, it was determined that the 2-phenoxyethanol was successfully immobilized based on infrared spectroscopy data. 
     Following confirmation that the 2-phenoxyethanol could be bonded to the self-assembled monolayer, the Mitsunobu reaction was also successfully applied to immobilize ticagrelor to the surface of the coupons using the same conditions as for the 2-phenoxyethanol immobilization. 
     Characterization of Self-Assembled Monolayers 
     Three types of self-assembled monolayers were formed, as previously mentioned, in an attempt to immobilize the ticagrelor molecules. The first self-assembled monolayer was 16-carboxyhexadecylphosphonic acid, the second was a mixed self-assembled monolayer (tetradecylphosphonic acid and 16-carboxyphosphonic acid), and the third was 12-aminododecylphosphonic acid. The self-assembled monolayers were analyzed by diffuse reflectance infrared spectroscopy (“DRIFT”). A Nexus 470 Fourier Transform Infrared Spectrometer with the DRIFT attachment was used to characterize substrates after both monolayer formation and ticagrelor immobilization. Spectra were collected under nitrogen for 256 scans with a resolution of 4 cm −1  on each sample and corrected with respect to a background reference spectrum of unmodified SS316L. The substrates were then sonicated in THF for 15 min to test the mechanical stability of the monolayers. 
     The infrared spectra indicated that all three monolayers formed. Further, using the symmetric methylene stretching (CH 2 symm ) and asymmetric methylene stretching (CH 2 assymm ) peaks in the infrared spectrum, the alkyl chains of the monolayers were determined to be all-trans ordered. Specifically, as shown in  FIG. 7 , which shows the infrared spectrum of a mixed monolayer of 16-carboxyhexadecylphosphonic acid and tetradecylphosphonic acid, the mixed self-assembled monolayer spectrum had peaks at 2914 cm −1  and 2846 cm −1 , which are indicative of CH 2 symm  and CH 2 asymm  stretches, respectively, while a peak at 1706 cm −1  is consistent with the carboxylic acid tail group that is not hydrogen bound. The spectra of  FIG. 7  indicates that the mixed monolayers formed with all-trans alkyl chains and carboxylic acids are available at the interface for further reactions. 
     In another example, for the spectrum of 12-aminododecyl phosphonic acid, peaks indicative of the alkyl chain were determined to be at 2913 cm −1  and 2846 cm −1 , and the free amine peak was at 1666 cm −1  and 1555 cm −1 . The phosphonic acid head group was bonded to the surface in a tridentate manner based on the P—O group stretch at 1091 cm −1 . 2-phenoxyethanol was then immobilized on the surface of the 12-aminododecylphosphonic acid monolayer-modified coupons via the Mitsunobu reaction, as described previously. The spectrum for the 2-phenoxyethanol immobilized to the monolayer is shown in  FIG. 8 . Peaks in the spectrum in  FIG. 8  are consistent with the aromatic ring (1588, 1436 cm −1 ) in 2-phenoxyethanol. Further, the alkyl stretches were still present in the 2900 cm −1  region (e.g., 2913 cm −1  and 2846 cm −1 ), which is indicative of the monolayer. 
     Next, ticagrelor was immobilized to coupons comprising 12-aminododecylphosphonic acid monolayer. The infrared spectra for the immobilized ticagrelor characterized by DRIFT spectroscopy is shown in  FIG. 9 . Peaks indicative of the ticagrelor molecule include: hydroxyl groups at 3273 cm −1  and 1324 cm −1 ; aromatic peaks at 1608 cm −1 , 1518 cm −1 , and 1436 cm −1 ; and an aryl ether at 1324 cm −1 . The peaks attributed to the self-assembled monolayer linker molecule include CH 2  peaks at 2916 and 2850 cm −1 , and peaks in the spectrum attributed to P—O at 1119 cm −1  and 995 cm −1 , indicating phosphonic acid bonding to the surface, as shown in  FIG. 9 . 
     AFM Characterization Protocol 
     The coated coupons were also analyzed by atomic force microscopy (“AFM”). In order to perform the AFM analysis, the metal coupons were adhered to glass slides using double-sided tape. The glass slides were then mounted on a magnet and analyzed using AFM. The AFM instrument was auto-tuned, placed in phase scanning mode, centered, and then engaged the tip to the surface. The phase was ensured to be less than 90° to indicate tapping mode. Images of the coupons are shown in  FIGS. 10A-10C . Particularly,  FIG. 10A  shows an artifact on the coupon surface representative of a bare metal stent.  FIG. 10B  shows a monolayer comprising 12-amino-dodecylphosphonic acid (ADPA) linker molecules.  FIG. 10C  shows ticagrelor molecules on the surface immobilized to the monolayer. 
     Example 2 
     Formation of Coated Stents Formed from SS316L Stents 
     Monolayers of 12-amino-dodecylphosphonic acid were formed on the native oxide surface of the SS316L stents using aerosol deposition. Samples were aerosol sprayed with a 0.5 mM solution of ADPA in ethanol using thin layer chromatography sprayer, and then dried at 120° C. for 30 minutes. This process was repeated until the substrates had been sprayed 3 times, at which point the substrates were annealed at 120° C. for 24 hours. Once annealed, the substrates were rinsed and sonicated in ethanol to remove any physisorbed molecules. Monolayer formation was confirmed using contact angle goniometry, DRIFT spectroscopy, and Atomic Force Microscopy. 
     Self-assembled monolayer-modified stents and 0.1 g ticagrelor were placed in a flask. The flask was sealed and purged with nitrogen gas, five milliliters of dry THF was injected, followed by 60 microliters (μL) of tributylphosphosphine, after which the reaction was placed in an ice bath. Two hundred microliters of diethyl azodicarboxylate (“DEAD”) was injected via syringe pump at five microliters per minute while stirring. The reaction came to room temperature and was stirred for 48 hours. Substrates were then removed, sonicated in THF, and dried under vacuum. 
     Contact Angle Characterization Protocol 
     A Rame-Hart goniometer was used to measure static contact angles of water to determine the uniformity of the ADPA monolayers. Contact angles were measured using 2 μL drops of deionized water (Millipore 18Ω) to characterize the hydrophobicity of the surface modifications. Three measurements were performed on three substrates for a total of 9 measurements per modification. The average contact angle value and standard deviation (n=9) have been reported. 
     AFM Characterization Protocol 
     The coated stents were cut lengthwise, unfolded, and adhered to the glass slides with the double-sided tape. The glass slides were then mounted on a magnet and analyzed using AFM. The AFM instrument was auto-tuned, placed in phase scanning mode, centered, and then engaged the tip to the surface. The phase was ensured to be less than 90° to indicate tapping mode. 
     Platelet Adhesion Quantification and SEM Protocol 
     Ticagrelor molecules were immobilized on bare metal stents formed from 316L stainless steel, via deposition of a self-assembled monolayer and subsequent use of a Mitsonobu reaction. Three sets of four substrates were placed in a 24 well-plate with one set of wells left empty to act as a control. The sample sets were as follows: four empty control wells; four bare SS316L stents: four monolayer-coated substrates; and four ticagrelor-modified substrates. One milliliter of human platelet rich plasma (“PRP”, Innovative Research Inc.) was gently pipetted into each of the wells and were left for one hour at room temperature. After the time had elapsed, the unmodified and ticagrelor coated stents were removed from the PRP and placed in 5% glutaraldehyde for 7 days. The stents were then removed and submerged in 2% Osmium tetroxide (“OsO 4 ”) for 1 hour. The stents were then dehydrated in a series of ethanol solutions of increasing concentrations (25%, 50%, 75%, and 100%), for 20 minutes each. Dehydration was completed by final immersion in hexamethyldisilazane for 10 minutes. The stents were then desiccated for 1.5 hours prior to performing scanning electron microscopy (“SEM”). Images were taken at a magnification of 500×, working distance of 10 mm, and accelerating voltage of 5000 kV. Captured SEM images for a bare stent ( FIG. 11A ), an ADPA coated stent ( FIG. 11B ), and a stent with immobilized ticagrelor ( FIG. 11C ) are provided herein. 
     The remaining PRP was centrifuged at 3500 rpm for ten minutes to separate the remaining platelets and the supernatant for analysis. Immediately after centrifugation and the removal of the supernatant, platelet pellets were resuspended in phosphate buffered saline (PBS). The resulting platelet suspensions were incubated with both anti-human CD62P and CD42a antibodies according to manufacturer&#39;s instructions. Platelets were washed twice with PBS after incubation to remove unbound antibodies and then analyzed via flow cytometry. 
     Results and Discussion 
     Monolayers were formed from 12-aminododecylphosphonic acid to provide a functionalized amine surface for ticagrelor attachment. Self-assembled monolayers (SAMs) were formed via aerosol deposition of a 0.5 mM solution of 12-aminododecylphosphonic acid in ethanol on the oxide layer of the stents 
     Substrates were sonicated in ethanol to remove any physisorbed molecules and were then characterized by DRIFT spectroscopy and contact angle measurements. Stable and ordered monolayers are known to have alkyl chains in an all trans conformation, indicated by IR absorptions at ν CH2sym ≤2918 cm −1  and ν CH2sym ≤2848 cm −1 . 
       FIGS. 12A and 12B  are spectral graphs showing spectra obtained by DRIFT spectroscopy for the 12-amino-dodecylphosphonic acid (ADPA) monolayer. As shown in  FIG. 12A , peaks were observed at ν CH2asym =2915 cm −1  and ν CH2sym =2848 cm −1  indicating the formation of a stable and ordered SAM. An additional peak was observed at ν NH3+ =2937 cm −1 , which corresponds to the primary amine salt on the tail-group from 12-aminododecylphosphonic acid. A large peak corresponding to the C—N stretching vibration is found at ν C—N =1119 cm −1 . The peaks at ν P—O =1220 cm −1 , ν P—O =1052 cm −1  and, ν P—OH =929 cm −1  indicate monodentate binding of the phosphonic acid head group to the surface, as shown in  FIG. 12B . The ordered alkyl chains presented the amine tail groups at the interface in a consistent manner available for further modification. The Mitsunobu reaction is a well-known method for the condensation of alcohols with various nucleophiles. Following SAM formation, tributyl phosphine was used in conjunction with diethyl azodicarboxylate (“DEAD”) to form a secondary amide cross-link between the functionalized surface and the primary hydroxyl on ticagrelor. 
     DRIFT spectra of pure ticagrelor and ticagrelor immobilized on SS316L stents were collected and overlaid to demonstrate the presence of ticagrelor on the surface. A spectral graph for the pure ticagrelor overlaid with the immobilized ticagrelor is shown in  FIG. 13 . As shown in  FIG. 13 , peaks at ν CH2asym ≤2916 cm −1  and ν CH2sym ≤2849 cm −1  correspond to the CH 2  symmetric and asymmetric stretching, respectively. The peak at ν NH3+ =2958 cm −1  is due to residual unreacted primary amine salts. Indicative peaks from the immobilized ticagrelor are present at ν Aromatic =1521 cm −1 , ν Aromatic =1465 cm −1 , and ν C—N =1327 cm −1 . Peaks for the asymmetric and symmetric aryl ether stretching are also present at ν Asym Aryl Ether =1218 cm −1  and ν Sym Aryl Ether =1058 cm −1 . Prominent peaks can be seen at ν N—H Bend =1608 cm −1  and ν C—N Stretch =1118 cm −1 , corresponding to the N—H bend and C—N stretch present on both the secondary amine on ticagrelor and the primary amine of the SAM 
     Static contact angle measurements were taken to evaluate changes in the wettability of the surface after SAM formation and ticagrelor immobilization. Nine measurements were collected for each sample set (3 per substrate in triplicate). Prior to reporting, the data was averaged, and the standard deviation was calculated. The contact angle of bare SS316L was found to be 72.8±4.8 degrees. The mild hydrophilicity of the surface can be attributed to the presence of oxo- and hydroxyl-groups on the native oxide layer of the metal. The contact angle measurements for the 12-aminododecylphosphonic acid coated monolayers were found to be 59.7±6.4 degrees, demonstrating a notable increase in hydrophilicity, which is expected of an amine functionalized surface. After the immobilization of ticagrelor, the contact angle was found to be 56.5±8.4 degrees. While this contact angle is effectively unchanged from that of the SAM, it is consistent with the polar structure of ticagrelor. 
     Once ticagrelor was immobilized on the stents a surface, a platelet challenge was used to test the efficacy of the system in the inhibition of thrombosis formation. Scanning electron microscopy (SEM), flow cytometry (FC), and an adenosine diphosphate enzyme linked immunosorbent assay (ADP ELISA) were utilized to elucidate the extent of platelet activation and aggregation on each sample. Substrates were placed into a 24 well-plate and 1 mL of platelet rich plasma (PRP) was gently pipetted into each well. The well-plate was covered and left to rest in ambient conditions for 1 hour. After exposure to the PRP, the substrates were removed and fixed in glutaraldehyde in preparation for SEM as described previously above. After the stent samples were removed, the remaining PRP from each well was centrifuged to separate the remaining platelets and the supernatant. The supernatant was removed from the platelet pellets via pipette and frozen for future analysis via ADP ELISA. 
     The platelet pellet was resuspended and incubated with fluorescent antibodies in preparation for measurement with the flow cytometer SEM micrographs, shown in  FIGS. 14A-14C , were collected from the surface of each substrate (SS316L stents exposed to PRP for one hour) to identify changes in platelet morphology and an extent of platelet aggregation.  FIG. 14A  shows a bare metal stent.  FIG. 14B  shows an ADPA coated stent.  FIG. 14C  shows a ticagrelor coated stent. Platelets maintain a globular conformation prior to activation. Once activated, platelets adhere to the surface of the substrate and flatten, extending dendritic tendrils outwards to form a network with other activated platelets. The SEM micrographs of the bare SS316L surface display large aggregates of platelets, which demonstrate a fully activated morphology. Platelets adsorbed in visibly smaller quantities to 12-aminododecylphosphonic acid coated substrates. The ticagrelor immobilized surface has even less surface platelet density with maintaining a comparatively greater level of platelet aggregation after one hour of exposure to PRP than either of the other sample sets. Platelet coverage on surfaces of the stents after one hour was determined using the SEM images. As shown in  FIG. 18 , platelet coverage for bare metal stents was 60.33%±11.40, while platelet coverage for ticagrelor coated stents was 1.64%±1.36. Further, on both the 12-aminododecylphosphonic acid coated and ticagrelor immobilized substrates, many platelets can be seen to retain a globular morphology indicating an incomplete state of activation despite clinging to the surface. 
     As described above, the resulting platelet suspensions were incubated with both anti-human CD62P and CD42a antibodies according to manufacturer&#39;s instructions. Platelets were washed twice with PBS after incubation to remove unbound antibodies and then analyzed via flow cytometry. The graphs in  FIG. 15  show flow cytometric platelet populations for a control stent (top left), a bare metal stent (BMS) (top right), a stent coated by an ADPA self-assembled monolayer (bottom left), and a stent with ticagrelor immobilized to the monolayer (bottom right). Control and BMS samples, shown in the top row of graphs in  FIG. 15 , appear to have lower levels of activation (4.3% and 4.6%) than their 12-aminododecylphosphonic acid and ticagrelor coated counter-parts (13.4% and 17.9%), shown by the bottom row of graphs in  FIG. 15 . 
     It is believed that this discrepancy is a result of the large number of platelets adhered to the BMS. In that sample set, most of the activated platelets were no longer present during centrifugation, having been removed along with the substrates. With less activated platelets to bind to, it follows that those samples show less total binding by either of the fluorescence conjugated antibodies. In the case of the control samples, decreased levels of activation is expected as no foreign material is present to promote activation. It can be seen in the SEM micrographs (shown in  FIGS. 14A-14C ) that the ticagrelor immobilized samples ( FIG. 14C ) had greater levels of protection from adherence than the SAM coated samples ( FIG. 14B ), which is consistent with the inverse relation found in the flow cytometric data sets. 
     Activated platelets release Adenosine diphosphate (ADP) and other platelet activating granules as part of the coagulation. An ADP ELISA was used to investigate ADP concentration in the supernatant of each sample set following centrifugation, results of which are shown in  FIG. 16 . Results from the assay show that there is an equivalent amount of ADP released in each sample set and the results are shown to be significant after analysis with one-way analysis of variance (ANOVA). This indicates that, after centrifugation, all sample sets have demonstrated complete activation. These results are consistent with those of the other analyses, indicating that the surface of the substrates is protected from platelet aggregation, but does not inhibit the activation of platelets in solution. Platelets are notoriously susceptible to activation having been shown to activate upon contact with foreign materials including both polymer surfaces and fixation solvents, or even simple shear forces experienced during pipetting or centrifugation. While it is difficult to identify exactly what caused platelet activation in each of the samples, the inventors determine that the results indicate that surfaces of the ticagrelor-immobilized substrates are protected from aggregation. 
     Example 3 
     Formation of Coated Stents Formed from Chromium Cobalt 
     Self-assembled monolayers of 12-aminododecylphosphonic acid were formed on a CoCr substrate to show effects of the invention on different substrate materials. In order to form CoCr substrates, thin foils of CoCr were sanded using 150, 320, 400, and 600 grit sandpaper. The sanded foils were then cleaned in acetone and methanol. Bare metal stents of CoCr produced by Abbott Laboratories were also cleaned in ethanol. As in previously described examples, self-assembled monolayers were formed by single aerosol deposition of 1 mM 12-aminododecylphosphonic acid (in un-dry ethanol) onto the substrates. The coated substrates were then dried at 120° C. The substrates were then sonicated in ethanol for 15 minutes and dried for an additional 1 hour at 60° C. The amine tail group was used to link the ticagrelor molecule through a Mitsunobu reaction by stirring at room temperature in tetrahydrofuran with 50 mM ticagrelor, 50 mM triphenylphosphine, and 50 mM diethyl azdodicarboxalate. Formation of the self-assembled monolayer and immobilization of ticagrelor were characterized by DRIFT spectroscopy with peaks consistent with the ticagrelor molecule hydroxyl groups and aromatic peaks. A DRIFT spectra of immobilized ticagrelor on CoCr substrate compared to solid ticagrelor is shown in  FIG. 17 . 
     Non-limiting aspects or embodiments of the present invention will now be described in the following numbered clauses: 
     Clause 1: An implantable device comprising: a body configured to be implanted within a body of a patient; a self-assembled monolayer comprising molecules comprising a first portion (moiety) bonded to a surface of the body, a second portion (moiety) opposite the first portion, and a linkage portion (moiety) extending between the first portion and the second portion; and a therapeutic agent comprising at least one therapeutic molecule covalently bonded to the second portion of the molecules of the self-assembled monolayer. 
     Clause 2: The implantable device of clause 1, wherein the implantable device comprises a device configured to be blood contacting. 
     Clause 3: The implantable device of clause 2, wherein the blood-contacting device comprises at least one of a stent, filter, shunt closure device, ventricular assist device, or fixation device. 
     Clause 4: The implantable device of clause 1 of clause 2, wherein the blood-contacting device comprises a stent or a filter, and wherein the body of the blood-contacting device comprises a plurality of interconnected elongated members. 
     Clause 5: The implantable device of clause 4, wherein the plurality of interconnected members form one or more of closed or open cells, helical coils, or radially expandable rings. 
     Clause 6: The implantable device of any of clauses 1-5, wherein the body comprises at least one of stainless steel, cobalt chromium, titanium oxide, titanium aluminum vanadium, and nickel titanium oxide. 
     Clause 7: The implantable device of any of clauses 1-5, wherein the body comprises 316L stainless steel. 
     Clause 8: The implantable device of any of clauses 1-3, wherein the body comprises at least one of polyurethane or silicone tubing. 
     Clause 9: The implantable device of any of clauses 1-8, wherein the first portions of the molecules of the self-assembled monolayer comprise an organic acid, and wherein the linkage portions of the molecules comprise an alkyl chain of 12 to 18 carbon atoms, such as a linear alkane moiety. 
     Clause 10: The implantable device of clause 9, wherein the organic acid of the first portions of the molecules of the self-assembled monolayer comprise one or more of carboxylic acid, phosphonic acid, or bromic acid. 
     Clause 11: The implantable device of any of clauses 1-10, wherein the molecules of the self-assembly monolayer comprise 12-aminododecylphosphonic acid. 
     Clause 12: The implantable device of any of clauses 1-11, wherein the second portions of the molecules of the self-assembled monolayer comprise an amine, carboxylic acid, alcohol, thiol, methyl, or bromine 
     Clause 13: The implantable device of any of clauses 1-12, wherein the second portions of the molecules of the self-assembled monolayer comprise an amine. 
     Clause 14: The implantable device of any of clauses 1-13, wherein the therapeutic molecules comprise at least one of ticagrelor, enoaparin, fondaparinux, sirolimus, tacrolimus, everolimus, or prasugrel. 
     Clause 15: The implantable device of any of clauses 1-14, wherein the therapeutic agent comprises ticagrelor. 
     Clause 16: The implantable device of clause 15, wherein molecules of ticagrelor are covalently bonded to the second portion of the molecules of the self-assembled monolayer at an amine terminus of the molecules of the self-assembled monolayer. 
     Clause 17: The implantable device of any of clauses 1-16, wherein the self-assembled monolayer further comprises spacer molecules comprising tail portions that are non-reactive with the therapeutic agent. 
     Clause 18: The implantable device of clause 17, wherein a ratio of the molecules which are reactive with the therapeutic agent and the spacer molecules, which are non-reactive with the therapeutic agent, is about 9:1. 
     Clause 19: The implantable device of any of clauses 1-16, wherein the self-assembled monolayer comprises first molecules comprising tail portions configured to bind to a first type of therapeutic agent, and second molecules comprising tail portions configured to bind to a second type of therapeutic agent. 
     Clause 20: The implantable device of clause 19, wherein the first type of therapeutic agent comprises an anti-platelet agent, and the second type of therapeutic agent comprises a cytotoxic drug that reduces or prevents cell proliferation about the implantable device. 
     Clause 21: A method of deploying an implantable device, comprising: advancing the implantable device of any of clauses 1-20 through a vascular system of the patient to a preselected deployment site through a delivery catheter; and extending the implantable device from a distal end of the delivery catheter, thereby causing the implantable device to expand from a contracted state to a deployed state. 
     Clause 22: A method of preparing an implantable device coated by a therapeutic agent, the method comprising: preparing a body portion of an implantable device, which is configured to be blood contacting when implanted; exposing surfaces of the body of the implantable device to a solution containing molecules configured to form a self-assembled monolayer on the surfaces of the implantable device; and immersing the coated device comprising the self-assembled monolayer in a solution containing a therapeutic agent comprising at least one site configured to covalently bond to the at least one site of the self-assembled monolayer layer. 
     Clause 23: The method of clause 22, wherein the implantable device comprises at least one of a stent, filter, closure device, or fixation device. 
     Clause 24: The method of clause 22 or clause 23, wherein preparing the implantable device comprises oxidizing one or more surfaces of the implantable device to prepare the surfaces to bond to molecules of the self-assembled monolayer. 
     Clause 25: The method of any of clauses 22-24, wherein the body of the implantable device comprises at least one of stainless steel, cobalt chromium, titanium oxide, titanium aluminum vanadium, and nickel titanium oxide. 
     Clause 26: The method of clause 25, wherein the body of the implantable device comprises a plurality of interconnected radially expandable rings positioned along a longitudinal axis of the body. 
     Clause 27: The method of clause 22, wherein the implantable device comprises at least one of polyurethane or silicone tubing. 
     Clause 28: The method of any of clauses 22-27, wherein exposing the surfaces of the implantable device to the solution containing the self-assembled monolayer molecules comprises applying the solution to the surfaces by aerosol spraying. 
     Clause 29: The method of any of clauses 12-28, wherein molecules configured to form the self-assembled monolayer comprise a first portion comprising an organic acid bonded to the surface of the implantable device, and a linkage portion extending from the first portion comprising an alkyl chain of 12 to 18 carbon atoms, such as a linear alkane moiety. 
     Clause 30: The method of clause 29, wherein the organic acid of the first portions of the molecules of the self-assembled monolayer comprise at least one of carboxylic acid, phosphonic acid, or bromic acid. 
     Clause 31: The method of clause 29, wherein the self-assembled monolayer comprises molecules of 12-aminododecylphosphonic acid. 
     Clause 32: The method of any of clauses 22-31, wherein molecules of the self-assembled monolayer comprise a second portion bonded to a molecule of the therapeutic agent, the second portion comprising at least one of an amine, carboxylic acid, alcohol, thiol, methyl, or bromine. 
     Clause 33: The method of any of clauses 22-32, wherein the therapeutic agent comprises at least one of ticagrelor, enoaparin, fondaparinux, sirolimus, tacrolimus, everolimus, or prasugrel. 
     Clause 34: The method of any of clauses 22-33, wherein the therapeutic agent comprises ticagrelor, and wherein molecules of the ticagrelor are covalently bonded to molecules of the self-assembled monolayer at an amine terminus of the molecules of the self-assembled monolayer. 
     Clause 35: The method of any of clauses 22-34, wherein the covalent bonding of the therapeutic agent to the at least one site of the self-assembled monolayer layer occurs by a Mitsunobo reaction. 
     Clause 36: A method of deploying an implantable device, comprising: advancing an implantable device formed according to the method of any of clauses 22-36 through a vascular system of the patient to a preselected deployment site through a delivery catheter; and extending the implantable device from a distal end of the delivery catheter, thereby causing the implantable device to expand from a contracted state to a deployed state.