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Title:
SURFACE-FUNCTIONALIZED TUBULAR STRUCTURES, AND METHODS OF MAKING AND USING THE SAME
Document Type and Number:
WIPO Patent Application WO/2018/107092
Kind Code:
A1
Abstract:
A method for functionalizing a tubular structure with an array of metal oxide nanotubes or an array of metal oxide-free polymer nanotubes is provided. The method may include positioning an electrode in a lumen of a suitable tubular structure having a tubular polymeric scaffold, where the lumen is lined with a metal substrate, and the electrode is configured to avoid electrical contact between the conductive portion of the electrode and the metal substrate; introducing an electrolyte solution into the lumen; and generating an electrical potential difference across the electrolyte solution between the electrode and the metal substrate. A tubular structure functionalized with an array of metal oxide nanotubes, devices and systems for making the same, and methods of using the same, are also provided.

Inventors:
NUHN HARALD (US)
DESAI TEJAL A (US)
Application Number:
PCT/US2017/065417
Publication Date:
June 14, 2018
Filing Date:
December 08, 2017
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
UNIV CALIFORNIA (US)
International Classes:
C25D7/04; C25D5/02
Foreign References:
US20050038498A12005-02-17
US20050070995A12005-03-31
US20150322583A12015-11-12
US20150068910A12015-03-12
US6375826B12002-04-23
US20090035859A12009-02-05
US20100031819A12010-02-11
US20140090983A12014-04-03
US20050261760A12005-11-24
Attorney, Agent or Firm:
BABA, Edward J. (US)
Download PDF:
Claims:
CLAIMS

What is claimed is:

1. A method of functionalizing a tubular structure with an array of metal oxide nanotubes, comprising:

positioning an electrode in a lumen of a tubular structure, wherein the tubular structure comprises:

i) a tubular polymeric scaffold surrounding the lumen and comprising an inner surface; and

ii) a metal substrate overlying the inner surface, wherein the metal substrate is in electrical contact with an anode and comprises a surface interfacing the lumen, and wherein the electrode comprises:

a) a first conductive structure in electrical contact with a cathode; and b) one or more spacers configured to prevent an electrical short between the first conductive structure and the scaffold;

introducing an electrolyte solution into the lumen; and

maintaining an electrical potential difference across the electrolyte solution between the anode and the cathode, in a manner sufficient to form an array of metal oxide nanotubes on the surface of the metal substrate, wherein the metal substrate and the electrode are at least partially submerged in the electrolyte solution.

2. The method of claim 1, wherein the first conductive structure is a conductive wire.

3. The method of claim 2, wherein the conductive wire is a metal wire.

4. The method of claim 3, wherein the conductive wire is a platinum wire.

5. The method of any one of claims 1 to 4, wherein the one or more spacers are non- conductive.

6. The method of claim 5, wherein the one or more spacers comprise a polymeric or ceramic material.

7. The method of any one of claims 1 to 4, wherein the one or more spacers are semi- conductive.

8. The method of any one of claims 1 to 7, wherein the one or more spacers circumscribe at least a portion of the first conductive structure.

9. The method of any one of claims 1 to 8, wherein the one or more spacers have a cross- sectional shape of a rectangle, flat sheet, cross, triangle, square, circle, ellipse, diamond, or X- shaped.

10. The method of any one of claims 1 to 9, wherein the one or more spacers are configured to position the first conductive structure substantially in the center of the lumen.

11. The method of any one of claims 1 to 10, wherein the one or more spacers comprise at least two spacers.

12. The method of claim 11, wherein the spacers are evenly distributed along a length of the tubular structure from a first end to a second end opposite the first end, wherein the length is further defined by a path along a center of the lumen.

13. The method of any one of claims 1 to 12, wherein the tubular structure comprises a conductive, biocompatible wire disposed between the inner surface and the metal substrate, wherein the conductive, biocompatible wire is in electrical contact with the anode and the metal substrate.

14. The method of any one of claims 1 to 13, wherein the conductive, biocompatible wire is a helical wire disposed between the inner surface and the metal substrate.

15. The method of any one of claims 1 to 14, wherein the electrical contact between the metal substrate and the anode comprises a second conductive structure penetrating the scaffold from the inner surface, to an outer surface opposite the inner surface.

16. The method of any one of claims 1 to 15, wherein the metal substrate is a metal wire, metal mesh, or a metal foil.

17. The method of claim 16, wherein the metal foil has a thickness in the range of 0.01 μιη to 100 μιη.

18. The method of any one of claims 1 to 17, wherein the metal substrate overlies 10% or more of the inner surface.

19. The method of any one of claims 1 to 18, wherein the surface of the metal substrate is substantially smooth.

20. The method of any one of claims 1 to 18, wherein the surface of the metal substrate comprises a microstructure.

21. The method of claim 20, wherein the microstructure comprises a groove, pillar, pit, or a combination thereof.

22. The method of any one of claims 1 to 21, wherein the electrical potential difference is in the range of 1.0 V to 1,000 V.

23. The method of any one of claims 1 to 22, wherein the electrical potential difference is applied for a time period in the range of 1 min to 180 min.

24. The method of any one of claims 1 to 23, further comprising maintaining the electrolyte solution at temperature in the range from above a freezing point of the electrolyte solution to below the boiling point of the electrolyte solution, during the maintaining.

25. The method of claim 24, further comprising maintaining the electrolyte solution at temperature in the range of about 10 °C to about 50 °C, during the maintaining.

26. The method of any one of claims 1 to 25, wherein the metal substrate comprises aluminum, niobium, tantalum, titanium, tungsten, zirconium, vanadium, or a mixture thereof.

27. The method of claim 26, wherein the metal substrate comprises a titanium alloy.

28. The method of any one of claims 1 to 27, wherein the electrolyte solution comprises a fluoride salt, chloride salt, organic nitrates, perchlorate, bromide salt, or a mixture thereof.

29. The method of claim 28, wherein the electrolyte solution comprises ammonium fluoride, ammonium chloride, sodium chloride, potassium chloride, potassium bromide, sodium bromide, or a mixture thereof.

30. The method of any one of claims 1 to 29, wherein the scaffold comprises

polytetrafluoroethylene (PTFE), polyethylene terephthalate (PET), and/or polyurethane (PU).

31. The method of any one of claims 1 to 30, wherein the tubular structure is a vascular graft.

32. The method of any one of claims 1 to 31, wherein the tubular structure comprises a proximal end and a distal end and wherein the metal substrate overlies the inner surface of the tubular structure at only the proximal and distal ends.

33. The method of claim 32, wherein method results in functionalization of the tubular structure with an array of metal oxide nanotubes at only the proximal and distal ends of the tubular structure.

34. A tubular structure comprising:

i) a tubular polymeric scaffold surrounding a lumen and comprising an inner surface; and ii) a metal substrate overlying the inner surface, wherein a surface of the metal substrate interfaces the lumen and comprises an array of metal oxide nanotubes extending a distance from the metal substrate surface, wherein the metal oxide nanotubes of the array have an average diameter in the range of about 10 nm to about 1,000 nm.

35. The tubular structure of claim 32, wherein the array of metal oxide nanotubes overlies 5% or more of the inner surface.

36. The tubular structure of claims 32 or 33, wherein the metal substrate overlies 10% or more of the inner surface.

37. The tubular structure of any one of claims 32 to 34, wherein the tubular structure comprises a conductive, biocompatible wire disposed between the inner surface and the metal substrate, wherein the conductive, biocompatible wire is in electrical contact with the metal substrate.

38. The tubular structure of claim 37, wherein the conductive, biocompatible wire is a helical wire disposed between the inner surface and the metal substrate.

39. The tubular structure of any one of claims 32 to 36, wherein the metal substrate comprises a metal wire, metal mesh, or a metal foil.

40. The tubular structure of claim 37, wherein the metal foil has a thickness in the range of 0.01 μιη ΐο 100 μιη.

41. The tubular structure of any one of claims 32 to 38, wherein the surface of the metal substrate is substantially smooth.

42. The tubular structure of any one of claims 32 to 38, wherein the surface of the metal substrate comprises a microstructure.

43. The tubular structure of claim 40, wherein the microstructure comprises a groove, pillar, pit, or a combination thereof.

44. The tubular structure of any one of claims 32 to 41, wherein the metal substrate comprises aluminum, niobium, tantalum, titanium, tungsten, zirconium, vanadium, or a mixture thereof.

45. The tubular structure of claim 42, wherein the metal substrate comprises a titanium alloy.

46. The tubular structure of any one of claims 32 to 43, wherein the nanotubes comprise an oxide of a metal of the metal substrate.

47. The tubular structure of claim 44, wherein the oxide of the metal is an oxide of aluminum, niobium, tantalum, titanium, tungsten, zirconium, or a mixture thereof.

48. The tubular structure of any one of claims 32 to 45, wherein the distance is in the range of lO nm to 10,000 nm.

49. The tubular structure of any one of claims 32 to 46, wherein the scaffold comprises polytetrafluoroethylene (PTFE), polyethylene terephthalate (PET), and/or polyurethane (PU).

50. The tubular structure of any one of claims 32 to 47, wherein the tubular structure is a vascular graft.

51. The tubular structure of claim 48, wherein the tubular structure comprises a luminal valve.

52. The tubular structure of claim 48 or 49, wherein the inner surface does not comprise a biological anti -thrombotic agent.

53. The tubular structure of any one of claims 34-50, wherein the tubular structure comprises a proximal end and a distal end and wherein the metal substrate overlies the inner surface of the tubular structure at only the proximal and distal ends.

54. The tubular structure of any one of claims 34-50, wherein the tubular structure comprises a proximal end and a distal end and wherein the metal substrate overlies the inner surface of the tubular structure at only the proximal and distal ends and wherein the tubular structure is functionalized with an array of metal oxide nanotubes at only the proximal and distal ends of the tubular structure.

55. A tubular structure functionalized with metal oxide nanotubes using a method according to any one of claims 1 to 33.

56. A synthetic vascular graft comprising a tubular scaffold surrounding a lumen and comprising an inner surface, wherein the inner surface is a functionalized surface that renders the vascular graft anti -thrombotic and anti-inflammatory without the use of a biological antithrombotic or an anti -inflammatory agent.

57. The vascular graft of claim 54, wherein the functionalized surface is a surface comprising an array of metal oxide nanotubes, wherein the metal oxide nanotubes of the array have an average diameter in the range of about 10 nm to about 1,000 nm.

58. The vascular graft of claim 54 or claim 55, wherein the functionalized surface is located at only a proximal end and a distal end of the vascular graft.

59. A method of treating a vascular tissue defect in an individual, comprising implanting the tubular structure of any one of claims 33 to 53, or the vascular graft of any one of claims 54-56, at a site in an individual comprising a defective vascular tissue, to amend a defective vascular tissue with the tubular structure or the vascular graft.

60. A kit comprising:

a tubular structure of any one of claims 33 to 51, or the vascular graft of claim 52 or 53; and

a packaging comprising a compartment for holding the tubular structure or the vascular graft.

61. The kit according to claim 55, wherein the compartment is substantially sterile.

Description:
SURFACE-FUNCTIONALIZED TUBULAR STRUCTURES,

AND METHODS OF MAKING AND USING THE SAME

CROSS REFERENCE TO RELATED APPLICATIONS

This application is based upon and claims priority to U.S. provisional patent application

62/432,098, filed December 9, 2016, which is incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with Government support under Grant No. TR000004, awarded by the National Institutes of Health. The Government has certain rights in the invention.

BACKGROUND

Coatings and other surface modifications are utilized to provide beneficial characteristics such as reduced wear and improved biocompatibility to a variety of devices including, for example, implantable medical devices. Polymers and metal oxides are versatile materials which are used in a variety of applications including, for example, in optical coatings and as biocompatible coatings for bone implants. Accordingly, new coating techniques and devices, particularly those with applicability to polymer and metal oxide coating can be expected to positively affect a variety of important technologies including, for example, medical device fabrication.

SUMMARY

A method for functionalizing a tubular structure with an array of metal oxide nanotubes is provided. The present method may include positioning an electrode in a lumen of a tubular structure, wherein the tubular structure contains: i) a tubular polymeric scaffold surrounding the lumen and comprising an inner surface; and ii) a metal substrate overlying the inner surface, wherein the metal substrate is in electrical contact with an anode, and wherein the electrode includes: a) a conductive structure in electrical contact with a cathode; and b) one or more spacers configured to prevent electrical contact between the conductive structure and the scaffold; introducing an electrolyte solution into the lumen, thereby submerging the metal substrate and the electrode with the electrolyte solution; and generating an electrical potential difference across the electrolyte solution between the anode and the cathode, in a manner sufficient to form an array of metal oxide nanotubes on a surface of the metal substrate interfacing the lumen.

BRIEF DESCRIPTION OF THE FIGURES

The skilled artisan will understand that the drawings, described below, are for illustration purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

Figure 1 is a collection of schematic diagrams of a vascular graft made of a titanium coil covered by polyurethane tubing, according to embodiments of the present disclosure.

Figure 2 is an image showing titanium wire embedded in a polymeric tube, according to embodiments of the present disclosure.

Figure 3 is a collection of scanning electron micrography (SEM) images showing titanium oxide (Ti0 2 ) nanotubes coating a titanium wire in a titanium coil vascular graft, according to embodiments of the present disclosure.

Figure 4 is a schematic diagram showing variations in a vascular graft made of a titanium wire covered by polymeric tubing, according to embodiments of the present disclosure.

Figures 5A-5C are a collection of SEM images showing a titanium film deposited onto vascular graft material, according to embodiments of the present disclosure.

Figure 6 is an SEM image of a Ti0 2 nanotube coating formed over a titanium film deposited over a vascular graft material, according to embodiments of the present disclosure.

Figures 7A and 7B are a collection of images showing a vascular graft with an inner lumen modified with an unpatterned titanium foil functionalized with Ti0 2 nanotubes, according to embodiments of the present disclosure.

Figure 8 is a functionalized vascular graft implanted into the abdominal aorta of a rabbit, according to embodiments of the present disclosure.

Figures 9A and 9B are a collection of SEM images showing inner lumen of a vascular graft functionalized with Ti0 2 nanotubes, according to embodiments of the present disclosure.

Figures 10A and 10B are a collection of a schematic diagram and an image showing a device and system for coating a titanium foil-lined vascular graft with Ti0 2 nanotubes, according to embodiments of the present disclosure.

Figure 11 shows Table 1, listing the parameters used for coating a titanium foil-lined vascular graft with Ti0 2 nanotubes, according to embodiments of the present disclosure.

Figure 12 is a schematic diagram showing a tubular structure with protruding metal substrate in the form of a latch. Figure 13 is an image showing an electrode of the present invention comprising a rectangular-shaped spacer.

Figure 14 is a schematic diagram showing a system according to one embodiment of the present disclosure.

Figure 15 is an image showing a test probe according to one embodiment of the present disclosure.

Figure 16 shows Table 2, listing the parameters used for coating a titanium foil-lined vascular graft with Ti0 2 nanotubes, according to embodiments of the present disclosure.

Figure 17 shows an example of a parameter that worked for coating a titanium foil-lined vascular graft with Ti0 2 nanotubes, in which nanotubes were created and exposed, and an image showing the nanotubes.

Figure 18 shows an example of a parameter that did not work, and an image showing the resulting material.

Figure 19A is a schematic diagram of a vascular graft shown in light gray with titanium foil (depicted in dark grey) carrying Ti0 2 nanotubular arrays, disposed along the inner circumference on the proximal and distal ends of the graft. Figure 19B shows a graft with titanium foil inserted into an end (dark region) and a graft with no insert.

DEFINITIONS

An "individual" refers to any animal, e.g., a mouse, rat, rabbit, goat, dog, pig, monkey, non-human primate, or a human.

As used herein, "substantially" may be applied to modify any quantitative representation that could permissibly vary without resulting in a change in the basic function to which it is related. For example, a spacer may position a conductive structure somewhat away from the center of the lumen of a tubular structure, if the array of metal oxide nanotubes formed on the surface of the metal substrate is not materially altered.

As used herein, the terms "treat," "treatment," "treating," and the like, refer to obtaining a desired surgical and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. "Treatment," as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, e.g., causing regression of the disease, e.g., to completely or partially remove symptoms of the disease.

"Polymeric" as used herein, may be used to describe an organic compound composed of repeating units of one or more monomers containing carbon and hydrogen atoms. The monomers can also include other atoms such as Si, O, N, P, F, and S. A polymer may have a solid bulk polymer matrix.

"Biocompatible," as used herein, refers to a property of a material that allows for prolonged contact with a tissue in a subject without causing toxicity or significant damage.

"Functionalize" as used herein, refers to modifying or associating at least the surface of a structure with a new material that confers properties that are not present in the structure alone. The new material may be covalently attached, or may be non-covalently associated (e.g., coated) with the structure.

As used herein, the term "anode" refers to a positively charged electrode of an electrolytic cell or an electrode which is capable of serving as a positively charged electrode of an electrolytic cell.

As used herein, the term "cathode" refers to a negatively charged electrode of an electrolytic cell or an electrode which is capable of serving as a negatively charged electrode of an electrolytic cell.

The term "conductive polymer" means an electrically conductive polymeric material. As used herein, the terms "nanostructure", "nanostructured" and the like refer to structures or objects modified with structures having at least one dimension greater than 0.1 nm and less than 1000 nm.

As used herein, the terms "microstructure", "microstructured" and the like refer to structures or objects modified with structures having at least one dimension greater than or equal to 1 μπι and less than 1000 μπι.

"Tubular" as used herein, may describe a structure that includes a scaffold that substantially surrounds a hollow central portion, which may be called a lumen. The hollow central portion may include an opening at a first end of the scaffold and/or at a second end of the scaffold opposite the first end. The structure in some cases is elongated along a path defined by the first end and the second end along the center of the lumen, where a length of the path is longer than the average diameter of the lumen as measured along a plane substantially perpendicular to the path. In some cases, the structure is cylindrical. In some cases, the cross section of the structure is circular, square, rectangular, hexagonal, or irregular shaped. A "nanotube" as used herein, may refer to a tubular structure, where the diameter of the lumen is on a nanometer scale.

"Array" as used herein, may describe a spatial distribution of elements on a surface, where the elements may be distributed randomly, in a substantially regular pattern, or in an irregular pattern. In some cases, an element of the array may touch a neighboring element, or may be defined at least in part by a structural element that is continuous with that defining at least in part a neighboring element.

Before the various embodiments are described, it is to be understood that the teachings of this disclosure are not limited to the particular embodiments described, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present teachings will be limited only by the appended claims.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described in any way. While the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the present disclosure.

The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present claims are not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided can be different from the actual publication dates which can need to be independently confirmed.

It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims can be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which can be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present teachings. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

One with skill in the art will appreciate that the present invention is not limited in its application to the details of construction, the arrangements of components, category selections, weightings, pre-determined signal limits, or the steps set forth in the description or drawings herein. The invention is capable of other embodiments and of being practiced or being carried out in many different ways.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present teachings, some exemplary methods and materials are now described.

DETAILED DESCRIPTION

As summarized above, a tubular structure, e.g., a vascular graft, functionalized on the inner surface with an array of metal oxide nanotubes, and methods and devices for making the same are provided. The method may include positioning a conductive structure having spacers, e.g., an electrode, inside the lumen of a tubular structure, such as a vascular graft, such that the spacer prevents an electrical short between the conductive structure and a metal surface overlying the inner surface of the tubular structure. Application of an electrical field between the conductive structure and the metal surface, through an electrolyte solution in the lumen submerging the conductive structure and the metal surface, induces an anodization reaction and the formation of an array of metal oxide nanotubes on the metal surface.

The present method, and devices and systems for performing the same, provide for synthesis of an array of metal oxide nanotubes, e.g., titanium oxide (Ti0 2 ) nanotubes, where the nanotubes have controlled dimensions (e.g., controlled diameter and controlled length of nanotubes in the array). The dimensions of the nanotubes of the array may be varied by, e.g., adjusting the duration of applying the electrical field (e.g., duration of applying voltage), the amplitude of the applied electrical field (e.g., amplitude of the applied voltage), and/or the temperature and/or the composition of the electrolyte.

Further aspects of the present disclosure are now described. METHODS

Methods of functionalizing a tubular structure or patch structure with an array of metal oxide nanotubes

Aspects of the present disclosure include methods of functionalizing, e.g., coating, a tubular structure or patch structure with an array of metal oxide nanotubes, using an anodization process. In general terms the present method may include positioning an electrode in a lumen of a tubular structure; introducing an electrolyte solution into the lumen; and maintaining an electrical potential difference across the electrolyte solution between the electrode and the inner surface of the lumen, to coat the inner surface of the tubular structure with an array of metal oxide nanotubes, where the inner surface and the electrode are at least partially submerged in the electrolyte solution. A metal substrate may overlie the inner surface, and the array of metal oxide nanotubes may be formed on the metal substrate by the anodization process, where the metal substrate and the electrode are at least partially submerged in the electrolyte solution. The present method may be performed using any suitable device or system for functionalizing, e.g., coating and/or surface modifying, the inner lumen of a tubular structure with an array of metal oxide nanotubes, such as the devices and systems of the present disclosure, as described herein. In some embodiments, the functionalized tubular structure may be modified into a

functionalized patch structure, e.g., cut open into a patch structure.

Tubular Structures and Patch Structures

The tubular structure may in general contain a polymeric scaffold surrounding the lumen, where the inner surface of the scaffold faces the lumen. "Face" as used herein, indicates that the surface of a structure is proximal to the object compared to another surface on the opposite side of the structure. The tubular structure may further include a metal substrate that covers at least part of the inner surface, where the metal substrate exposes a surface to the lumen.

The patch structure comprises two surfaces and may in general contain a polymeric scaffold on the outside surface of the structure, where the inner surface of the scaffold faces the electrode. The patch structure may further include a metal substrate that covers at least part of the inner surface, where the metal substrate exposes a surface to the electrode.

The patch structure to be functionalized, e.g., coated and/or surface modified, by the present method may include any suitable polymeric scaffold on the outer surface, and may have any suitable dimensions. Where the patch structure to be functionalized is, e.g., a vascular patch, it may be configured to have any suitable dimensions required to, e.g., repair a blood vessel, perform a successful endarterectomy. The tubular structure to be functionalized, e.g., coated and/or surface modified, by the present method may include any suitable tubular polymeric scaffold to form a lumen, and may have any suitable dimensions. In some cases, the tubular structure has an inner diameter (e.g., diameter of the luminal cross section, from one side of the lumen to the diametrically opposite side) of 0.1 millimeters (mm) or more, e.g., 0.5 mm or more, 1.0 mm or more, 2.0 mm or more, 5.0 mm or more, including 10 mm or more, and in some cases 100 mm or less, e.g., 50 mm or less, 10 mm or less, including 5.0 mm or less. In some cases, the tubular structure has an inner diameter in the range of 0.1 mm to 100 mm, e.g., 0.5 mm to 50 mm, including 1.0 mm to 10 mm.

In some cases, the tubular structure or patch structure to be functionalized, e.g., coated and/or surface modified, by the present method has a longitudinal length, defined by the length of the structure between a first end and a second end opposite the first end, of 1.0 mm or more, e.g., 5.0 mm or more, 10 mm or more, 20 mm or more, 30 mm or more, 50 mm or more, including 100 mm or more, and in some cases has a longitudinal length of 1.0 meter (m) or less, e.g., 50 centimeters (cm) or less, 10 cm or less, 5.0 cm or less, 1.0 cm or less, 50 mm or less, including 10 mm or less. In some embodiments, the tubular structure or patch structure has a longitudinal length in the range of 1.0 mm to 1.0 m, e.g., 5.0 mm to 50 cm, 5.0 mm to 10 cm, including 1.0 cm to 10 cm.

The polymeric scaffold may be made of any suitable material, such as a biocompatible polymeric material. In some cases, the polymeric scaffold is non-degradable in a physiological environment, e.g., an implantation site in an individual's body. In certain embodiments, the polymeric scaffold includes polytetrafluoroethylene (PTFE; such as Teflon®), polyethylene terephthalate (PET), and/or polyurethane (PU). In some cases, the polymeric scaffold includes an expanded PTFE (ePTFE) material (such as GoreTex®). In some cases, the polymeric scaffold is a polymeric tubing, e.g., a vascular graft material. In some cases, the polymeric scaffold is a polymeric patch, e.g., a vascular patch material. The polymeric scaffold may be a watertight material and may prevent a liquid material contained in the lumen or one side of the patch from leaking out through the wall of the scaffold. The polymeric scaffold may be a woven or a non- woven material.

The metal substrate that covers the inner surface of the polymeric scaffold of the tubular structure or patch structure, and on which the metal oxide nanotubes are formed, as described herein, may be any suitable metal substrate. As the metal substrate overlies the inner surface of the scaffold, the metal substrate may have substantially the same form factor as the polymeric scaffold. In some cases, the metal substrate is a metal wire, metal mesh, or a metal foil (see, for example, Figures 1 and 4). In some cases, the metal wire is a metal coil (e.g., Figure 1). The metal coil may be in the form of a substantially regular spiral having a defined pitch. In some cases, the pitch is about 1.0 times or more, e.g., 1.2 times or more, 1.5 times or more, 2.0 times or more, 2.5 times or more, including 3.0 times or more of the width of the metal wire, and in some cases, is 5.0 times or less, e.g., 4.0 times or less, 3.0 times or less, including 2.5 times or less of the width of the metal wire. In some embodiments, the pitch of the metal coil spiral is in the range of 1.0 to 5.0 times the width of the metal wire, e.g., 1.2 to 4.0 times the width of the metal wire, 1.5 to 3.0 times the width of the metal wire, including 2.0 to 3.0 times the width of the metal wire. The metal foil may have any suitable thickness. In some embodiments, the metal foil has a thickness of 0.01 μπι or more, e.g., 0.02 μπι or more, 0.05 μπι or more, 0.1 μπι or more, 0.2 μπι or more, 0.5 μπι or more, 1.0 μπι or more, 2.0 μπι or more, 5.0 μπι or more, including 10 μπι or more, and in some cases may have a thickness of 100 μπι or less, e.g., 50 μπι or less, 20 μπι or less, 10 μπι or less, 8.0 μπι or less, 5.0 μπι or less, 2.0 μπι or less, including 1.0 μπι or less. In some embodiments, the metal foil has a thickness in the range of 0.01 to 100 μτη, e.g., 0.02 to 50 μιη 0.05 to 20 μιη, 0.1 to 10 μιη, 0.1 to 8.0 μιη, including 0.1 to 5.0 μιη.

The metal substrate may include any suitable metal, and may be a biocompatible metal. In some cases, the metal substrate includes iron, cobalt, aluminum, niobium, tantalum, titanium, tungsten, zirconium, vanadium, or a mixture thereof. In some cases, the metal substrate includes a metal alloy, e.g., a titanium alloy, such as TiA16V4.

The metal substrate may be deposited on the inner surface of the tubular scaffold or patch scaffold using any suitable method. Suitable methods include, without limitation, cathodic arc deposition, electron beam physical vapor deposition, evaporative deposition, pulsed laser deposition, and sputter deposition. In some cases, the metal substrate is deposited over an intermediate layer that overlies the inner surface of the scaffold, to increase adhesion of the metal substrate to the scaffold. In some cases, the metal substrate is deposited over an intermediate layer of adhesive that overlies the inner surface of the scaffold. Where the metal substrate is deposited over a layer of adhesive that overlies the inner surface of the scaffold, in some cases, a first plasma activation step (e.g., ammonia plasma or oxygen plasma) for both the metal substrate and scaffold may increase each's interaction with the adhesive. In some cases, the scaffold may be plasma activated to increase adhesion to the adhesive. In some cases, a metal surface may be plasma activated before attaching to an adhesive to increase interaction with the adhesive. In some cases, the inner surface of the scaffold may be plasma activated and the surface of the metal substrate to be adhered to the inner surface of the scaffold may both be plasma activated to increase interaction with the adhesive used to attach the scaffold to the metal tube. In some cases the metal substrate is adhered to the scaffold without the use of any adhesive. Where the metal substrate is adhered to the scaffold without any adhesive, in some cases, a reactive species is deposited via plasma to the metal substrate and scaffold, resulting in a covalent linkage between the metal substrate and scaffold.

Exemplary biocompatible adhesives include, for example, epoxy based adhesives, such as EP21TDCS MED or MasterSil 151Med (Masterbond). Other exemplary adhesives include silanes or urethanes. In some cases, an adhesive free, covalent bond between the polymer and the metal substrate via reactive groups, e.g. Ti-OH on the foil and Si-OH on the polymers (e.g. PDMS) may also be used. These can be introduced via physical or chemical surface treatments, e.g. plasma, electro chemical or chemical (etch).

The metal substrate may cover any suitable portion of the inner surface of the scaffold. In some embodiments, the metal substrate overlies 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, and up to about 100% of the inner surface of the scaffold. In some cases, the metal substrate may be located on the inner circumference of the tubular structure at only the proximal and distal ends. In some cases, the metal substrate may be located on the inner circumference of the tubular structure covering substantially all of the inner surface of the scaffold.

In some cases, the metal substrate includes openings that expose the underlying inner surface of the scaffold. The openings may be any suitable shape, including, without limitation, circular, round, elliptical, rectangular, squared, hexagonal, or diamond.

The surface of the metal substrate on which the metal oxide nanotubes are formed may be substantially smooth (e.g., without any regular or irregular microstructures), or may include microstructures. In some embodiments, a smooth surface may be obtained by electropolishing. In some cases, the surface of the metal substrate is patterned into microstructures including a groove, pillar, pit, or a combination thereof. The microstructures, e.g., grooves, pillars, or pit, may be any suitable shape, including, without limitation, circular, triangular, rectangular, or square. The microstructures may have any suitable dimensions, ranging from sub-micrometer to micrometer range in width, spacing and/or height. In some cases, the surface of the metal substrate conforms to the inner surface of the scaffold which the metal substrate overlies. For example, if the scaffold is a woven structure, the surface of the metal substrate may have a micro structure that conforms to the weaves of polymeric material exposed on the inner surface of the scaffold (see, for example, Figures 3A-3C).

In some cases, the tubular structure or patch structure includes a conductive,

biocompatible wire disposed between the inner surface and the metal substrate, where the conductive, biocompatible wire is in electrical contact with the metal substrate. The conductive, biocompatible wire may be used to increase the conductivity along the metal substrate during synthesis of the array of nanotubes on the surface of the metal substrate, as described herein. In some cases, the conductive, biocompatible wire is a helical wire disposed between the inner surface and the metal substrate of the tubular or patch structure. In some cases, a helical, conductive, biocompatible wire increases kink-resistance and assists in keeping the lumen of the tubular structure in an open (e.g., non-collapsed) configuration. In some cases, a tubular structure having increased kink-resistance allows for easier manipulation of the tubular structure. For example, where the tubular structure is a medical device (e.g., a vascular graft), a tubular structure having increased kink-resistance allows the surgeon to perform the suturing procedure easier and more efficiently. As such, a person of ordinary skill in the art would recognize any shape in which the conductive, biocompatible wire can have increased kink-resi stance and improved suturing properties.

A tubular structure or patch structure of the present disclosure may, in some cases, be a medical device, e.g., a surgical implant, for use to treat an individual in need. In some embodiments, the medical device is a vascular graft, stent (e.g., cardiovascular stents, peripheral stents such as saphenous vein stents, cerebrovascular stents and coils), shunt, or a vascular patch. In some embodiments, the medical device is a vein graft, a fistula, arteriovenous shunt, cerebrospinal fluid shunt, etc. In some cases, the tubular structure may be a graft including a proximal end and a distal end, where the proximal and distal ends connect to vascular tissue, e.g., a vein, artery, or a blood capillary and where the proximal and distal ends include a cuff or a ring of metal disposed on the inner circumference of the tubular structure such that the metal is exposed to the vascular tissue. In some cases, a nanotubular array is present on the cuff or ring of metal disposed at the distal ends to prevent or minimize growth of tissue, such as, scar tissue at the interface between the graft and the vascular tissue. In some cases, the cuff may extend up to 0.5-3 cm into the ends of the graft. In some cases, the tubular structure may be a graft including a proximal end and a distal end, where the proximal and distal ends connect to vascular tissue, e.g., a vein, artery, or a blood capillary and where the proximal and distal ends include a cuff or a ring of a polymer disposed on the inner circumference of the tubular structure such that the polymer is exposed to the vascular tissue. In some cases, a nanotubular array is present on the cuff or ring of polymer disposed at the distal ends to prevent or minimize growth of tissue, such as, scar tissue at the interface between the graft and the vascular tissue. In some cases, the cuff of polymer may extend up to 0.5-3 cm into the ends of the graft. In some embodiments, the array of metal oxide-free polymer microtubes or nanotubes overlies the inner surface of the scaffold at distal and proximal ends of the tubular scaffold, such that while the inner surface in the central region of the tubular scaffold is free of such an array (due to lack of presence of a polymer substrate disposed on the inner surface in the central region of the tubular scaffold), the ends of the tubular scaffold which would be in contact with vascular tissue upon grafting into a subject's vascular system, include the array of polymer nanotubes to minimize growth of scar tissue at the interface between the tubular scaffold and the vascular tissue. The terms proximal and distal ends as used herein refer to the opposite ends of a tubular structure and are same as a first and a second end. In certain cases, the array of metal oxide-free polymer microtubes or nanotubes overlies the inner surface of the scaffold at distal and proximal ends of the tubular scaffold, such that about 1% to 10% of the length of the tubular scaffold is covered at each end. In some cases, the tubular structure includes in the luminal side one or more valves configured to regulate the flow of a fluid, e.g., blood, through the tubular structure when implanted in an individual.

In some embodiments, the tubular structure or patch structure, e.g., a tubular or patch medical device, includes surgical attachment sites or surgical attachment structures, such as suture sites or suture tabs. In some cases, surgical attachment sites on the tubular structure or patch structure may not have an overlying metal substrate.

In some cases, a polymer solution (e.g., a metal- or metal oxide-free polymer solution) may be coated on the inner circumference of the tubular structure at only the proximal and distal ends of the tubular structure. In some cases, a polymer solution may be coated on the inner circumference of the tubular structure covering substantially all of the inner surface of the scaffold. In some cases, the polymer solution may be coated on the inner circumference of the tubular structure at only the proximal and distal ends of the tubular structure to provide a ring or a cuff of polymer at the ends. In some cases, such a ring or cuff may be treated to form a nanotubular array. In some cases, a metal- or metal oxide-free polymer sheet comprising a microtubular or nanotubular array may be attached to the inner circumference at the ends of the tubular structure. Any polymer suitable for generation of nanoarrays, such as, nanotubes may be used, such as, poly(8-caprolactone) (PCL), poly(DL-lactide-co-glycolide) (PLGA), poly(DL- lactide-co-8-caprolactone) (DLPLCL), or poly(methyl methacrylate).

Electrodes

The electrode may be an electrode that is suitably adapted to be inserted into the lumen of a tubular structure, as described above, and to carry out an anodization process in the presence of an electrolyte in the lumen. Thus, aspects of the present disclosure include a device for use as an electrode in the present method, and may be described with reference to Figure 10A.

In some embodiments, the device includes a conductive structure 1020 that may be in electrical contact with a cathode (i.e., an electron sink, or equivalently, a current source) from the bottom of the tubular structure, and spacers 1040 associated with the conductive structure (e.g., circumscribing sections of the conductive structure, as shown in Figure 10A), which conductive structure and spacers together form an electrode. In use, a counter electrode may be provided on the inner surface of the tubular structure, where the inner surface may be overlaid by a metal substrate 1030 electrically connected to the anode (i.e., an electron source, or equivalently, a current sink). The spacers are configured such that when the electrode is inserted into the luminal space of a tubular structure to be functionalized, e.g., coated and/or surface modified, the spacer prevents short circuiting of the device when the cathode is used against a counter electrode anode to maintain an electric potential difference. Thus the spacers may be configured to prevent electrical contact between the conductive structure and the metal substrate.

In some embodiments, depending on the length of the tubular structure to be

functionalized, an electrode may include one or more spacers, e.g., two spacers, three spacers, four spacers, five spacers, six spacers, seven spacers, eight spacers, nine spacers, ten or more spacers. An electrode including one or more spacers may have at least 20% of the conductive structure exposed to the electrolyte (i.e., free of the spacers), e.g., at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%), at least 94%, at least 95%, at least 96%, at least 97%, at least 98%. In one example, a tubular structure having a length of 20 mm may include an electrode that includes two spacers, one positioned at the bottom of the tubular structure, and the other positioned at the top of the tubular structure, wherein about 94-98%> of the conductive structure is exposed to the electrolyte (i.e., free of the spacers). In one example, a tubular structure having a longer length may include an electrode that includes additional spacers, e.g. four spacers, resulting in about 60% of the conductive structure free of the spacers.

After the present electrode 1020 is positioned in the lumen of the tubular structure and the luminal space of the tubular structure is filled with a suitable electrolyte solution, described further below, an electrical potential difference maintained in a suitable manner between the anode and the cathode, across the electrolyte solution, may anodize the surface of the metal substrate 1030 interfacing the lumen, thereby functionalizing, e.g., coating and/or surface modifying, the surface with one or more layers of an array of metal oxide nanotubes. The spacers 1040 may also be configured to allow sufficient flow of the electrolyte and gas evacuation during the anodization process.

Sufficient flow of the electrolyte and gas evacuation during the anodization process may be achieved when the system or device 1000 is completely submerged into the electrolyte solution. Complete submersion of the system or device in the electrolyte solution may prevent any issues that can occur at the electrolyte/air interface (e.g., corrosion of the tubular structure). Where the system or device 1000 is completely submerged into the electrolyte solution, any suitable modifications may be made to allow a more convenient complete submersion of the device. For example, the metal surface can protrude from the top of the tubular structure 1210 (i.e., end of the tubular structure that is proximal to the electrolyte/air interface) and may be modified to include a latch 1260. In some cases, such a modification is made by cutting off half of the circumference for a length of the metal surface (see, e.g. Figure 12). In some cases, the latch is about 10 mm long, e.g., 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm or longer.

In some cases, a gap between the spacer and the surface of the tubular structure (e.g., lumen-facing surface) can provide sufficient flow of the electrolyte and gas evacuation during the anodization process. Where there is a gap between the spacer and the surface of the tubular structure, the gap is sized appropriately to allow sufficient flow of the electrolyte and gas evacuation during the anodization process. In some cases, a hole in the spacer (or multiple holes in the spacer, e.g., spacer is porous) can provide sufficient flow of the electrolyte and gas evacuation during the anodization process. Where there is a hole in the spacer, the hole is sized appropriately to allow sufficient flow of the electrolyte and gas evacuation during the anodization process.

In other words, a device of the present disclosure may be a counter electrode against a metal substrate electrically connected to an anode and positioned over an inner luminal surface of a tubular structure, as described herein, where the counter electrode is adapted for use in a method of functionalizing, e.g., coating, the inner luminal surface of the tubular structure with one or more layers of an array of metal oxide nanotubes, as described herein.

The conductive structure 1020 may be made from, or coated with, a variety of suitable materials known in the art, e.g., platinum, titanium, vanadium, gold, aluminum, copper, lead, nickel, palladium, iron, cobalt, tantalum, tungsten, graphite, tin, and alloys including one or more of the above. See, e.g., Allam and Grimes, Solar Energy Materials & Solar Cells 92 (2008) 1468-1475, the disclosure of which is incorporated by reference herein. In some embodiments, one or more of parts of the conductive structure may serve as a sacrificial part which is at least partially consumed during the anodization reaction. In addition, the length and diameter of the conductive structure may vary depending on particular application of the system. For example, in some embodiments the conductive structure may have a diameter of from about 0.2 mm to about 5 mm or greater, e.g., from about 0.3 mm to about 5 mm, about 0.4 mm to about 5 mm, about 0.5 mm to about 5 mm, about 0.6 mm to about 5 mm, about 0.7 to about 5 mm, about 0.8 mm to about 5 mm, about 0.9 mm to about 5 mm, about 1 mm to about 5 mm, about 2 mm to about 5 mm, about 3 mm to about 5 mm, or about 4mm to about 5 mm. In some embodiments, the conductive structure may have a diameter of from about 5 mm to about 0.2 mm, e.g., from about 4 mm to about 0.2 mm, from about 3 mm to about 0.2 mm, from about 2 mm to about 0.2 mm, from about 1 mm to about 0.2 mm, from about 0.9 mm to about 0.2 mm, from about 0.8 mm to about 0.2 mm, from about 0.7 mm to about 0.2 mm, from about 0.6 mm to about 0.2 mm, from about 0.5 mm to about 0.2 mm, from about 0.4 mm to about 0.2 mm, or from about 0.3 mm to about 0.2 mm. The conductive structure may be provided in a variety of forms, e.g., as a wire, cylinder, or any other suitable form.

The spacer 1040 may be any suitable material and shape, and may be associated with the conductive structure 1020 in any suitable manner to prevent contact between the conductive structure and the surface of the metal substrate 1030. As such, the spacer provides for at least a minimum distance between the conductive structure and the surface of the metal substrate along the length of the conductive structure, where the minimum distance is sufficient to prevent the electrical short. The spacers 1040 may also be configured to allow sufficient flow of the electrolyte and gas evacuation during the anodization process. For example, the shape of the spacers may be configured to allow sufficient flow of the electrolyte and gas evacuation during the anodization process. Any shape of the spacers may be suitable. In some cases, the spacers can be porous to allow sufficient flow of the electrolyte and gas evacuation during the anodization process. Generally, the spacer should be selected such that it is compatible and non- reactive under the selected anodization conditions, e.g., with the selected electrolyte solution. In some cases, the spacer is a non-conductive material (i.e., an insulator), including, for example, any suitable non-conductive polymer, co-polymer, or polymer combination. Suitable non- conductive polymers may include thermoplastic polymers, e.g., acrylonitrile butadiene styrene (ABS), polyethylene (PE), polypropylene (PP), polystyrene (PS), polyvinyl chloride (PVC), and polyetheretherketone (PEEK), fluorinated polymers, e.g., polytetrafluoroethylene (PTFE) (Teflon™), among others. In some cases, the non- conductive material is a ceramic material, such as, without limitation, steatite, cordierite, 100% metal oxide alumina, 100% metal oxide zirconia. In some cases, suitable non-conductive ceramic material includes, without limitation, zirconium barium titanate, strontium titanate (ST), calcium titanate (CT), magnesium titanate (MT), calcium magnesium titanate (CMT), zinc titanate (ZT), lanthanum titanate (TLT), and neodymium titanate (TNT), barium zirconate (BZ), calcium zirconate (CZ), lead magnesium niobate (PMN), lead zinc niobate (PZN), lithium niobate (LN), barium stannate (BS), calcium stannate (CS), magnesium aluminium silicate, magnesium silicate, barium tantalate, titanium dioxide, niobium oxide, zirconia, silica, sapphire, beryllium oxide, and zirconium tin titanate. In some cases, the spacer is a semi-conductive material, such as, without limitation, silicon, germanium, gallium arsenide, silicon carbide, organic semi-conductive materials, etc.

The spacer 1040 may have any cross-sectional shape (e.g., along a plane perpendicular to the long dimension of the conductive structure 1020 in Figure 10A) that can provide at least a minimum distance between the conductive structure and the metal substrate along the length of the conductive structure, where the minimum distance is sufficient to prevent the electrical short. In some cases, the spacers have a cross-sectional shape of a triangle, square, circle, ellipse, diamond, rectangle, flat sheet, cross (see, Figure 13). In some cases, the spacers have a cross- sectional X-shape.

The spacers 1040 may be associated with the conductive structure 1020 in any suitable manner. In some cases, the spacer wraps around, or circumscribes, the conductive structure along a region of the conductive structure.

As the spacer 1040 is configured to prevent an electrical short between the conductive structure 1020 and the metal substrate 1030, the spacer may be configured to provide at least a minimum distance between the conductive structure and the metal substrate along the length of the conductive structure, where the minimum distance is sufficient to prevent the electrical short. In some cases, the spacers are configured to position the conductive structure at substantially the center of the lumen of the metal substrate along the length of the conductive structure. In some cases, the distance between the conductive structure and the metal substrate is in the range of a few microns to several centimeters, e.g., about 1 micron, about 5 microns, about 10 microns, about 50 microns, about 100 microns, about 500 microns, about 1000 microns, about 5000 microns, about 1 cm, about 5 cm, about 10 cm, about 15 cm or more. In some cases, the distance between the conductive structure and the metal substrate is in general, the difference between half the diameter of the metal substrate and half the diameter of the conductive structure.

In some cases, the present device includes at least two, e.g., at least three, at least 4, at least 5, including at least 6, spacers 1040 associated with the conductive structure 1020. As would be evident, the number of spacers present associate with the conductive structure may depend on the length of the inner surface of the tubular structure to be functionalized, e.g., coated and/or surface modified, the width of each spacer, and the spacing between consecutive spacers. In some cases, the spacers are evenly distributed along the conductive structure, where the distances between successive spacers along the conductive structures are substantially constant.

As indicated above, the present method generally includes introducing an electrolyte into the lumen of the tubular structure and at least partially submerging the metal substrate to be functionalized, e.g., coated and/or surface-modified, and the electrode structure connected to the cathode in an electrolyte solution. The positioning of the electrode in the lumen and introducing the electrolyte into the lumen may be performed in any suitable order (or concurrently with each other). Any suitable amount of the electrolyte solution may be introduced into the lumen. In some cases, the amount of electrolyte solution introduced into the lumen is sufficient to substantially fill the entire volume of the lumen of the tubular structure. In some cases, the amount of electrolyte solution introduced into the lumen is sufficient to submerge all or at least a portion of the surface of the metal substrate and at least a portion of the conductive structure of the electrode.

A variety of electrolyte solutions may be utilized depending on the particular application of the method, e.g., the desired nanotube dimensions or morphologies, and the materials used, e.g., the composition and/or the structure of the metal substrate overlying the inner surface of the lumen and to be functionalized, e.g., coated and/or surface-modified, and the electrode. Suitable electrolytes may include, for example, one or more of ammonium fluoride, a chloride salt (e.g., ammonium chloride, sodium chloride, and potassium chloride), organic nitrates,

perchlorate/chloride-containing electrolytes, fluoride-free electrolytes (e.g., sodium chloride and potassium bromide) and other suitable electrolytes known in the art. In some embodiments, in addition to one or more of the above electrolytes, the electrolyte solution may include, e.g., ethylene glycol and/or water.

In some embodiments, an electrolyte solution for use in connection with the disclosed methods of funtionalizing a tubular structure includes ethylene glycol, water at a ratio of 90: 10 or more, e.g., 92:8 or more, 94:6 or more, including 95:5 or more, and ammonium fluoride of about 0.5 g/L to about 4.5 g/L, e.g., 1 g/L to about 4 g/L, 2 g/L to about 4 g/L, such as, 0.5 g/L, 1 g/L, 1.5 g/L, 2 g/L, 2.5 g/L, 3 g/L, 3.5 g/L, 4 g/L, 4.5 g/L.

In some embodiments, the electrolyte solution acts as an etchant for the metal substrate to be functionalized, e.g., coated and/or surface modified.

In some embodiments, the source material from which the array of nanotubes as described is derived from the electrolyte solution via a sol-gel process. For example, the electrolyte solution may include Ti(OC 3 H7) which is converted to Ti0 2 nanostrucutres, e.g., nanotubes, on a metal substrate during anodization. In such embodiments, the metal substrate on which the nanostructures, e.g., nanotubes are to be formed, can include, e.g., stainless steel or CoCr. See, e.g., Kang et al. Nano Letters (2009), vol. 9, no. 2, pp. 601-606, the disclosure of which is incorporated by reference herein in its entirety.

In some embodiments of the disclosed methods, it may be desirable to control the temperature of the electrolyte solution during anodization. For example, a method according to the present disclosure may include maintaining the electrolyte solution at a substantially constant temperature for a period of time. In some embodiments, the substantially constant temperature is above the freezing point of the electrolyte solution and below the boiling point of the electrolyte solution. For example, in some embodiments, the substantially constant temperature may be about 25 °C. In some embodiments, the substantially constant temperature may exceed the boiling point of the electrolyte solution where, e.g., the electrolyte solution is maintained in a relatively high-pressure environment.

In other embodiments, the temperature may be adjusted or allowed to change during the time period, e.g., within a range above the freezing point of the electrolyte solution and below the boiling point of the electrolyte solution.

As discussed previously herein, the temperature of the electrolyte solution may be controlled, e.g., maintained or adjusted, with the use of a temperature controlled vessel, e.g., a jacketed beaker, and a temperature sensor as described herein.

In some embodiments, the electrolyte solution may be mixed during the electrolysis, e.g., anodization process. In some embodiments, the electrolyte solution may be stirred during the electrolysis, e.g., anodization process.

As discussed above, the disclosed methods may include maintaining an electrical potential difference across the electrolyte solution between the anode and the cathode (i.e., between the metal substrate overlying the inner surface of the tubular polymeric scaffold and the electrode). In some cases, the method includes applying a constant voltage or a constant current for a period of time between the anode and the cathode. Where the method includes maintaining a potential difference (e.g., applying a constant voltage) for a period of time, the potential difference may be from about 1 mV to about 100 kV, e.g., from about 10 mV to about 10 kV, from about 100 mV to about 1 kV, from about 1 V to about 1,000 V, or about 10 V to about 100 V. In some embodiments, where the method includes maintaining a potential difference (e.g., applying a constant voltage) for a period of time, the potential difference may be from about 10 mV to about 100 kV, from about 100 mV to about 100 kV, from about 1 V to about 100 kV, from about 10 V to about 100 kV, from about 100 V to about 100 kV, from about 1 kV to about 100 kV, or from about 10 kV to about 100 kV. The period of time may be from about 5 seconds (s) to about 5 days, e.g., about 10 s to about 5 days, about 30 s to about 5 days, about 1 minute (min) to about 5 days, about 5 min to about 5 days, about 10 min to about 5 days, about 30 min to about 5 days, about 1 hour to about 5 days, from about 5 hours to about 5 days, from about 10 hours to about 5 days, or from about 1 day to about 5 days. In some embodiments the period of time may be from about 5 min to about 90 min, e.g, from about 10 min to about 60 min, from about 20 min to about 50 min, or from about 30 min to about 40 min. In some cases, the period of time is about 10 s to about 1 day, e.g., about 30 s to about 12 hours (h), about 1 min to 6 h, including 1 min to 3 h. In some cases, the period of time is about 15 min, about 30 min, about 60 min, about 90 min or about 120 min.

In some embodiments, the disclosed methods include applying a substantially constant voltage in a range of from about 1 V to about 110 V (e.g., 10 V-100 V, such as 30 V-50 V) for a period of time within a range of about 4 min to 90 min (e.g., 30 min-90 min).

Where the method includes maintaining a potential difference by applying a constant current for a period of time, the constant current may be from about 1 fA to about 100 kA, e.g., from about 1 pA to about 100 kA, from about 1 nA to about 100 kA, from about 1 μΑ to about 100 kA, from about 1 mA to about 100 kA, from about 1 A to about 100 kA, or from about 1 kA to about 100 kA.

In some embodiments, the voltage and/or current may vary during the anodization process. For example, in some embodiments, the voltage may vary between about 1 mV and about 100 kV (or within one of the ranges discussed above) during the anodization process and/or the current may vary between about 1 fA and about 100 kA (or within one of the ranges discussed above).

In some embodiments, the anodization process is a two-step anodization process. A two- step anodization process as used in the present methods may include a first step comprising the use of high voltage or current to prime the surface to be functionalized, and a second step comprising a lower or higher voltage or current to create the desired nanostructures. Those of ordinary skill in the art will recognize the various conditions under which the first and second anodization steps may occur to create the desired outcome.

The first step is performed at a voltage between 5 - 250 V. The electrolyte may be replaced, then the current is set to a voltage below or above the previously applied voltage. The electrolyte may be of the same composition and concentration e.g. 3 g/L NH4F, 10% water, 90% ethylene glycol or vary in composition (e.g. 0.05 - lOg/L H4F, 0.1 - 20% water, 80 99.9% ethylene glycol or the composition is changed, adding, for example HCl) to perform the second step. Currents in each step can vary from 0.0001 mA to 200 mA. Temperature ranges from -5°C to 50°C.

In some embodiments, the metal substrate to be functionalized, e.g., e.g., coated and/or surface-modified, may be treated prior to the electrolysis, e.g., anodization process. For example, the metal substrate to be functionalized, e.g., coated, and/or surface-modified, may be electro-polished using methods known in the art prior to the electrolysis, e.g., anodization process. The metal substrate to be functionalized, e.g., coated, and/or surface-modified, may be subjected to one or more cleaning treatments (using, e.g., soap, acetone and/or ethanol) and/or ultrasound treatments, e.g., as described in the experimental section herein. In some

embodiments, the metal substrate to be functionalized, e.g., coated, and/or surface-modified, may be subjected to an etching step, e.g., via plasma etching, prior to the electrolysis, e.g., anodization process.

Independently or in addition to one of the above pre-anodization treatment methods, metal substrate having one or more microstructures or nanostructures, e.g., metal oxide nanotubes, formed thereon using the disclosed methods may be subjected to one or more post-anodization treatments, e.g., one or more ultrasound or electro-polishing treatments. Such post-anodization treatments may be desirable, for example, to remove surface debris (e.g., titania needles) remaining on the surface of the metal substrate following anodization.

In some embodiments, a post-anodization treatment used in methods of the present disclosure is performed to increase the stability and/or density of the resulting array of metal oxide nanostructures present on a functionalized surface. In some embodiments, a post- anodization treatment is performed to increase the efficiency of obtaining metal oxide nanostructures having desired dimensions and morphologies. In some cases, a post-anodization treatment includes an anodization step that is performed in the absence of fluoride (e.g., performed in fluoride-free electrolyte), as described in Yu et al., ACS Applied Materials and Interfaces (2014), 6:8001-8005 and Xiong et al., The Journal of Physical Chemistry C (2011), 115:4768-4772, both disclosures of which are incorporated by reference herein. In some cases, the fluoride-free electrolyte used in the post-anodization treatment step contains H 3 PO 4 in ethylene glycol (EG) (e.g., 5 wt % H 3 PO 4 in EG). Where a post-anodization treatment step is performed, a compact oxide layer is formed encompassing the array of metal oxide

nanostructures. In some cases, a post-anodization treatment step does not result in any formation of a compact oxide layer. Voltage range from 5-110 V, current from 0.01 mA - 500 mA. H 3 PO 4 concentration from over a range from 0.1 - 10 wt%. Temperature from -5°C to 50°C. Reaction time from 5 min to 120 min. In some embodiments, a post-anodization treatment involves exposing the metal oxide nanostructures to anodization procedure in a fluoride-free electrolyte for a period of about 30 min-120 min (e.g., 60 min), at a voltage of 60V-100V (e.g., 80V) at a temperature of 20 °C -50 °C (e.g., 30 °C). In certain cases, the electrolyte may include 1-10% (e.g., 5%) phosphoric acid.

In some embodiments, a post-anodization treatment used in methods of the present disclosure does not involve use of annealing to increase adhesion between the metal substrate and the metal oxide nanostructures, such as, annealing described in Xiong et al., The Journal of Physical Chemistry C (2011), 115:4768-4772. The nanostructures produced by the methods described herein show improved adherence to the metal substrate without requiring an annealing step, such as, heating the functionalized metal substrate at a high temperature of around 500°C for about 5 h or 10 h.

One or more steps of the methods disclosed herein may be computer controlled. For example, an electrical circuit including a power supply connected to the anode and the cathode or cathodes of the devices or systems disclosed herein may be under computer control. For example, such an electrical circuit may include a computer controlled relay to open and close the electrical circuit for the period of time. Where one or more temperatures sensors are present, such sensors may also be computer controlled. By integrating computer control of a temperature controlled jacketed beaker, a system can be provided which allows a user to program desired anodization conditions including time and temperature of the anodization. In this way, microstructures and/or nanostructures (nanotubes) having desired dimensions and morphologies can be obtained on a variety of structures.

TUBULAR STRUCTURES FUNCTIONALIZED WITH METAL OXIDE NANOTUBES

The present method finds use in functionalizing, e.g., coating, a tubular structure, as described herein, with an array of metal oxide nanotubes or an array of polymer nanotubes. Thus, also provided herein is a tubular structure with a lumen, as described above, where the lumen is lined with one or more layers of an array of metal oxide nanotubes or an array of polymer nanotubes, where optionally the array is only located at the ends of the tubular structure. In some cases, the lumen may be substantially completely lined with one or more layers of an array of metal oxide nanotubes. In other cases, the lumen may be partially lined such that one or more layers of an array of metal oxide nanotubes are located at only the two ends of the tubular structure. In some cases, while the one or more layers of an array of metal oxide nanotubes may be disposed at only the ends of the tubular structure, they may not extend to the very end or may include a gap towards the ends to provide space for insertion of suture needle to facilitate grafting of the tubular to vascular tissue without damage to the suture needle. In some cases, while the one or more layers of an array of metal oxide-free polymer microtubes or nanotubes may be disposed at only the ends of the tubular structure, they may not extend to the very end or may include a gap towards the ends to provide space for insertion of suture needle to facilitate grafting of the tubular to vascular tissue without damage to the suture needle. In some cases, the one or more layers of an array of metal oxide-free polymer microtubes or nanotubes may be disposed at only the ends of the tubular structure, they may extend to the very end and may not include a gap towards the ends to provide space for insertion of suture needle.

Metal oxide microtubes or nanotubes disposed on the present tubular structure, or provided according to the disclosed methods and/or using the disclosed devices and/or systems generally include a lumen or bore defined by one or more side walls. In some embodiments, the microtubes or nanotubes may have a generally tubular structure, a generally conical structure, or a generally frustoconical structure. In some embodiments, a drug (e.g., a bioactive compound) or biologically active agent may be positioned in the lumen or bore of the microtubes or nanotubes described herein. In some embodiments, a material, e.g., a polymeric material (e.g., an erodible polymer) may be positioned over the drug or active agent in the lumen or bore, e.g., to provide for controlled or delayed release of the drug or active agent in vivo. In other words, the drug or active agent containing lumen or bore of the microtubes or nanotubes may be capped with a material, e.g., a polymeric material (e.g., an erodible polymer), e.g., provide for controlled or delayed release of the drug or active agent in vivo. Suitable drug or active agent materials are described, for example, in U.S. Patent Application Publication Nos. 2010/0318193 and

2012/0114734, the disclosures of each of which are incorporated by reference herein in their entireties. It should be noted that materials other than drugs or biologically active agents may be incorporated into the lumen or bore of the microtubes or nanotubes, e.g., where the application of the functionalized, e.g., coated, and/or surface-modified structure is for use in a context other than the medical device context. Such materials may include, e.g., compounds, macromolecules, polymers, and the like.

In some cases, the metal oxide is an oxide of one of aluminum, niobium, tantalum, titanium, tungsten, and zirconium.

The metal oxide nanotubes may be arranged in a densely packed array, where each nanotube contacts a neighboring nanotube on all directions (see, e.g., Figures 3 and 9B). The metal oxide nanotubes may have any cross-sectional shape, and in some cases, may range from hexagonal to circular. The metal oxide nanotubes and the metal oxide-free polymer microtubes or nanotubes may have any suitable dimensions. In some embodiments, metal oxide or the metal oxide-free polymer microtubes or nanotubes lining the lumen of the tubular structure have an average diameter of from about 1 nm to about 1,000 nm, e.g., from about 10 nm to about 1,000 nm, from about 50 nm to about 800 nm, from about 100 nm to about 700 nm, from about 200 nm to about 600 nm, from about 300 nm to about 500 nm, or from about 450 nm to about 500 nm. In some embodiments, metal oxide nanotubes produced according to the disclosed methods have an average diameter of from about 10 nm to about 200 nm, from about 30 nm to about 180 nm, from about 50 nm to about 160 nm, from about 80 nm to about 140 nm, or from about 100 nm to about 120 nm. In some embodiments, metal oxide nanotubes produced according to the disclosed methods have an average diameter of from about 70 nm to about 150 nm, from about 90 nm to about 120 nm, from about 80 nm to about 120 nm, from about 80 nm to about 130 nm, from about 80 nm to about 140 nm, from about 80 nm to about 150 nm, from about 70 nm to about 120 nm, from about 70 nm to about 130 nm, from about 70 nm to about 140 nm, from about 60 nm to about 120 nm, from about 60 nm to about 130 nm, from about 60 nm to about 140 nm, from about 60 nm to about 150 nm, or about 100 nm.

Across the array, the diameter of the nanotubes may vary. In some cases, the diameter of the nanotubes varies across the array by 50% or less, e.g., 40% or less, 30% or less, 20% or less, 10%) or less, including 5.0% or less, and in some cases, may vary by 1.0% or more, e.g., 2.0 % or more, 5.0% or more, 10% or more, including 20% or more. In some embodiments, the diameter of the nanotubes varies across the array by a range or 1.0 to 50%, e.g., 2.0 to 40%, 5.0 to 30%, including 5.0 to 20%.

The metal oxide nanotubes may extend from the metal substrate surface such that an end of the nanotube (e.g., an end distal to the metal substrate surface) is at a distance from the metal substrate surface. The distance may also define a length of the metal oxide nanotube. In some embodiments, such metal oxide nanotubes have an average length of from about 10 nm to about 600 μηι, e.g., from about 10 nm to about 100 μηι, from about 10 nm to about 10 μηι, from about 10 nm to about 400 nm, from about 400 nm to about 600 nm, from about 600 nm to about 800 nm, from about 800 nm to about 1000 nm, from about 1 μπι to about 10 μηι, from about 1 μπι to about 50 μηι, from about 50 μπι to about 100 μηι, from about 100 μπι to about 200 μηι, from about 200 μπι to about 300 μηι, from about 300 μπι to about 400 μηι, from about 400 μπι to about 500 μηι, or from about 500 μπι to about 600 μηι. In some embodiments, such metal oxide nanotubes have an average length of from about 400 nm to about 600 μηι, from about 600 nm to about 600 μηι, from about 800 nm to about 600 μηι, from about 1 μπι to about 600 μηι, from about 50 μηι to about 600 μηι, from about 100 μιη to about 600 μπι, from about 200 μιη to about 600 μπι, or from about 400 μιη to about 600 μm.

In some embodiments, such metal oxide and the metal oxide-free polymer microtubes or nanotubes have an average length of from about 0.5 μιη to about 10 μπι, e.g., from about 1 μιη to about 9.5 μπι, from about 1.5 μιη to about 9 μπι, from about 2 μιη to about 8.5 μπι, from about 2.5 μπι to about 8 μπι, from about 3 μιη to about 7.5 μπι, from about 3.5 μιη to about 7 μπι, from about 4 μιη to about 6.5 μπι, from about 4.5 μιη to about 6 μπι, or from about 5 μιη to about 5.5 μπι.

The metal oxide nanotubes may generally overlie an area of the inner surface of the tubular scaffold where the metal substrate is present. In some cases, the area covered by the metal oxide nanotubes is coextensive with the area of the inner surface of the scaffold covered by the metal substrate. In some embodiments, the array of metal oxide nanotubes overlies 5% or more, e.g., 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60 % or more, 70% or more, 80% or more, 90% or more, 95% or more, 97% or more, and up to about 100 % of the inner surface of the scaffold. In some embodiments, the array of metal oxide nanotubes overlies the inner surface of the scaffold at distal and proximal ends of the tubular scaffold, such that while the inner surface in the central region of the tubular scaffold is free of such an array (due to lack of presence of a metal substrate disposed on the inner surface in the central region of the tubular scaffold), the ends of the tubular scaffold which would be in contact with vascular tissue upon grafting into a subject's vascular system, include the array of metal oxide nanotubes to minimize growth of scar tissue at the interface between the tubular scaffold and the vascular tissue. The terms proximal and distal ends as used herein refer to the opposite ends of a tubular structure and are same as a first and a second end. In certain cases, the array of metal oxide nanotubes overlies the inner surface of the scaffold at distal and proximal ends of the tubular scaffold, such that about 1% to 10% of the length of the tubular scaffold is covered at each end.

In some cases a tubular structure comprising i) a tubular polymeric scaffold surrounding a lumen and comprising an inner surface; and ii) a polymer substrate overlying the inner surface, wherein a surface of the polymer substrate interfaces the lumen and comprises an array of polymer nanotubes extending a distance from the polymer substrate surface, wherein the metal oxide-free polymer nanotubes of the array have an average diameter in the range of about 10 nm to about 1,000 nm. In some cases, the polymer substrate comprising the array of metal oxide- free polymer microtubes or nanotubes may be located only at the ends of the tubular polymeric scaffold to prevent formation of scar tissue at the site where the tubular polymeric scaffold is grafted onto a blood vessel.

SYSTEMS

Further aspects of the present disclosure include systems that find use in functionalizing, e.g., coating, a tubular structure with an array of metal oxide nanotubes. The system 1000 may include a device that includes a conductive structure 1020 that is in electrical contact with a cathode from the bottom of the conductive structure, and spacers 1040 associated with the conductive structure, where the conductive structure is positioned within the lumen of a tubular structure, as described above, having a tubular polymeric scaffold 1010 and a metal substrate 1030 overlying the inner surface of the scaffold, where the metal substrate is configured to be in electric contact with an anode that serves as the counter-electrode to the cathode. The conductive structure 1020 and the spacers 1040 may constitute a counter electrode to the metal substrate 1030 serving as the anode in the present system 1000. In some embodiments, the system includes a power supply connected to the anode and the cathode. In some embodiments, the conductive structure 1020 is no longer than the tubular structure, e.g. the end of the conductive structure 1020 ends flush with the end of the tubular structure.

Referring now to Figure 14, the system 1400 may include a device that includes a conductive structure 1420 that is in electrical contact with a cathode from the bottom of the conductive structure, and spacers associated with the conductive structure, where the conductive structure is positioned within the lumen of a tubular structure, as described above, having a tubular polymeric scaffold 1410 and a metal substrate 1430 overlying the inner surface of the scaffold, where the metal substrate is configured to be in electric contact with an anode that serves as the counter-electrode to the cathode. The metal substrate 1430 may be modified to protrude from the top of the tubular structure, and may be further modified to include a latch 1460. The conductive structure 1420 and the spacers may constitute a counter electrode to the metal substrate 1430 serving as the anode in the present system 1400. In some embodiments, the system includes an electrode support 1470 and a spacer 1480 located at the bottom of the conductive structure. In some embodiments, the system includes a power supply connected to the anode and the cathode. In some embodiments, the conductive structure 1420 is no longer than the tubular structure, e.g. the end of the conductive structure 1420 ends flush with the end of the tubular structure.

In some embodiments, the system may include a test probe (see, Figure 15) that grabs the latch 1460 and holds the graft in place. UTILITY

The tubular structures functionalized, e.g., coated, with one or more layers of an array of metal oxide nanotubes, as described herein, find use where the inner lumen of the tubular structure provides a conduit for a fluid material, where the metal oxide nanotube coating on the inner surface of the scaffold of the tubular structure confers desirable properties for interacting with the fluid material. In some cases, as described herein, the tubular structure is a medical device, e.g., a surgical implant, and may be used to treat a tissue defect in an individual in need, e.g., a patient. The fluid material may be any suitable fluid, such as, without limitation, blood and cerebral-spinal fluid.

The tubular structure, e.g., vascular graft, of the present disclosure may be an antithrombotic and/or anti-inflammatory nano-tubular structure, e.g., when the tubular structure is implanted at a surgical site as a conduit for biological fluids. Thus, the present tubular structure having an inner lumen surface functionalized with an array of metal oxide nanotubes, when the inner lumen is used as a conduit for a bodily fluid, e.g., blood, and comes into contact with the bodily fluid, provides for a reduced rate of fibrin deposition on the surface of the inner lumen compared to a tubular structure that does not include the functionalized surface. In some cases, the present tubular structure having an inner lumen surface functionalized with an array of metal oxide nanotubes can provide an anti -thrombotic effect in the absence of other anti -thrombotic agents and treatments, such as biological anti -thrombotic agents and treatments (e.g., heparin coatings, anti -thrombotic protein coatings, etc.).

In some cases, the tubular structure, e.g., vascular graft, of the present disclosure is an anti-inflammatory tubular structure for use as an implant, where the tubular structure does not include a biological or pharmaceutical anti-inflammatory/immunosuppressive agent. Examples of an immunosuppressive agent include an immunosuppressive drug, such as, but not limited to tacrolimus and cyclosporine.

In some cases, the functionalized structure created according to the present methods is a functionalized patch structure. In some cases, functionalized patch structures of the present disclosure find use in repairing a damage conduit (e.g., blood vessel), where the inner surface of where the metal oxide nanotube coating on the inner surface of the scaffold of the patch structure confers desirable properties for interacting with the fluid material. Methods of treating a vascular defect using a tubular structure or patch structure functionalized with an array of metal oxide nanotubes

The tubular structure or patch structure of the present disclosure finds use in treating a vascular defect in an individual in need. Thus, aspects of the present disclosure includes a method of treating a vascular tissue defect in an individual including the step of implanting a tubular structure or patch structure, e.g., a vascular graft or vascular patch, as described herein, at a surgical site to replace or amend defective vascular tissue with the tubular structure or patch structure. The defective vascular tissue may be any suitable vascular tissue, and may include, without limitation, an artery or a vein, an aorta, pulmonary artery or vein, coronary artery, carotid artery, femoral artery, etc. The implanting may be done by, e.g., suturing the ends of the tubular structure to the disjointed ends of the vascular tissue, or suturing the ends of the patch structure to the damaged portion of the vascular tissue.

The present method of treating a vascular tissue defect may provide for a vascular graft that is anti -thrombotic and/or anti-inflammatory and/or prevents or minimizes formation of scar tissue, as described above. In some cases, the tubular structure provides for a vascular graft that is anti -thrombotic and/or anti-inflammatory in the absence of a biological antithrombotic agent, or an anti-inflammatory drug. In addition, a tubular structure modified to include nanotubular arrays, as described herein, at only the ends connected to blood vessels (to bypass a defective or diseased blood vessel) is effective in minimizing fibrin deposition (in a porcine model, no fibrin deposition was detected 28 days after grafting) and formation of scar tissue.

The present tubular structure may also find use as other medical devices, such as stents and shunts. Thus in some cases, the tubular structure is implanted within the lumen of a blood vessel to function as a stent. In some cases, the tubular structure is implanted in the brain to drain cerebrospinal fluid (CSF) and reduce intracranial pressure caused by CSF buildup.

KITS

Also provided herein is a kit that includes a functionalized tubular structure of the present disclosure, and a packaging with a compartment to hold the tubular structure. In some cases, e.g., where the tubular structure is a medical device for implanting into a patient, the compartment of the packaging is a sterile compartment.

In some embodiments, the present kit includes instructions for making and/or using a tubular structure functionalized, e.g., coated, with an array of metal oxide nanotubes of the present disclosure. The instructions are generally recorded on a suitable recording medium. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or subpackaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, digital versatile disc (DVD), flash drive, Blue-ray Disc™ etc. In yet other embodiments, the actual instructions are not present in the kit, but methods for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, the methods for obtaining the instructions are recorded on a suitable substrate.

Components of a subject kit can be in separate containers; or can be combined in a single container.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

EXAMPLES

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the disclosed subject matter, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s); pi, picoliter(s); s or sec, second(s); min, minute(s); h or hr, hour(s); aa, amino acid(s); kb, kilobase(s); bp, base pair(s); nt, nucleotide(s); i.m., intramuscular(ly); i.p., intraperitoneal(ly); s.c, subcutaneous(ly); and the like. Example 1 : Wire design vascular graft

A vascular graft made of a Titanium coil, covered by polyurethane (PU) tubing was fabricated (Figure 1). The tubing prevented leaking. The spacing between the windings was 1- 1.5x the width of the wire, yielding 40-50 % titanium coverage.

Figure 1: Schematic of a vascular graft device. The straight lines reflect the outer tubing, surrounding the functionalized coil. The coil can be either made of a ribbon, or wire of any shape.

The 1 mm gap on the left and right of the center coil allows the surgeon to suture the device to the blood vessel, not damaging the needle by hitting the wire. The straight lines in the image represent the PU coating. The Titanium frame in the tubing is exposed to the blood stream.

Figure 2 shows the titanium wire with a round cross-section and embedded in the polymeric tube.

The titanium wire was coated with titanium oxide (Ti0 2 ) nanowires, as described in Example 4, and as shown by scanning electron microscopy (SEM) in Figure 3.

Figure 3: Scanning electron microscopy (SEM) image of Ti0 2 nanotubes introduced to coil device. Top left: nanotubes, detached Ti0 2 nanotubes on the edge of cut Ti wire. Bottom right: Nonporous surface.

Figure 4 shows additional design variations of the vascular graft.

Example 2: Depositing titanium onto the graft material

Physical or chemical deposition was used to introduce the titanium substrate on a polymeric surface (Figures 5A-5C). The surface was pretreated using a plasma cleaning step, immediately followed by titanium deposition. Methods of deposition included electron beam physical vapor deposition and sputter deposition. Film thickness was 1.5-2.0 μιη (eBeam); 500 nm (sputter).

Figures 5A-5C: SEM image of deposited titanium film onto vascular graft material of velour (Figure 5A), or polyethylene terephthalate (PET) (Figures 5B, 5C). Deposition method by e-Beam (Figures 5A, 5B), or sputtering (Figure 5C).

The Ti0 2 nanotube film was introduced onto the titanium substrate deposited on the vascular graft material (Figure 6).

Figure 6: Ti0 2 Nanotube film (-100 nm) on vascular graft material (see Figures a). Titanium film was deposited by e-beam (2.0 μ). Example 3 : Vascular graft with thin titanium alloy foil in the inner lumen

The inner lumen of a vascular graft made of expanded polytetrafluoroethylene (ePTFE) was modified with an unpatterned titanium foil, functionalized with Ti0 2 nanotubes (Figure 7A). The graft was sutured into an aorta in an ex -vivo model (Figure 7B).

A functionalized vascular graft, measuring 3 cm long and having an inner diameter of 3mm, was implanted into the abdominal aorta of a rabbit (Figure 8). As with the above, the inner lumen of the graft was coated with Ti0 2 nanotubes and the graft material was ePTFE.

Figures 9A and 9B show SEM images of the Ti0 2 nanotube functionalized inner lumen of the vascular graft.

Example 4: Synthesis of TiO? nanotubes

The electrolyte contained ammonium fluoride (3g/L), in a mixture of distilled water and ethylene glycol (1 :9 ratio).

The dimensions (e.g., diameter and length) of the nanotubes were altered by varying the synthesis time, voltage, and temperature, as shown in Table 1 in Figure 11.

ePTFE was plasma activated, e.g. ammonia plasma. The Titanium surface was plasma activated, Oxygen plasma, 90 seconds. Plasma treatment increased the interaction with the adhesive that was used. No delamination was observed between the Titanium surface and adhesive, or between ePTFE and adhesive. Exemplary biocompatible adhesives include, for example, epoxy based adhesives, such as EP21TDCS MED or MasterSil 151Med (Masterbond). Other exemplary adhesives include silanes or urethanes. In some cases, an adhesive free, covalent bond between the polymer and the metal substrate via reactive groups, e.g. Ti-OH on the foil and Si-OH on the polymers (e.g. PDMS) may also be used. These can be introduced via physical or chemical surface treatments, e.g. plasma, electro chemical or chemical (etch).

A post-anodization treatment step was performed to increase the stability of the Ti02 nanotube array. This was performed by having an additional anodization step in a fluoride-free electrolyte (5 wt % H3P04 in EG).

Figures 10A and 10B: Schematic representation of the Ti0 2 nanotube synthesis setup. (Figure 10A) The counter electrode is attached to the Ti foil at either one or both ends graft. (Figure 10B) An example of an electrode used to introduce nanotube arrays to a titanium foil lined graft.

Figure 11: Table 1 - Synthesis parameter for Ti-foil modified graft and resulting nanotube (NT) features. Example 5: Conditions tested for the synthesis of TiO? nanotubes

Various conditions were tested for the synthesis of Ti02 nanotubes.

Figure 16: Table 2 - Experimental conditions that were tested for the synthesis of Ti0 2 nanotubes.

Figure 17: An example of a condition that worked, in which nanotubes were created and exposed.

Figure 18: An example of a condition that did not work, in which nanotubes were too short, brittle, delaminated, or nanotubes were covered by an oxide film (solid, porous), attacked, dissolved, substrate-altered.

While the present disclosure has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto.