Stents are generally cylindrical shaped devices that are radially expandable to hold open a segment of a blood vessel or other anatomical lumen after implantation into the body lumen. Stents have been developed with coatings to deliver drugs or other therapeutic agents.
Stents are used in conjunction with balloon catheters in a variety of medical therapeutic applications including intravascular angioplasty. For example, a balloon catheter device is inflated during PTCA (percutaneous transluminal coronary angioplasty) to dilate a stenotic blood vessel. The stenosis may be the result of a lesion such as a plaque or thrombus. After inflation, the pressurized balloon exerts a compressive force on the lesion thereby increasing the inner diameter of the affected vessel. The increased interior vessel diameter facilitates improved blood flow. Soon after the procedure, however, a significant proportion of treated vessels re-narrow.
To prevent restenosis, short flexible cylinders, or stents, constructed of metal or various polymers are implanted within the vessel to maintain lumen size. The stents acts as a scaffold to support the lumen in an open position. Various configurations of stents include a cylindrical tube defined by a mesh, interconnected stents or like segments. Some exemplary stents are disclosed in U.S. Pat. No. 5,292,331 to Boneau, U.S. Pat. No. 6,090,127 to Globerman, U.S. Pat. No. 5,133,732 to Wiktor, U.S. Pat. No. 4,739,762 to Palmaz and U.S. Pat. No. 5,421,955 to Lau. Balloon-expandable stents are mounted on a collapsed balloon at a diameter smaller than when the stents are deployed. Stents can also be self-expanding, growing to a final diameter when deployed without mechanical assistance from a balloon or like device.
Stents have been used with coatings to deliver drug or other therapy to the patient at the site of the stent, such as the interior wall of an artery or vessel. Typically, the coating forms a uniform radial layer over the stent elements with a fixed ratio of drug to polymer. Although many factors (such as the hydrophilicity, hydrophobilicity, and molecular size of the drug, and the hydrophilicity, hydrophobilicity, amorphous, crystallinity, morphology, glass transition temperature of the polymer matrix) affect the diffusion rate of the drug from the coating, the diffusion rate is generally proportional to the difference in drug concentration across the coating (ΔC). This causes problems with the dose of drug delivered with time. Initially, the drug concentration is high, so a large quantity of drug is released. This is called burst releasing and results in local tissue damage for certain drugs that are toxic in high doses. Later after implantation, the drug concentration is depleted and the ΔC become smaller and smaller, so little drug is released. This results in delivery of a less-than-effective dose. With a uniform radial drug coating, stent designer must choose between a stent which risks initial tissue damage and a stent which has a limited effective drug lifetime.
A uniform drug coating may not provide the most effective therapy over time. Immediately after stent implantation, inflammation and thrombosis occur due to the tissue trauma from the angioplasty and the presence of the stent. While the inflammation normally subsides after a few days, tissue growth may result in restenosis three to six months after stent implantation. A uniform, single drug coating is unable to treat both conditions. Anti-inflammatory drugs are desirable initially, but anti-proliferative drugs are required later.
There are also difficulties associated with manufacturing stents having multiple components or multiple layers. The coating is typically applied to the stent by dipping or spraying the stent with a liquid containing the drug or therapeutic agent dispersed in a polymer/solvent mixture. The liquid coating then dries to a solid uniform coating. Combinations of dipping and spraying can also be used.
Problems also arise during manufacture when the drugs, polymers, or solvents are incompatible. For example, one solvent may be suitable for a particular drug, but unsuitable for a particular polymer. The combination of a particular drug and a particular polymer may be incompatible and one or the other degrade when held in solution too long. Incompatibility results in ineffective drugs or defective coatings.
Manufacturing techniques producing multiple coating layers with varying characteristics have been developed, but such methods increase the time and expense of manufacturing. Separate steps are required to apply each coating layer, which must dry and have its surface prepared before the next layer is applied. In dip coating, several pots holding solutions with different drug/polymer ratios can be prepared. The stent is then dipped in each pot, starting with the solution of highest drug/polymer ratio and ending with the lowest to form a profile coating. In such a stepwise approach, however, each drug/polymer coat can be dissolved by subsequent dip process if similar solvent is used. Poor surface preparation and layer incompatibilities can cause voids and defects at the boundaries between coating layers.
It would be desirable to have a gradient coated stent and methods of making the same that would overcome the above disadvantages.