Coating for medical devices

Abstract

The present teachings relate to medical devices, at least a section of which is coated with a coating having a substrate, a functional layer, one or more peptides with integrin-binding motif, and optionally a carrier layer, methods of preparing such medical devices, and methods of using such medical devices, where the functional layer includes an acrylate, where some medical devices demonstrate superior antithrombogenic and anti-cell adhesion property and some medical devices demonstrate superior antithrombogenic property whilst promote effective endothelial cell adhesion.

Description

PATENT Attorney Docket No. PWAL-027PCTCOATING FOR MEDICAL DEVICESBACKGROUND OF THE INVENTION

[0001] The current state of the art for medical devices involves their use to treat a wide variety of clinical conditions, including those that require temporary or permanent implantation in the vascular system or body of the patient. One of the major challenges associated with these medical devices is the potential for blood clotting and thrombus formation, which can lead to serious or life-threatening complications.

[0002] To mitigate this risk, dual platelet inhibition is currently used, which involves administering a combination of platelet aggregation inhibitors to the patient prior to and after the procedure. However, this approach has several disadvantages, including its systemic nature, which increases the risk of bleeding for the patient as a whole, and the fact that it may not be suitable for certain patients due to the increased risk of bleeding.

[0003] The objective of the present teachings is therefore to provide a medical device that does not elicit undesirable reactions from the body, such as blood clotting, and thus eliminates the need for dual platelet inhibition. Specifically, the present teachings propose a coating for medical devices that imparts biomimetic and / or bio-repulsive properties to the device's surface, thereby reducing or eliminating platelet adhesion and aggregation. This would allow patients to receive treatment with minimized risk of thrombus formation and other complications associated with blood clotting.

[0004] In addition, some of the neurovascular devices, for example, neurovascular stents, in the market today have coatings that can either reduce or eliminate thrombus formation or promote endothelial cell adhesion and ingrowth. For example, the Shield Technology™, developed by Medtronic, modifies the surface of a medical device with synthetic phosphorylcholine polymer so that it was claimed that the blood cells won’t react to the implants having the Shield Technology™ coating. As another example, the CARMED A® Bioactive Surface is a heparin-based coating and was found to reduce thrombus formation on bloodPATENT Attorney Docket No. PWAL-027PCT contacting medical devices. US 11,779,686 to Phenox GmbH (the ’686 patent) discloses a saccharide-based coating for medical devices. Without characterizing the inventions or disclosures therein, the coating in the ’686 patent includes a functional layer of oligomer or polymer made from a monosaccharide and the coating exhibits reduced platelet adhesion and aggregation.

[0005] It was, however, unexpected to discover that coatings of the present teachings can improve the antithrombogenicity of and promote endothelial cell growth on the surface of medical devices where the coatings are applied.SUMMARY OF THE INVENTION

[0006] The present teachings provide medical devices with an antithrombogenic and fast healing coating that can improve the safety and efficacy of various medical applications.

[0007] One aspect of the present teachings relates to a medical device, at least a section of which comprises a substrate and a functional layer. The functional layer may be understood as a layer that provides a specific function or property to the medical device. It may be provided that the functional layer comprises a polyacrylate. A polyacrylate may be understood as a polymer derived from acrylic acid or its derivatives.

[0008] One technical advantage of the present teachings is that the use of polyacrylate in the functional layer of the medical device provides a biocompatible and non-thrombogenic surface. This can reduce the risk of thrombus formation on the device, which can lead to serious complications such as blood clots, stroke, or heart attack.

[0009] In many embodiments, the medical device of the present teachings comprises a substrate and a functional layer, wherein the functional layer comprises an acrylate. In some embodiments, wherein the functional layer is bonded to the substrate. In some embodiments, wherein the functional layer is bonded to the substrate through a covalent bond.

[0010] In many embodiments, the medical device comprises a carrier layer, wherein the functional layer is bonded to the carrier layer. In some embodiments, wherein the bonding of thePATENT Attorney Docket No. PWAL-027PCT functional layer to the carrier layer is through a covalent bond. In some embodiments, wherein the carrier layer comprises an adhesion promoter.

[0011] In many embodiments, in the medical device according to the present teachings, the adhesion promoter is bonded to the substrate. In some embodiments, the bonding of the adhesion promoter to the substrate is through a covalent bond. In some embodiments, the adhesion promoter comprises a silicon adhesion promotor.

[0012] In many embodiments, the substrate is selected from a Ni-Ti-alloy, a Co-Cr alloy, a Ni-Ti-Pt alloy, a Mo-Re alloy, a Ni-Ti-Nb-Y alloy, a Ti-Nb-Hf-Sn alloy, a Ni-Ti-Au alloy, a Mg-Al alloy, a Mg-Y alloy, a Mg-Mn alloy, X5CrNil8-10, a Pt-W alloy, a Pt-Ir alloy, Ti-6A1-4V, a Ti-Nb-Ta alloy, TaWlO, or a combination of any of the foregoing.

[0013] In many embodiments, the medical device comprises a peptide with an integrin-binding motif. In some embodiments, the peptide is a RGD peptide. In particular embodiments, the RGD peptide is a linear peptide comprising the sequence of glycine-arginine-glycine-aspartic acid-serine (Gly-Arg-Gly-Asp-Ser or GRGDS).

[0014] Another technical advantage of the present teachings is that the use of polyacrylate in the functional layer provides a smooth and durable coating on the medical device. This can reduce the risk of abrasion, wear, or delamination of the coating over time, which can maintain the functionality and safety of the device.

[0015] One aspect of the present teachings relates to a method of preparing a medical device. In many embodiments, the method comprises a multi-stage treatment in which the substrate is reacted with an adhesion promoter. In many embodiments, the functionalized substrate is then reacted with acrylic acid or its derivates or a mixture of them. In many embodiments, a peptide, in particular peptides with an RGD sequence, is covalently bound to the polymeric layer. In many embodiments, the substrate is treated with an oxygen-based plasma.

[0016] One aspect of the present teachings relates to a method of using a medical device of the present teachings.PATENT Attorney Docket No. PWAL-027PCT BRIEF DESCRIPTION OF DRAWINGS

[0017] The foregoing will be apparent from the following more particular description of embodiments, as well as the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments.

[0018] FIG. 1 is a photographic representation of the antithrombogenic properties of Ni-Ti-alloy plates treated with the acrylate coatings in accordance with several embodiments of the present teachings.

[0019] FIG. 2 is a photographic representation of the antithrombogenic properties and endothelial cell promotion properties of Ni-Ti-alloy plate specimens treated with different coatings, including the acrylate coating and / or RGD peptide coating, in accordance with several embodiments of the present teachings.DETAILED DESCRIPTION OF THE INVENTION

[0020] The present teachings can be understood more readily by reference to the following detailed description, the figures and the examples included herein.

[0021] Before the present teachings are disclosed and described, it is to be understood that they are not limited to specific methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present teachings, example methods and materials are now described.

[0022] Moreover, it is to be understood that unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that anPATENT Attorney Docket No. PWAL-027PCT order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, and the number or type of aspects described in the specification.

[0023] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present teachings. Nothing herein is to be construed as an admission that the present teachings are not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0024] Certain terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0025] As used herein, the term “a,” “an,” or “the” should be understood to include plural reference unless the context clearly indicates otherwise.

[0026] As used herein, unless the context requires otherwise, the term “comprise,” and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of, e.g., a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integer or step. As used herein, the term “comprising” can be substituted with the term “containing” or “including.”

[0027] As used herein, “consisting of’ excludes any element, step, or ingredient not specified in the claim element. As used herein, “consisting essentially of’ does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any of the terms “comprising,” “containing,” “including,” and “having,” whenever used herein in the context of an aspect or embodiment of the disclosure, can in some embodiments, be replaced with the term “consisting of,” or “consisting essentially of’ to vary scopes of the disclosure.PATENT Attorney Docket No. PWAL-027PCT

[0028] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or”, a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and, therefore, satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and, therefore, satisfy the requirement of the term “and / or.”

[0029] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0030] As used herein, the term “alkyl” includes saturated aliphatic groups, including straight- chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (e.g., isopropyl, tert- butyl, isobutyl, etc.), cycloalkyl groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In some embodiments, a straight-chain alkyl has 12 or few carbon atoms in its backbone (e.g., C1-C12). In certain embodiments, a straight-chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C1-C6). In particular embodiments, a straight- chain alkyl has 4 or fewer carbon atoms in its backbone (e.g., C1-C4). In some embodiments, a branched-chain alkyl has 12 or few carbon atoms in its backbone (e.g., C3-C12). In certain embodiments, a branched-chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C3-C6). In particular embodiments, a branched-chain alkyl has 4 or fewer carbon atoms in its backbone (e.g., C3-C4). In some embodiments, a cycloalkyl has 12 or few carbon atoms in its backbone (e.g., C3-C12). In certain embodiments, a cycloalkyl has 6 or fewer carbon atoms in itsPATENT Attorney Docket No. PWAL-027PCT backbone (e.g., C3-C6). In particular embodiments, a cycloalkyl has from 3-8 carbon atoms in their ring structure. For example, a cycloalkyl has 5 or 6 carbons in the ring structure.

[0031] In addition, the term alkyl includes both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing one or more hydrogens on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, cyano, amino (including alkyl amino, alkenyl amino, alkynyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, alkenylthio, alkynylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, alkenylaryl, alkynylaryl, oxo, or an aromatic or heteroaromatic moiety. In many embodiments, such substituents include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkoxyl, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino), alkylthio, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, oxo, or an aromatic or heteroaromatic moiety. In certain embodiments, such substituents include alkenyl, halogen, hydroxyl, alkoxyl, cyano, amino (including alkyl amino or dialkylamino), acylamino (including alkylcarbonylamino), trifluoromethyl, or oxo. In particular embodiments, such substituents include halogen, hydroxyl, alkoxyl amino (including alkyl amino or dialkylamino) or oxo. Cycloalkyls can be further substituted, e.g., with the substituents described above.

[0032] As used herein, the term “aryl” includes aromatic groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole,PATENT Attorney Docket No. PWAL-027PCT tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term “aryl” includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles”, “heterocycles,” “heteroaryls” or “heteroaromatics”. The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinate, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).

[0033] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. The term alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In some embodiments, a straight-chain alkenyl has 12 or few carbon atoms in its backbone (e.g., C2-C12). In certain embodiments, a straight-chain alkenyl has 6 or fewer carbon atoms in its backbone (e.g., C2-C6). In particular embodiments, a straight-chain alkenyl has 4 or fewer carbon atoms in its backbone (e.g., C2-C4). In somePATENT Attorney Docket No. PWAL-027PCT embodiments, a branched-chain alkenyl has 12 or few carbon atoms in its backbone (e.g., C3-C12). In certain embodiments, a branched-chain alkenyl has 6 or fewer carbon atoms in its backbone (e.g., C3-C6). In particular embodiments, a branched-chain alkenyl has 4 or fewer carbon atoms in its backbone (e.g., C3-C4). In some embodiments, a cycloalkenyl has 12 or few carbon atoms in its backbone (e.g., C3-C12). In certain embodiments, a cycloalkenyl has 6 or fewer carbon atoms in its backbone (e.g., C3-C6). In particular embodiments, a cycloalkenyl has from 3-8 carbon atoms in their ring structure. For example, a cycloalkenyl has 5 or 6 carbons in the ring structure.

[0034] In addition, the term alkenyl includes both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing one or more hydrogens on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkenyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, cyano, amino (including alkylamino, alkenylamino, alkynylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, oxo, or an aromatic or heteroaromatic moiety. In many embodiments, such substituents include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkoxyl, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino), alkylthio, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, oxo, or an aromatic or heteroaromatic moiety. In certain embodiments, such substituents include alkenyl, halogen, hydroxyl, alkoxyl, cyano, amino (including alkyl amino or dialkylamino), acylamino (including alkylcarbonylamino), trifluoromethyl, or oxo. In particular embodiments, suchPATENT Attorney Docket No. PWAL-027PCT substituents include halogen, hydroxyl, alkoxyl amino (including alkyl amino or dialkylamino) or oxo.

[0035] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, the term “alkynyl” includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. The term alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In some embodiments, a straight- chain alkynyl has 12 or few carbon atoms in its backbone (e.g., C2-C12). In certain embodiments, a straight-chain alkynyl has 6 or fewer carbon atoms in its backbone (e.g., C2-C6). In particular embodiments, a straight-chain alkynyl has 4 or fewer carbon atoms in its backbone (e.g., C2-C4). In some embodiments, a branched-chain alkynyl has 12 or few carbon atoms in its backbone (e.g., C3-C12). In certain embodiments, a branched-chain alkynyl has 6 or fewer carbon atoms in its backbone (e.g., C3-C6). In particular embodiments, a branched-chain alkynyl has 4 or fewer carbon atoms in its backbone (e.g., C3-C4). In some embodiments, a cycloalkynyl has 12 or few carbon atoms in its backbone (e.g., C3-C12). In certain embodiments, a cycloalkynyl has 6 or fewer carbon atoms in its backbone (e.g., C3-C6). In particular embodiments, a cycloalkynyl has from 3-8 carbon atoms in their ring structure. For example, a cycloalkynyl has 5 or 6 carbons in the ring structure.

[0036] In addition, the term alkynyl includes both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkenyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,PATENT Attorney Docket No. PWAL-027PCT oxo, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. In many embodiments, such substituents include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkoxyl, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino), alkylthio, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, oxo, or an aromatic or heteroaromatic moiety. In certain embodiments, such substituents include alkenyl, halogen, hydroxyl, alkoxyl, cyano, amino (including alkyl amino or dialkylamino), acylamino (including alkylcarbonylamino), trifluoromethyl, or oxo. In particular embodiments, such substituents include halogen, hydroxyl, alkoxyl amino (including alkyl amino or dialkylamino) or oxo.

[0037] Unless the number of carbons is otherwise specified, “lower alkyl” as used herein means an alkyl group, as defined above, but having from 1 to 5 carbon atoms in its backbone structure. “Lower alkenyl” and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.

[0038] As used herein, the term “acyl” includes compounds and moieties which contain the acyl radical (CH3CO — ) or a carbonyl group. It includes substituted acyl moieties. The term “substituted acyl” includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide; nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.PATENT Attorney Docket No. PWAL-027PCT

[0039] As used herein, the term “acylamino” includes moieties wherein an acyl moiety is bonded to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

[0040] As used herein, the term “aroyl” includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.

[0041] As used herein, the terms “alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl” include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.

[0042] As used herein, the term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy.

[0043] As used herein, the term “amine” or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term includes “alkyl amino” which comprises groups and compounds wherein the nitrogen is bound to at leastPATENT Attorney Docket No. PWAL-027PCT one additional alkyl group. The term “dialkyl amino” includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups. The term “arylamino” and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. The term “alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group. The term “alkaminoalkyl” refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.

[0044] As used herein, the term “amide,” “amido” or “aminocarbonyl” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes “alkaminocarbonyl” or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl or alkynyl groups bound to an amino group bound to a carbonyl group. It includes arylaminocarbonyl and arylcarbonylamino groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. The terms “alkylaminocarbonyl,” “alkenylaminocarbonyl,” “alkynylaminocarbonyl,” “arylaminocarbonyl,” “alkylcarbonylamino,” “alkenylcarbonylamino,” “alkynylcarbonylamino,” and “arylcarbonylamino” are included in term “amide.” Amides also include urea groups (aminocarbonylamino) and carbamates (oxy carbonylamino).

[0045] As used herein, the term “carbonyl” or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. The carbonyl can be further substituted with any moiety which allows the compounds of the invention to perform its intended function. For example, carbonyl moieties may be substituted with alkyls, alkenyls, alkynyls, aryls, alkoxy, aminos, etc. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

[0046] As used herein, the term “thiocarbonyl” or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.

[0047] As used herein, the term “ether” includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includesPATENT Attorney Docket No. PWAL-027PCT “alkoxyalkyl” which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.

[0048] As used herein, the term “ester” includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term “ester” includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are as defined above.

[0049] As used herein, the term “thioether” includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term “alkthioalkenyls” and alkthioalkynyls” refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.

[0050] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH.

[0051] As used herein, the term “oxo” includes groups with an =0.

[0052] As used herein, the term “halogen” includes fluorine, bromine, chlorine, iodine, etc. The term “perhalogenated” generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.

[0053] As used herein, the term “heteroatom” includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen (N), oxygen (O), sulfur (S) and phosphorus (P).

[0054] As used herein, the term “antithrombogenic” refers to properties that prevent the adhesion of platelets on the surface of the coated medical device.

[0055] As used herein, the term “fast-healing” refers to properties that enhance the adhesion and proliferation of certain, desired cell-types (e.g., endothelial cells).PATENT Attorney Docket No. PWAL-027PCT

[0056] As used herein, the term “integrin” refers to transmembrane receptors that are capable of promoting cell adhesion to any extracellular matrix (ECM). In many instances, an integrin is made of two subunits, alpha (a) and beta (p), and integrins are generally considered as the primary receptors that eukaryotic cells use to bind to the ECM. Integrins have been recognized to serve many functions, including but not limited to cell adhesion, cell migration, cell signaling, cell growth, tissue repair, inflammation, infection, and angiogenesis, and neuroplasticity. In addition, integrins have also been recognized to bind glycoproteins, proteins, short peptides, or peptidomimetic sequences that mimic the integrin binding motifs. For example, some integrins bind peptides and proteins which comprise the RGD motif. RGD peptides interact with the integrin receptor sites, which can initiate cell-signaling processes. The integrin av03 has an RGD binding site and peptides containing the sequence RGD home to avP3 integrin.

[0057] As used herein, the term “RGD sequence” or “RGD motif’ refers to the arginine-glycine-aspartic acid (Arg-Gly-Asp) sequence or motif. Among some 25 integrins known to date, at least eight of them have a high affinity to the RGD motif as the primary recognition sequence in their ligands.

[0058] As used herein, the terms “RGD-containing peptide” or “RGD peptide” are used herein interchangeably and refer to a peptide containing the RGD sequence or RGD motif. As used herein, the term “RGD peptidomimetic” refers to compounds, particularly, non-peptidic compounds, that mimic peptides having the RGD motif. For example, a RGD peptidomimetic can be a non-peptidic compound comprising a guanidine and a carboxyl terminal groups spaced by a chain of 11 atoms, at least 5 of which are carbon atoms, which the chain comprises one or more O, S, or N atoms and may optionally be substituted with oxo, thioxo, halogen, amino, Cl-C6 alkyl, hydroxyl, or carboxy.

[0059] In many embodiments, an RGD peptide of the present teachings is a linear peptide. In some embodiments, the RGD peptide is a linear peptide comprising from 3 to 300 amino acid residues. In some embodiments, the RGD peptide is a linear peptide comprising from 3 to 200 amino acid residues. In some embodiments, the RGD peptide is a linear peptide comprising from 3 to 100 amino acid residues. For example, the RGD peptide can be a linearPATENT Attorney Docket No. PWAL-027PCT peptide comprising from 3 to 50 amino acid residues, from 3 to 40 amino acid residues, from 3 to 20 amino acid residues, or from 3 to 10 amino acid residues. In certain embodiments, the RGD peptide is a linear peptide comprising 3 amino acid residues, 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, 7 amino acid residues, 8 amino acid residues, 9 amino acid residues, 10 amino acid residues, or 25 amino acid residues. In particular embodiments, the RGD peptide is a linear peptide comprising 6 amino acid residues. For example, the RGD peptide can be a peptide comprising the sequence of glycine-arginine-glycine-aspartic acid-serine (Gly-Arg-Gly-Asp-Ser or GRGDS).

[0060] In many embodiments, an RGD peptide of the present teachings is a non-linear peptide. In some embodiments, the RGD peptide is a non-linear peptide comprising from 3 to 300 amino acid residues. In some embodiments, the RGD peptide is a non-linear peptide comprising from 3 to 200 amino acid residues. In some embodiments, the RGD peptide is a nonlinear peptide comprising from 3 to 100 amino acid residues. For example, the RGD peptide can be a non-linear peptide comprising from 3 to 50 amino acid residues, from 3 to 40 amino acid residues, from 3 to 20 amino acid residues, or from 3 to 10 amino acid residues. In certain embodiments, the RGD peptide is a non-linear peptide comprising 3 amino acid residues, 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, 7 amino acid residues, 8 amino acid residues, 9 amino acid residues, 10 amino acid residues, or 25 amino acid residues. In particular embodiments, the RGD peptide is a non-linear peptide comprising 6 amino acid residues. For example, the RGD peptide can be a peptide comprising the sequence of glycine-arginine-glycine-aspartic acid-serine (Gly-Arg-Gly-Asp-Ser or GRGDS).

[0061] In many embodiments, an RGD peptide of the present teachings is a cyclic peptide. In some embodiments, the RGD peptide is a cyclic peptide comprising from 3 to 100 amino acid residues. For example, the RGD peptide can be a cyclic peptide comprising from 3 to 50 amino acid residues, from 3 to 40 amino acid residues, from 3 to 20 amino acid residues, or from 3 to 10 amino acid residues. In certain embodiments, the RGD peptide is a cyclic peptide comprising 3 amino acid residues, 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, 7 amino acid residues, 8 amino acid residues, 9 amino acid residues, 10 amino acidPATENT Attorney Docket No. PWAL-027PCT residues, or 25 amino acid residues. In particular embodiments, the RGD peptide is a cyclic peptide comprising 6 amino acid residues.

[0062] As used herein, the term “amino acid” includes the 20 naturally occurring amino acids as well as non-natural amino acids. Examples of natural amino acids include, but are not limited to, Ala, Arg, Asp, Cys, Gin, Glu, Gly, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Tyr, and Vai. Examples of non-natural amino acids include, but are not limited to, 4-aminobutyric acid (Abu), 2-aminoadipic acid, diaminopropionic (Dap) acid, hydroxylysine, homoserine, homovaline, homoleucine, norleucine (Nle), norvaline (Nva), ornithine (Orn), TIC, naphthylalanine (Nal), ring-methylated derivatives of Phe, halogenated derivatives of Phe or o-methyl-Tyr.

[0063] The term “amino acid” herein includes also modified amino acids such as modifications that occur post-translationally in vivo, for example, hydroxyproline, phosphoserine and phosphothreonine; D-modification; N-alkylation, preferably N-methylation, of the peptide bond; acylation or alkylation of the amino terminal group or of the free amino group of Lys; esterification or amidation of the carboxy terminal group or of a free carboxy group of Asp or Glu; and esterification or etherification of the hydroxyl group of Ser or Tyr.

[0064] The term “amino acid” includes both D- and L-amino acids. Thus, the RGD peptides can be all-D (except for glycine), all-L or L,D-amino acids. D-modifications as well as N-alkylation of the peptide bond are most beneficial to prevent peptide cleavage by enzymes in the organism.

[0065] One aspect of the present teachings relates to a medical device comprising a substrate and a functional layer. In many embodiments, the functional layer is bonded to the substrate. In some embodiments, the functional layer is bonded to the substrate through a bond. In some embodiments, the functional layer is bonded to the substrate through an intermolecular force. In certain embodiments, the functional layer is bonded to the substrate through a covalent bond.

[0066] In many embodiments, the medical device comprises a carrier layer. In some embodiments, the carrier layer comprises an adhesion promoter. Without being limited to anyPATENT Attorney Docket No. PWAL-027PCT theory or hypothesis, a functional layer of the present teachings can be bonded to the substrate through the carrier layer. In certain embodiments, the medical device comprises a substrate, a carrier layer, and a functional layer, where the functional layer is bonded with the substrate through the carrier layer.

[0067] In many embodiments, the adhesion promotor comprises a silane adhesion promoter, a polyolefinic adhesion promoter, an adhesion promoters based on titanates or zirconates, a thiol and dithio compound, an amine or alcohol, a carboxylic acid, a phosphonic acid, or a chelating agent. In some embodiments, the adhesion promotor is a silane adhesion promotor. In some embodiments, the adhesion promotor is a polyolefinic adhesion promoter. In certain embodiments, the adhesion promoter is a chlorinated polyolefin (CPO) or acrylated polyolefin (APO). In some embodiments, the adhesion promotor is a titanate or zirconate. In some embodiments, the adhesion promotor is a thiol or dithio compound. In some embodiments, the adhesion promotor is an amine. In some embodiments, the adhesion promotor is an alcohol. In some embodiments, the adhesion promotor is a carboxylic acid. In some embodiments, the adhesion promotor is a phosphonic acid. In some embodiments, the adhesion promotor is a chelating agent. In certain embodiments, the adhesion promotor is a silane adhesion promotor.

[0068] In many embodiments, a silane adhesion promotor according to the present teachings has the general formula RnSiX4-n, where n is 1, 2, 3, or 4; R is alkyl, alkenyl or aryl groups, and X is a hydrolyzable group or a covalent bond. In some embodiments, X is OR’, OH halogen, or a covalent bond, where R’ is alkyl, alkenyl or aryl. In some embodiments, the silane compound comprises the general formula RSiXs, where X each independently is OR’, OH, halogen, where R is alkyl, alkenyl, or aryl, and R’ is alkyl. In some embodiments, the covalent bond binds the silane adhesion promotor to the substrate.

[0069] In many embodiments, a silane adhesion promotor according to the present teachings has the general formula -SiRnX3-n, where n is 1, 2, or 3, R is alkyl, alkenyl, or aryl group, - is a covalent bond, and X is a hydrolyzable group. In some embodiments, R is unsubstituted or substituted alkyl group. In some embodiments, - is a covalent bond that binds the silane adhesion promotor to the substrate.PATENT Attorney Docket No. PWAL-027PCT

[0070] In some embodiments, X is OR’, OH or halogen, where R’ is alkyl. In some embodiments, the silane compound comprises the general formula -SiRXo, where X is OR’, OH or halogen, where R is alkyl, alkenyl, or aryl, and R’ is alkyl. In some embodiments, - is a covalent bond that binds the silane adhesion promotor to the substrate.

[0071] In some embodiments, a silane adhesion promotor has Formula I:

[0072] In some embodiments, a silane adhesion promotor has Formula II:

[0073] In many embodiments, the functional layer comprises a polymer. In some embodiments, the functional layer comprises a polyacrylate. In some embodiments, the polyacrylate has Formula III:

[0074] wherein Ri, R2, R3, and R4 each independently is H, alkyl, alkenyl, alkynyl, aryl, alkoxy, amino, amido, carboxy, hydroxy, cyano, or halogen; and p is an integer.

[0075] In many embodiments, Ri is H, alkyl, alkenyl, alkynyl, or aryl. In some embodiments, Ri is H or alkyl. In certain embodiments, Ri is H. In certain embodiments, Ri is C1-C6 alkyl.PATENT Attorney Docket No. PWAL-027PCT

[0076] In many embodiments, R2 and R3 each independently is H, alkyl, alkenyl, alkynyl, or aryl. In some embodiments, R2 and R3 each independently is H or alkyl. In certain embodiments, R2 is H. In certain embodiments, R2 is alkyl. In particular embodiments, R2 is Cl-C12 alkyl. For example, R2 can be C1-C6 alkyl. In certain embodiments, R3 is H. In certain embodiments, R3 is alkyl. In particular embodiments, R3 is C1-C12 alkyl. For example, R3 can be Cl-C6 alkyl.

[0077] In many embodiments, R4 is H, alkyl, alkenyl, alkynyl, aryl, alkoxy, amino, cyano, or halogen. In certain embodiments, R4 is H, alkyl, alkoxy, amino, cyano, or halogen. In particular embodiments, R4 is H, alkyl, cyano, or halogen. For example, R4 can be H. For example, R4 can be C1-C6 alkyl. For example, R4 can be cyano. For example, R4 can be Cl, Br, or I.

[0078] In many embodiments, the medical device comprises a carrier layer and a functional layer. In many embodiments, the functional layer is covalently bonded to the carrier layer or the substrate. For example, the functional layer is prepared by polymerization where the functional layer is produced on the carrier layer or the substrate. In some embodiments, the functional layer comprises a hydrophilic matrix and the hydrophilic matrix comprises a molecule having a main chain as a polymeric backbone. In some embodiments, the main chain comprises polymerised acrylic or methacrylic compounds or derivatives thereof and / or isomers thereof or combinations thereof.

[0079] In some embodiments, the carrier layer and the functional layer are connected with a bond. In some embodiments, the carrier layer and the functional layer are connected with a covalent bond. In certain embodiments, the medical device comprises a carrier layer and a functional layer where the carrier layer and the functional layer have Formula IV:PATENT Attorney Docket No. PWAL-027PCT

[0080] wherein R5 and Re each independently is H, alkyl, alkenyl, alkynyl, or aryl; R9 is H, alkyl, alkenyl, alkynyl, or aryl; and p is an integer.

[0081] In some embodiments, R5 is H, or alkyl. In certain embodiments, R5 is H. In certain embodiments, R5 is alkyl. In particular embodiments, R5 is C1-C6 alkyl.

[0082] In some embodiments, Re is H or alkyl. In certain embodiments, Re is H. In certain embodiments, Re is alkyl. In particular embodiments, Re is C1-C6 alkyl. For example, Re can be methyl, ethyl, or isopropyl.

[0083] In some embodiments, R9 is H or alkyl. In certain embodiments, R9 is H. In certain embodiments, R9 is alkyl. In particular embodiments, R9 is C1-C6 alkyl. For example, R9 can be methyl, ethyl, or isopropyl.

[0084] In some embodiments, the medical device comprises a carrier layer and a functional layer where the carrier layer and the functional layer have Formula V:

[0085] where R7 and Rs each independently is H, alkyl, alkenyl, alkynyl, or aryl, and q is an integer.

[0086] In some embodiments, R7 is H or alkyl. In certain embodiments, R7 is H. In certain embodiments, R7 is alkyl. In particular embodiments, R7 is C1-C6 alkyl. For example, R7 can be methyl, ethyl, or isopropyl.

[0087] In some embodiments, Rs is H or alkyl. In certain embodiments, Rs is H. In certain embodiments, Rs is alkyl. In particular embodiments, Rs is C1-C6 alkyl.PATENT Attorney Docket No. PWAL-027PCT

[0088] In many embodiments, the functional layer covers the entire surface of the substrate. In many embodiments, the functional layer covers at least a part of the substrate. In many embodiments, the functional layer covers from 1 / 10 to 9 / 10 of the surface of the substrate. In some embodiments, the functional layer covers at least 1 / 10 of the surface of the substrate. In some embodiments, the functional layer covers at least 1 / 5 of the surface of the substrate. In some embodiments, the functional layer covers at least 3 / 10 of the surface of the substrate. In some embodiments, the functional layer covers at least 2 / 5 of the surface of the substrate. In some embodiments, the functional layer covers at least i of the surface of the substrate. In some embodiments, the functional layer covers at least 3 / 5 of the surface of the substrate. In some embodiments, the functional layer covers at least 7 / 10 of the surface of the substrate. In some embodiments, the functional layer covers at least 4 / 5 of the surface of the substrate. In some embodiments, the functional layer covers at least 9 / 10 of the surface of the substrate.

[0089] In many embodiments, the carrier layer covers the entire surface of the substrate. In many embodiments, the carrier layer covers at least a part of the substrate. In many embodiments, the carrier layer covers from 1 / 10 to 9 / 10 of the surface of the substrate. In some embodiments, the carrier layer covers at least 1 / 10 of the surface of the substrate. In some embodiments, the carrier layer covers at least 1 / 5 of the surface of the substrate. In some embodiments, the carrier layer covers at least 3 / 10 of the surface of the substrate. In some embodiments, the carrier layer covers at least 2 / 5 of the surface of the substrate. In some embodiments, the carrier layer covers at least i of the surface of the substrate. In some embodiments, the carrier layer covers at least 3 / 5 of the surface of the substrate. In some embodiments, the carrier layer covers at least 7 / 10 of the surface of the substrate. In some embodiments, the carrier layer covers at least 4 / 5 of the surface of the substrate. In some embodiments, the carrier layer covers at least 9 / 10 of the surface of the substrate.

[0090] In many embodiments, a medical device of the present teachings includes peptides. In some embodiments, the medical device includes an RGD peptide. In certain embodiments, the medical device includes a linear RGD peptide. In particular embodiments, the medical device includes a peptide comprising the sequence of glycine-arginine-glycine-aspartic acid-serine (Gly-Arg-Gly-Asp-Ser or GRGDS). In many embodiments, a medical device of thePATENT Attorney Docket No. PWAL-027PCT present teachings includes peptidomimetics. In some embodiments, the medical device includes an RGD peptidomimetic.

[0091] In many embodiments, the RGD peptide or the RGD peptidomimetic is connected with a substrate of the present teachings. In some embodiments, the RGD peptide or the RGD peptidomimetic is connected with the substrate through a covalent bond. In some embodiments, the RGD peptide or the RGD peptidomimetic is connected with the substrate through a functional layer. For example, the connection between the RGD peptide or the RGD peptidomimetic and the functional layer can be a covalent bond. In some embodiments, the RGD peptide or the RGD peptidomimetic is connected with the substrate through a carrier layer. For example, the connection between the RGD peptide or the RGD peptidomimetic and the carrier layer can be a covalent bond. In some embodiments, the RGD peptide or the RGD peptidomimetic is connected with the substrate through a functional layer and a carrier layer. For example, the connection between the RGD peptide or the RGD peptidomimetic and the functional layer can be a covalent bond.

[0092] In many embodiments, the present teachings provide a medical device comprising a substrate, a functional layer, a peptide with an integrin binding motif, a carrier layer, or a mixture of any of the foregoing. In some embodiments, a medical device comprises a functional layer, where the functional layer includes a polyacrylate, a substrate, where the substrate is a metal, a carrier layer, where the carrier layer includes a silane adhesion promotor, and a peptide, where the peptide includes an integrin binding motif. In certain embodiments, a medical device comprises a functional layer, where the functional layer includes a polyacrylate, a substrate, where the substrate is Ni-Ti-alloy, a carrier layer, where the carrier layer includes a silane adhesion promotor, and a peptide, where the peptide includes a RGD-peptide. In particular embodiments, the RGD peptide includes from 5 to 25 amino acid residues, preferably from 5 to 10 amino acids. In certain embodiments, the medical device includes a carrier layer, a functional layer, and a peptide having Formula VI:PATENT Attorney Docket No. PWAL-027PCTVI.

[0093] Although Formulae I to VI depict certain connections among the substrate, the carrier layer, the functional layer, and the peptide, a person with ordinary skills in the art understand that there are other connections among the substrate, the carrier layer, the functional layer, and the peptide as long as the resulting structures are stable, and these other connections are within the scope of the present teachings.

[0094] In many embodiments, the medical devices of the present teachings provide anti-thrombogenic properties. Without limiting the scope of the presenting teachings, referring to Fig.1, a photographic representation of Ni-Ti-alloy plate specimens treated with different coatings in accordance with several embodiments of the present teachings. In several embodiments, when Ni-Ti-alloy plate specimens were coated with polyacrylate and the coated Ni-Ti-alloy plate specimens were treated with heparinized human whole blood for 10 minutes, removed from the blood, washed two times with phosphate buffered solution, stained with fluorophore labelled anti-human-CD61 -antibody, and observed under the fluorescence microscope, these coated Ni-Ti-alloy plates showed virtually no platelet adhesion (lower row). In comparison, when the specimens were not treated with any coating (bare Ni-Ti-alloy plate specimens), treated with heparinized human whole blood for 10 minutes, removed from the blood, washed two times with phosphate buffered solution, stained with fluorophore labelled anti-human-CD61 -antibody, and observed under the fluorescence microscope, these bare Ni-Ti-alloy specimens showed many adherent platelets (upper row; positive control). Accordingly, in some embodiments, the adhesion of platelets to the Ni-Ti-alloy specimens coated in accordance with the present teachings was found to be significantly lower than that of the uncoated Ni-Ti-alloy plates.

[0095] In many embodiments, certain medical devices of the present teachings demonstrate superior anti-adhesive properties against platelets whilst superior cell adhesion property. FIG. 2 is a photographic representation of several embodiments of the presentPATENT Attorney Docket No. PWAL-027PCT teachings and such several embodiments were coated with different exemplary coatings according to the present teachings. Referring to FIG. 2, the upper row shows the results of platelet adhesion studies of some embodiments of the present teachings, where such some embodiments were treated with heparinized human whole blood after 10-minute incubation and stained with fluorophore labelled anti-human-CD61 -antibody under the fluorescence microscope. Continuing referring to FIG. 2, the lower row shows the results of endothelial cell adhesion studies. As FIG. 2 readily shows, the embodiments with polyacrylate coating (PAA) inhibit both platelets and endothelial cell adhesion (middle), the embodiments with the PAA coating and the RGD peptide (+RGD) inhibit platelet adhesion but allow endothelial cell adhesion (right). The uncoated Ni-Ti-alloy plates serve as control and allow both platelet and endothelial cell adhesion (left).

[0096] One aspect of the present teachings relates to methods of making a medical device of the present teachings. In many embodiments, the method comprises providing a substrate. For the purposes of the present teachings, a substrate can be a coatable substrate. Without limiting the present teachings to any theory or hypothesis, a substrate of the presentation teachings comprises a surface that is sufficiently reactive and / or sufficiently activatable to at least partially form bonds with an adhesion promoter or also directly with the functional layer.

[0097] In many embodiments, a coatable substrate comprises an oxidizable substrate. In some embodiments, the coatable substrate comprises a metal. In certain embodiments, the coatable substrate comprises nickel (Ni), titanium (Ti), platinum (Pt), iridium (Ir), gold (Au), cobalt (Co), chromium (Cr), aluminium (Al), iron (Fe), tungsten (W), magnesium (Mg), manganese (Mn), tantalum (Ta), niobium (Nb), an alloy of any of the foregoing, or a combination of any of the foregoing metals or alloys. In particular embodiments, the coatable substrate comprises nickel. In particular embodiments, the coatable substrate comprises titanium. In particular embodiments, the coatable substrate comprises platinum. In particular embodiments, the coatable substrate comprises iridium. In particular embodiments, the coatable substrate comprises gold. In particular embodiments, the coatable substrate comprises cobalt. In particular embodiments, the coatable substrate comprises chromium. In particular embodiments, the coatable substrate comprises aluminium. In particular embodiments, the coatable substratePATENT Attorney Docket No. PWAL-027PCT comprises an alloy. For example, the alloy can be a nickel / titanium alloy. In one example, the coatable substrate is a Ni-Ti-alloy. In other examples, the coatable substrate includes a Co-Cr alloy, a Ni-Ti-Pt alloy, a Mo-Re alloy, a Ni-Ti-Nb-Y alloy, a Ti-Nb-Hf-Sn alloy, a Ni-Ti-Au alloy, a Mg- Al alloy, a Mg-Y alloy, a Mg-Mn alloy, X5CrNil8-10, a Pt-W alloy, a Pt-Ir alloy, T1-6A1-4V, a Ti-Nb-Ta alloy, or TaWlO.

[0098] In many embodiments, the coatable substrate is an oxide, a nitride, or a carbide. In some embodiments, the coatable substrate is selected from TiO, TiCh, TiN, CrN, AIN, Fe4N, AI2O3, CrO, CnCh, FeC, TiC, CrC, SiC, WC, or a mixture of any of the foregoing materials.

[0099] In many embodiments, the coatable substrate is a glass. In many embodiments, the coatable substrate comprises a plastic. For example, the plastics can be polyamides (PA), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polylactides (PLA), polyester, polyether, polyurethane, polyolefin, or a block copolymer of any of the foregoing.

[0100] In many embodiments, the coatable substrate comprises a substrate coated with another coatable substrate as described herein. For example, a coatable substrate according to the present teachings can be a metal coated with a plastic that is coatable or a plastic coated with a coatable metal substrate. This can provide both biocompatibility and improved mechanical strength to the medical device.

[0101] The present teachings, however, are not limited to coatings of the plastics, ceramics, metals and glasses named herein, which in fact are to be understood only as examples. In principle, the present teachings are aimed at coatings of all conceivable materials that constitute a coatable substrate within the meaning of this present teachings.

[0102] In many embodiments, the method comprises a coating with one or more acrylates. In some embodiments, one of the acrylates is acrylic acid or alkyl acrylate. In certain embodiments, the acrylate is described in more detail herein. In many embodiments, the acrylate is in the form of a vapor or a solution. In some embodiments, the acrylate solution has a concentration from 0.05% (wt / wt) to 95% (wt / wt). In certain embodiments, the acrylate solution has a concentration from 0.1% (wt / wt) to 50% (wt / wt). In particular embodiments, the acrylate solution has a concentration from 0.5% (w / wt) to 10% (wt / wt). For example, the acrylatePATENT Attorney Docket No. PWAL-027PCT solution can have a concentration from 0.5% (wt / wt) to 1.0% (wt / wt), from 1.0% (wt / wt) to 2.0% (wt / wt), from 2.0% (wt / wt) to 3.0% (wt / wt), from 3.0% (wt / wt) to 4.0% (wt / wt), from 4.0% (wt / wt) to 5.0% (wt / wt), from 5.0% (wt / wt) to 6.0% (wt / wt), from 6.0% (wt / wt) to 7.0% (wt / wt), from 7.0% (wt / wt) to 8.0% (wt / wt), from 8.0% (wt / wt) to 9.0% (wt / wt), or from 9.0% (wt / wt) to 10.0% (wt / wt). In one embodiment, the acrylate solution has a concentration of 1.5% (wt / wt).

[0103] In many embodiments, the acrylate solution is in water, alcohol, acetone, acetonitrile, toluene, ethyl acetate, t-butyl acetate, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or a mixture of any of the foregoing. In some embodiments, the acrylate solution is in water.

[0104] In many embodiments, the polymerization is initiated by a stimulus, such as thermal energy or actinic radiation (e.g., ultraviolet light). In preferred embodiments, the method comprises coating with an acrylate in the presence of an initiator. The initiator may be a chemical compound, such as a radical initiator, an azo compound, or a peroxy compound. While the polymerization is preferably triggered by the initiator upon activation by the stimulus, in certain embodiments, the polymerization may also be initiated by the stimulus alone.

[0105] In many embodiments, the method comprises treating the substrate with an adhesion promotor. In some embodiments, the adhesion promotor is the one described herein in detail. In certain embodiments, the adhesion promotor is a silane adhesion promotor. For example, an appropriate adhesion promotion may be achieved by silanization, that is the chemical bonding of silicon compounds, in particular silane compounds. In certain embodiments, the treatment of the substrate with an adhesion promotor includes heating the substrate in a solution of an adhesion promotor. For example, the solution of the adhesion promotor can be an alcoholic solution. In particular embodiments, the treatment of the substrate with an adhesion promotor includes heating the substrate in the presence of the adhesion promotor in ethanol.

[0106] In many embodiments, the method comprises pre-treating the substrate. In some embodiments, the method comprises pretreating the substrate with an acid. In certain embodiments, the acid is an inorganic acid or an organic acid. For example, the acid can be sulfuric acid (H2SO4), hydrochloric acid (HC1), hydrobromic acid (HBr), phosphoric acidPATENT Attorney Docket No. PWAL-027PCT (H3PO4), formic acid, acetic acid, or a mixture of any of the foregoing. In some embodiments, the method comprises pretreating the substrate with a source of light. For example, the source light can be ultraviolet (UV) light or a blue light. In some embodiments, the method comprises pretreating the substrate with a plasma treatment. In certain embodiments, the method comprises pretreating the substrate with an oxygen-plasma treatment.

[0107] In many embodiments, the method comprising treating the functional layer with a peptide with integrin-biding motif. In some embodiments, the peptide with integrin-binding motif is an RGD peptide. In many embodiments, the RGD peptide is a linear peptide comprising from 3 to 100 amino acid residues. For example, the RGD peptide can be a linear peptide comprising from 3 to 50 amino acid residues, from 3 to 40 amino acid residues, from 3 to 20 amino acid residues, or from 3 to 10 amino acid residues. In certain embodiments, the RGD peptide is a linear peptide comprising 3 amino acid residues, 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, 7 amino acid residues, 8 amino acid residues, 9 amino acid residues, 10 amino acid residues, or 25 amino acid residues. In particular embodiments, the RGD peptide is a linear peptide comprising 3 amino acid residues. In particular embodiments, the RGD peptide is a linear peptide comprising 4 amino acid residues. In particular embodiments, the RGD peptide is a linear peptide comprising 5 amino acid residues. In particular embodiments, the RGD peptide is a linear peptide comprising 6 amino acid residues. For example, the RGD peptide can be a peptide comprising the sequence of glycine-arginine-glycine-aspartic acid-serine (Gly-Arg-Gly-Asp-Ser or GRGDS).

[0108] In many embodiments, the RGD peptide is a non-linear peptide comprising from 4 to 100 amino acid residues. For example, the RGD peptide can be a non-linear peptide comprising from 5 to 50 amino acid residues, from 5 to 40 amino acid residues, from 5 to 20 amino acid residues, or from 5 to 10 amino acid residues. In certain embodiments, the RGD peptide is a non-linear peptide comprising 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, 7 amino acid residues, 8 amino acid residues, 9 amino acid residues, 10 amino acid residues, or 25 amino acid residues. In particular embodiments, the RGD peptide is a non-linear peptide comprising 6 amino acid residues. For example, the RGD peptide can be a peptidePATENT Attorney Docket No. PWAL-027PCT comprising the sequence of glycine-arginine-glycine-aspartic acid-serine (Gly-Arg-Gly-Asp-Ser or GRGDS).

[0109] Another aspect of the presentation includes methods of using a medical device of the present teachings. Without limiting the scope of the present teachings, medical devices provided with the coating according to the present teachings are particularly suitable for endovascular, neurovascular and cardiovascular fields of application; however, the coating thus proposed by the present teachings can always be expediently applied on all medical devices that come into contact with blood. For example, medical devices of the present teachings can be catheters, guidewires, or other types of implantable or insertable medical devices that require an antithrombogenic coating for improved blood flow and reduced thromboembolism.

[0110] Examples

[0111] Example 1 : preparation of an exemplary medical device

[0112] The following scheme represents an example of preparing an exemplary medical device.

[0113] Example 2: Blood DonorsPATENT Attorney Docket No. PWAL-027PCT

[0114] Blood was voluntarily collected from eight healthy donors under the approval of the ethic commission of the Faculty of Medicine of the Ruhr-Universitat Bochum, Germany (registration number: 16-5991). Exclusion criteria for participation in the study were an abnormal blood count measured via haematology analyser (XQ-320, Sysmex, Norderstedt, Germany) and the intake of drugs that act on blood clotting. The number of platelets in the blood was recorded for each donor (not shown). Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and / or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

[0115] Example 3: In vitro blood assay

[0116] Heparinized venous blood was collected using S-Monovette Blood Collection System (SARSTEDT, Numbrecht, Germany) containing 16 IE Li-heparin per ml blood. In a 24-well plate and under sterile conditions, specimens were rinsed once in lx phosphate-buffered saline (PBS) (PAN-Biotech, Aidenbach, Germany) prior to incubation. Each specimen was incubated in 2 ml of whole blood for 10 min and 500 rpm on a platform shaker (Titramax 100, Heidolph Instruments). After incubation, specimens were rinsed twice in PBS to remove nonadherent cells before CD61 immunofluorescence staining.

[0117] Example 4: CD61 Immunohistochemistry

[0118] CD61 -positive adherent platelets were stained using CD61-PE antibody (BD Pharmingen, Heidelberg, Germany) fluorescence staining. After blood incubation and rinsing, the antibody was diluted 1 :5 in PBS and added to the Ni-Ti alloy specimens. After 15-min incubation in the dark, the Ni-Ti-alloy specimens were rinsed in PBS twice, fixed with 1% paraformaldehyde (Sigma- Aldrich, Taufkirchen, Germany) in PBS for 10 min and rinsed once with PBS. ROTI Mount FluorCare (Carl Roth, Karlsruhe, Germany) was added onto the Ni-Ti alloy specimens and analysed using a fluorescence microscope (Cytation 5, Biotek; Winooski, USA).

[0119] Example 5: Human umbilical vein endothelial cells (HUVEC) adhesionPATENT Attorney Docket No. PWAL-027PCT

[0120] In order to analyze the cell adhesion, HUVEC were cultured on different Ni-Ti-alloy specimens. HUVEC (2rd-6th passages) obtained from PromoCell (Heidelberg, Germany) were grown in cell culture (SARSTEDT, Numbrecht, Germany) using Endothelial Cell Growth Medium (PromoCell, Heidelberg, Germany) supplemented with Endothelial Cell Growth Medium SupplementPack (PromoCell, Heidelberg, Germany)) at 37 °C in a humidified atmosphere containing 5% CO2. For cell passage or harvest, adherent cells were washed three times with Hanks Buffered Salt Solution w / o calcium and magnesium (HBSS) (PAN-Biotech, Aidenbach, Germany) and detached from the culture flasks by the addition of 0.2 ml / cm20.05% trypsin / 0.02% ethylenediamine tetraacetic acid (PAN-Biotech, Aidenbach, Germany) for 3 min at 37 °C. Cell detachment was blocked by adding HBSS supplemented with 5% fetal calf serum (PAN-Biotech, Aidenbach, Germany). The cells were collected, centrifuged and resuspended in medium. A defined number off cells were seeded on the speciments.

[0121] Example 6: Actin histochemistry

[0122] After HUVEC cultivation on Ni-Ti-alloy specimens for a defined time, specimens were washed once with 37 °C HBSS and fixed with 4 % paraformaldehyde in PBS. After 10 min incubation, the specimens were incubated with 0.1 % TritonX-100 (Sigma, Taufkirchen, Germany) in PBS for 10 min and washed once with PBS. Phalloidin-tetramethylrhodamine (Sigma, Taufkirchen, Germany) was diluted 1 : 1000 in PBS and added to the Ni-Ti-alloy specimens. After incubation in the dark overnight, the Ni-Ti-alloy specimens were washed three times in PBS. ROTI Mount FluorCare DAPI (Carl Roth, Karlsruhe, Germany) was added onto the Ni-Ti alloy specimens and analyzed using a fluorescence microscope.

[0123] The foregoing description and accompanying drawings set forth a number of embodiments of the presentation teachings at the present time. Various modifications and alternative designs will become apparent to those skilled in the art in light of the foregoing teachings without departing from the spirit hereof, or exceeding the scope hereof, which is indicated by the following claims rather than by the foregoing description. All changes and variations that fall within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

PATENT Attorney Docket No. PWAL-027PCTClaims1. A medical device comprising a substrate and a first layer, wherein the first layer comprises a polyacrylate and a peptide with an integrin-binding motif.

2. The medical device according to claim 1 , wherein the peptide with an integrin-binding motif and the polyacrylate is connected through a covalent bond.

3. The medical device according to claim 1, wherein the peptide with an integrin-binding motif is a RGD peptide.

4. The medical device according to claim 3, wherein the RGD peptide is a linear peptide comprising from 3 to 100 amino acid residue.

5. The medical device according to claim 3, wherein the RGD peptide is a linear peptide comprising the sequence of glycine-arginine-glycine-aspartic acid-serine (Gly-Arg-Gly- Asp-Ser or GRGDS).

6. The medical device according to any one of claims 1 to 5, wherein the polyacrylate is derived from an acrylic acid.

7. The medical device according to any one of claims 6, wherein the polyacrylate has Formula III:wherein Ri, R2, R3, and R4 each independently is H, alkyl, alkenyl, alkynyl, aryl, alkoxy, amino, amido, carboxy, hydroxy, cyano, or halogen; and p is an integer.

8. The medical device according to claim 7, wherein Ri is H or alkyl.PATENT Attorney Docket No. PWAL-027PCT 9. The medical device according to claim 7, wherein Ri is H.

10. The medical device according to claim 7, wherein R2 and R3 each independently is H or alkyl.

11. The medical device according to claim 7, wherein R4 is H, C1-C6 alkyl, cyano, Cl, Br, or I.

12. The medical device according to claim 1, wherein the functional layer is bonded to the substrate.

13. The medical device according to claim 12, wherein the functional layer is bonded to the substrate through a covalent bond.

14. The medical device according to claim 1, wherein the medical device comprises a carrier layer, wherein the functional layer is bonded to the carrier layer.

15. The medical device according to claim 14, wherein the bonding of the functional layer to the carrier layer is through a covalent bond.

16. The medical device according to claim 14, wherein the carrier layer comprises an adhesion promoter.

17. The medical device according to claim 16, wherein the adhesion promoter is bonded to the substrate.

18. The medical device according to claim 17, wherein the bonding of the adhesion promoter to the substrate is through a covalent bond.

19. The medical device according to any one of claims 16 to 18, wherein the adhesion promoter comprises a silicon adhesion promotor.

20. The medical device according to claim 19, wherein the silicon adhesion promotor has the general formula RnSiX4-n, where n is 1, 2, 3, or 4; R is alkyl, alkenyl or aryl groups, and X is a hydrolyzable group.PATENT Attorney Docket No. PWAL-027PCT 21. The medical device according to claim 20, wherein X is OR’, OH halogen, or a covalent bond, where R’ is alkyl.

22. The medical device according to claim 20, wherein the silane adhesion promotor has Formula I:

23. The medical device according to claim 20, wherein the silane adhesion promotor has Formula II:H2CXOCH3'-SrOCH3OCH3II.

24. The medical device according to any one of claims 1 to 123, wherein the substrate comprises a metal.

25. The medical device according to any one of claims 1 to 24, wherein the substrate is selected from nickel (Ni), titanium (Ti), platinum (Pt), iridium (Ir), gold (Au), cobalt (Co), chromium (Cr), aluminium (Al), iron (Fe), tungsten (W), magnesium (Mg), manganese (Mn), tantalum (Ta), niobium (Nb), an alloy of any of the foregoing, or a combination of any of the foregoing metals or alloys.

26. The medical device according to any one of claims 1 to 24, wherein the substrate is selected from a Ni-Ti-alloy, a Co-Cr alloy, a Ni-Ti-Pt alloy, a Mo-Re alloy, a Ni-Ti-Nb-Y alloy, a Ti-Nb-Hf-Sn alloy, a Ni-Ti-Au alloy, a Mg-Al alloy, a Mg-Y alloy, a Mg-Mn alloy, X5CrNi 18-10, a Pt-W alloy, a Pt-Ir alloy, T1-6A1-4V, a Ti-Nb-Ta alloy, TaWlO, or a combination of any of the foregoing.PATENT Attorney Docket No. PWAL-027PCT 27. The medical device according to any one of claims 1 to 24, wherein the substrate is selected from TtO, T1O2, TiN, CrN, AIN, Fe4N, A12O3, CrO, Cr2O3, FeC, TtC, CrC, StC, WC, or a mixture of any of the foregoing materials.

28. The medical device according to any one of claims 1 to 23, wherein the substrate comprises a polymer.

29. The medical device according to claim 28, where the polymer is coated with the metal.

30. A method of preparing a medical device, wherein the medical device comprises a substrate and a first layer; comprising treating the substrate with a polyacrylate and a peptide with an integrin-binding motif.

31. The method according to claim 30, comprising treating the substrate with oxygen.

32. The method according to claim 30 or claim 31, comprising treating the substrate with a solution.

33. The method according to any one of claims 30 to 32, wherein the acrylic comprises a solution of the acrylate.

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