Adhesion resistant implantable device

Abstract

The present invention discloses implantable devices that resist adhesion of colloidal particles such as are present in biological fluids, and methods for their manufacture. In a particular embodiment, the device may be an endovascular stent and a method for its production, for reducing, and preferably eliminating, restenosis. This objective is accomplished by recognizing the fundamental coupling between the surface texture and composition, on one hand, and the drag and adhesive forces acting on a colloidal particle, on the other. The surfaces of the device are first exposed to fluid flow whereby they are polished via a micro and/or nano-abrasive media so that they are featureless on length scales that are commensurate with the sizes of colloidal particles that initiate restenosis. Secondly, the surface is treated with a thin coating that reduces, or preferably eliminates, hydrogen bonding with colloidal particles. In one embodiment, processes for treatment of such implantable devices are taught which result in targeted reduction of structural micro-anomalies in such devices and targeted reduction or elimination of the propensity for occlusive deposits to form therein, whereby properties of selective adherence of particular cell types are derived.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. is a cross-sectional model of a 1 mm diameter blood vessel;

FIG. 2. is a graph that illustrates the velocity field for the model in FIG. 1; arrows depict the velocity direction and magnitude, with the first set of vectors between −4 and −3.6 mm scaled to 20 cm/s velocity;

FIG. 3 is a graph that illustrates a depression showing contours of horizontal velocity. This velocity is zero at the wall; contours are spaced at intervals of 2.5mm/s with a maximum of 2 cm/s;

FIG. 4A is a graph that illustrates the horizontal velocities in the vicinity of the indentation.

FIG. 4B is a chart that illustrates the x-velocity as a function of the vertical (y) coordinate along each of these vertical slices;

FIG. 5 is a chart that illustrates fluid flow in a channel with periodic protuberances;

FIG. 6 is a schematic drawing of a colloidal particle (602) adjacent to a vessel wall (603) that is being impinged upon by a flow of fluid (601);

FIG. 7A is a chart that illustrates horizontal velocity profiles inside and beyond the indentation.

FIG. 7B is a graph that illustrates the velocity profiles set forth in FIG. 7A.

DETAILED DESCRIPTION OF THE INVENTION

The invention is applicable to any implantable device wherein it is desirable to provide surface modification to modify tissue adherence properties thereof. In a preferred, albeit non-limiting embodiment of the invention, an uncoated metal stent manufactured in accordance with known art is immersed in an aqueous colloidal suspension of abrasive particles, which particles may be defined as nano-abrasive particles, whose sizes are substantially less than 1 μm, preferably less than 100 nm, and ideally between 5 and 50 nm. Illustrative, albeit non-limiting examples of nano-abrasive particles are inorganic oxides such as Al₂O₃, SiO₂, CeO₂, and ZrO₂, and nano-diamonds, such as those available from NanoBlox, Inc., manufactured in accordance with U.S. Pat. Nos. 5,916,955 and 5,861,349, the contents of which are herein incorporated by reference. Illustrative, albeit non-limiting examples of micro-abrasive particles include inorganic oxides, crushed glass, glass beads, plastic media, silicon carbide, sodium bicarbonate, walnut shells, and the like, having particle sizes within the range of about 10 μm to 250 μm. A vibratory fluidized bed is formed wherein the suspension is excited by ultrasonic agitation at an amplitude and for a duration that is empirically determined to produce a particularly desired surface texture, e.g. a surface texture that is featureless on the spatial scales between 10 nm and 10 μm. In the case of a nano-abrasively polished stent, additional surface finishing can subsequently be accomplished by application of a thin film of less than 1 μm, preferably less than 100 nm, and ideally between 5 and 50 nm, of a material whose chemical composition lacks the capacity to form hydrogen bonds with biological colloids, illustrated by the noble metals Pd, Pt, Au, and organic polymers that lack accessible electronegative substituents such as N, O, and S provided that they maintain a smooth surface texture on the length scale of the colloidal particles. Alternatively, the polishing step may follow the coating step to produce a surface that is both featureless on the aforesaid length scales and unable to form hydrogen bonds.

The coating may be applied by electrolytic or electroless plating, vacuum sputtering, metalorganic chemical vapor deposition (MOCVD), plasma enhanced chemical vapor deposition, or other methods known to those practiced in the art of metal finishing.

One aspect of the preferred embodiment recognizes that thinner coatings are more likely to be plastically deformable (i.e. malleable) when the stent is deployed, so that the thinnest possible layer that is consistent with impeding hydrogen bonding is preferred.

Another aspect of the invention is that the coating is only critical on the surfaces that are exposed to fluid flow. Therefore a pharmaceutical agent may be applied to surfaces that are not impinged upon by fluid flow after the polishing and plating of the remaining surfaces. For example, a stent with cylindrical symmetry will, when deployed, have its outer surface in contact with the vessel endothelium. This surface may be coated with stenosis inhibiting drugs or the like, while the internal surfaces that contact the flowing blood are polished and finished according to the present invention.

It may be desirable to only target certain surfaces for texture modification, or to provide differentials in texture or surface characteristics. Such targeting will be effective in order to form areas of the device which have selective tissue adherence, or to impart selective structural properties to certain areas of the implant. It is within the purview of the instant invention to therefore utilize modifications to the sizes and types of micro and/or nano abrasive particles which are utilized, either singly or in a particularly desirable combination, in order to achieve the desired selectively targeted properties.

The method of the present invention may reduce the number and severity of microfractures on the device's surface. To the extent that brittle fracture is initiated by these surface defects the present invention reduces device failure under the stresses and strains that occur during deployment and under biomechanical processes.

In the preferred embodiment, the stent or other implantable device is polished in vitro prior to implantation.

Although application of the invention to vascular stents has been described in the preferred embodiment, the same principles apply to other implantable medical devices used in both the vascular and non-vascular systems, such as implantable artificial organs or parts thereof, e.g. artificial hearts, and heart valves, and implantable joint structures such as hip, knee, or shoulder joints, and implantable dental devices. These may further include metallic devices such as, Inferior Vena Cava Filters, Cardiac Pacemakers, artificial cardiac valves, artificial venous valves, vascular ports and the like. Additionally, the invention may be applied to non-metal medical implantable devices such as venous catheters, port catheters, biliary catheters, urinary catheters, drainage catheters and the like.

Now referring to FIG. 1, a model cross-section of a fluid vessel such as an artery, vein, bile duct, lymphatic vessel, renal duct, or the like is illustrated. Fluid enters at 101 and, in the model, experiences a slip boundary condition until it reaches the wall at 102, where the no-slip boundary condition on the Navier-Stokes fluid equations is applied. This generates velocity shear near the wall, with a parabolic velocity profile developing thereafter. The flow develops for 3 vessel diameters, where a surface depression 20 μm deep and 100 μm wide (104) is encountered. A symmetric boundary condition is applied at the centerline (103). The axis of symmetry is at the upper edge 103 of the drawing. A rectangular indentation whose size is commensurate with an epithelial cell (20 μm deep ×100 μm long) is included at 104.

Solution of the Navier-Stokes fluid equations results in velocity profiles for the flow in the vessel as shown in FIG. 2. A non-limiting embodiment illustrates peak velocity at the centerline is 30 cm/s, with a standard Blausius profile to the smooth section of the wall.

With reference to FIG. 3, an expanded view of the calculation showing contours of horizontal x-velocity in the vicinity of the indentation is shown. The dynamic pressure exerted on a particle suspended in the fluid is the product of the fluid density and the x-velocity. The horizontal force is the product of the pressure and the cross-sectional area of the particle. The importance of this force can be better understood with reference to FIGS. 4A & 4B.

FIGS. 4A and 4B show the horizontal or x-velocity both within and beyond the indentation. The locations of velocities within (401-405) and beyond (406) the depression are indicated in FIG. 4A. FIG. 4B displays the x-velocity as a function of the vertical (y) coordinate along each of these vertical slices. The average x-velocity within 20 μm of the wall outside of the indentation is 1.24 cm/s. The average x-velocities within 20 μm of the wall within the indentation at locations 401,402,403,404, and 405 are 0.12, 0.25, 0.42, 0.44, and 0.28 cm/s, respectively. In other words, the horizontal drag force on a particle within the indentation is reduced from what is experienced at the normal wall by a factor of 3 to 10 in this example.

Now referring to FIG. 5, results from a second exemplar fluid dynamical calculation are displayed, where a periodic undulation in the surface reveals regions where the fluid velocity is diminished (502) and streamlines (501) reveal that corresponding drag forces are reduced. The protuberances have a modulation depth of 20 μm and a period of 20 μm. The length of the simulated region is 130 μm, and the region within 50 μm of the wall is displayed. Velocity vectors (503) and streamlines (501) illustrate the stagnation of flow inside the depressions (502). The length scale of the vector (503) corresponds to a velocity of 3 mm/s.

The second facet of the present invention can be understood with reference to FIG. 6. A colloidal particle (602) flowing in the biological fluid is shown schematically adjacent to a boundary of the implantable device (603). As described previously, fluid dynamical drag caused by momentum transfer from the moving fluid (601) results in a force whose direction and magnitude are indicated by the vector (604). At the same time, chemical and physical interactions between the particle (602) and surface (603) from electrostatic attraction, hydrogen bonding, dispersion (or van der Waals) interactions, or other forms of chemical binding lead to an adhesive interaction indicated schematically by the force vector (605). If the shear force (604) is much larger than the adhesive force then the laws of mechanics will preclude permanent binding of the particle to the wall. Conversely, if the strength of the adhesive force (605) is adequate to prevent shear in the presence of drag force (601) then the particle will remain adhered to the surface.

Now referring to FIGS. 7A & 7B, horizontal velocity profiles inside (701-705) and beyond (706) the indentation is shown. FIG. 7B displays the x-velocity as a function of the vertical (y) coordinate along each of these vertical slices. The location of the positions corresponding to velocities in FIG. 7B are labeled in FIG. 7A.

Prior art stents are made from alloys that include oxidized states of metals such as iron, titanium, and the like. Oxides at the surface of these stents are able to form hydrogen bonds with colloidal particles that have hydroxyl functionalities on their surface, a result which is generally true of these biomolecules to an extent that depends in detail on their chemical composition and conformation in the suspension. The second aspect of the present invention recognizes that certain metals such as platinum, palladium, and gold do not form stable oxides. Therefore coating of the stent with a thin layer of one of these metals by electrodeposition, sputtering, metal-organic chemical vapor deposition, plasma spraying, or the like will prevent hydrogen bonding of colloidal particles, thereby reducing the magnitude of the adhesive force (605). An alternative embodiment of the invention would provide a hydrophobic coating such as a flexible fluoropolymer to preclude hydrogen bonding by colloidal particles.

Polishing of the implant surface, particularly the part of the surface that is in contact with flowing biological fluids imparts properties of selective tissue adherence, and can be accomplished by a variety of means familiar to those practiced in the art of surface finishing. In a preferred embodiment, a stainless steel or nitinol stent is immersed in and subjected to, a moving colloidal suspension containing micro and/or nano-abrasive particles. These particles are chosen to have a size, shape, and hardness effective to produce a surface finish that is smooth at the spatial scale corresponding to the size of colloidal particles in the biological fluid. For example, endothelial cells which may adhere to a stent and lead to occlusion are typically disk shaped with lateral dimensions of 10 μm and thickness of 1-2 μm. Leukocytes, neutrophils, and granulocytes have diameters in the 10-15 μm range.

TABLE I
Typical dimensions of colloidal particles in vivo
Endothelial cell               1 μm thick, 10 μm diameter
Basophil                       5–7 μm
Monocyte                       12–20 μm
Lymphocyte                     5–12 μm
Red Blood Cells                2 μm thick, 7 μm diameter
Fibrinogen/Fibrin              90 nm diameter, μm in length
Factor VIII (clotting protein) 4 × 6 nm to 8 × 12 nm
Low density Lipoprotein        10–20 nm diameter
Platelets                      1–4 μm diameter

It is to be understood that while a certain form of the invention is illustrated, it is not to be limited to the specific form or arrangement herein described and shown. It will be apparent to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is shown and described in the specification and drawings/figures. One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objectives and obtain the ends and advantages mentioned, as well as those inherent therein. The embodiments, methods, procedures and techniques described herein are presently representative of the preferred embodiments, are intended to be exemplary and are not intended as limitations on the scope. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention and are defined by the scope of the appended claims. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the art are intended to be within the scope of the following claims.

Claims

1. A device implanted in a flowing biological fluid characterized by the drag force on colloidal particles in the fluid exceeds the adhesive force between the particles and the device.

2. An implantable device having a surface which is essentially featureless on a spatial scale commensurate of the colloidal particles flowing within or around the device.

3. The implantable device according to claim 2 with a surface which is featureless and which includes a surface coating which renders said surface essentially inert to hydrogen bonding of flowing colloidal material.

4. Method for producing a device having a surface which is essentially featureless on a spatial scale conimensurate of the colloidal particles flowing within or around the device comprising: immersing said device in a fluid with abrasive particles whose size is chosen to produce a surface finish on a length scale to inhibit adhesion of circulating colloidal particles.

5. A method to produce a no-hydrogen bond surface comprising application to said surface of a noble metal deposition and O2 free polymer.

6. A method to produce a non-adhesive smooth surface comprising smoothing the surface to a length scale commensurate with the circulating colloidal particles and subsequently applying a coating to produce a hydrogen bonding free surface.

7. A method to produce a non-adhesive smooth surface comprising applying a surface coating to produce a hydrogen bonding free surface and subsequently polishing the surface to a length scale effective to inhibit adhesion of circulating colloidal particles.

8. The device of any one of claim 1, or claim 2 or claim 3 selected from a vascular stent, filter or other implantable metal endovascular device.

9. The device of any one of claims 1 or 2 or 3 wherein said coating is selected from a group of nobel metals such as gold, palladium and platinum, or an O2 polymer.