Overview of Stents

Restenosis represents re-narrowing or blockage of an artery at the site of a previous angioplasty or stent procedure. A stent is typically a scaffold device fabricated from metals, alloys, or polymers having the surface treated or covered with materials that reduce the rejection mechanisms. It is usually delivered into the body lumen in reduced size form using a catheter. The stent is expanded and released from the catheter, so that it engages the lumen wall when it reaches the desired location. Coronary artery stents coated with a variety of pharmacologic agents are used to prevent restenosis. Unlike earlier pharmacologic trials in which systemic agents were administered during/after percutaneous treatment to prevent restenosis, drug-eluting stents allow controlled local release of a drug directly to the injured endothelium, avoiding systemic side effects. The stents are coated with a polymer that acts as a drug reservoir and allows for the gradual elution of the drug over time.

A wide variety of therapeutic agents that can effectively inhibit inflammation and smooth-muscle cell growth are available, but administration of these agents systemically may lead to adverse effects. These therapeutic agents typically fall in one of the following groups: antiproliferative agents (Sirolimus and Paclitaxel – drugs used in the two FDA approved drug coated stents), immunomodulators, antithrombotics, and growth factor inhibitors. To reduce the restenosis occurrence and to limit the side effects, the therapeutic agents are delivered locally by coating the stents with these agents. In most cases the therapeutic agent is a drug that is typically coated and attached to the stent or coated onto the stent as a drug-polymer combination. The composition of the drug-polymer solution that is used to coat stents is selected not only to enhance reservoir characteristics, but also to control the release of the drug (beneficial agent).

Current Manufacturing Methods

The main processes used to apply the drug or drug/polymer solutions to the stents are based on one of the following methods: dipping, ultrasonic spray coating, painting (air brush), and deposition along the struts using syringes. Some techniques combine one of the deposition methods above with a continuous stent rotation to eliminate the excess fluid. However, these conventional drug loading technologies are associated with problems, such as variability in drug concentration from device to device, inability to tightly control and maintain drug concentration, inability to vary drug distribution in a controlled and predetermined manner for a more desirable drug loading profile, frequent webbing between the struts, and inability to control the local area density of the drug. Another issue is cost related as the methods listed above are all very wastefull and lead to a significant cost increase, as the active compounds are very expensive.

Advantages of Ink-Jet Coating for Stent Manufacturing

The main advantage of an ink-jet based coating system is the excellent process control. The drug and polymer solutions can be deposited very precisely (location and amount) onto the stent and, if desired, only on the outer strut surfaces. Some advantages of the ink-jet coating system derived from its data driven nature and precise control are:

1. Capability of producing very complex coatings: These coatings could be multilayer and use different drug and polymer solutions in each layer. The local density (or thickness) of the polymer and drug can be varied to achieve different release kinetics at different locations along the stent.
2. Deposition onto the struts’ outer surface only: This eliminates the polymeric bridges between the struts that are very dangerous as they can break off and enter the blood stream. Studies on the bidirectional (abluminal and luminal) release showed no improvement compared to abluminal release only, thus the deposition on the outer surface only does not decrease the beneficial effect of the drug.
3. Flexible fabrication system: Ink-jet is data driven thus the system allows very easy switching from a stent model to another just by loading the data for the new stent’s print pattern.

The ink-jet based coating allows generation of complex coatings using multiple different drugs or drug concentrations, or different polymers. These different solutions can be deposited in layers to adjust the drug release.

Prototype Stent Coating System and Initial Results

Prototype Stent Coating System

As part of a Phase I NIH grant, MicroFab built, using piezoelectric ink-jet technology, a prototype system for coating cardiovascular stents. This system, shown below, was used to: test solutions and print on the mock-up stents that were fabricated for this project. The preliminary results follow.

Ink-jet based coating system providing coordinated motion to the stent.

Detail of the rotational stage and the mandrel used to hold the stent.

Solution Development

The drug selected for this experiment was paclitaxel. Ink-jetable solutions using Paclitaxel and PC-polymer were developed and evaluated for dispensing characteristics. The PC polymer was provided by Biocompatibles and was selected for this study because it is a polymer used for coating of medical components and has been used lately to coat drug eluting stents. The photo to the right shows droplets made with a solution with 10mg/ml Paclitaxel and 4mg/ml PC polymer at a rate of 240Hz.

Mock-up Stent

MicroFab has fabricated mock-up stents having dimensions characteristics to actual stents. These mock-up stents with diamond shaped cells were used in the printing/coating excercises.

Stainless steel mock-up stent used in the system evaluation.

Mock-up stent under the ink-jet microdispenser.

Stent Printing/Coating

The mock-up stents were coated by moving the stent in a coordinated fashion under the ink-jet microdispenser. Printing was done "on-the-fly" by moving the stent continuously (rotation and axial movement) and generating drops based on the desired spot to spot spacing. The figure to the right was captured during printing. The fluid that was deposited just on the struts can be barely observed as a protrusion on the top strut surface to the right of the ink-jet microdispenser.

Movies (axial and lateral views) illustrating the coating process described above can be found here. Another movie illustrates the use of ink-jet in filling the wells on a cardiovascular stent.

Coated Stents

To visualize the deposition of the drug and polymer solution onto the stent struts a fluorescent dye was added.

Stent coated with a Paclitaxel - polymer solution. Coumarin was added for visualization.

To illustrate the capability of the ink-jet system in the local delivery of the drug and on the coating of multiple solutions a stent was coated on all its struts with a drug polymer solution containing Coumarin. The same stent was coated only on the struts wrapping towards the right using a solution containing Rhodamine Red, another fluorescent dye that is excited at a different wavelength. Pictures of the stent taken at the wavelengths corresponding to the two dyes were overlapped to produce the image below. The image shows that ink-jet can target localized areas. For the stent in the picture the whole length of the stent was covered with the "red drug", but it is easy to reprogram the print recipe to coat only the desired struts segments. Through the ability to dispense individual drops at the desired locations, ink-jet is capable of producing drug coated stents that have different amount of drugs per unit area along the length (e.g. more drug per unit area towards the end of the stent). This digital control, coupled with the availability of multiple solutions for printing, gives "infinite" degrees of freedom for the production of next generation stents.

Stent coated with two Paclitaxel - polymer solutions. The fluorescent dyes added to the two solutions for visualization were Coumarin and Rhodamine. The Coumarin solution was used to coat all struts while the the Rhodamine solution was used to coat only the right turning struts.

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