Aging and Stress within Medical Coatings

(by J.J.G. Bos)


Here follow some notes regarding aging of medical coatings, and related stress and strain forces. The term strain refers to pull forces, e.g. in the plane of the coating, or in the interfacial area between coating and device. The term stress refers to push forces, again in the plane of the coating, or perpendicular. Shear forces are drag forces along the top and bottom of the coating layer.

Also refer to the SciNote on Hydrogel Coatings.

Forces in the plane of the coating generally also induce pull-forces across the interface between coating and device. These forces may be so high that the coating dislodges from the device. Ideally, interfacial attraction-forces are significantly higher than the pull-forces caused by the bulk of the coating, so that no or little damage is done. The forces in the coating may give rise to cracking of the coating, which in itself causes localized strain-relief. But the question is what happened prior to cracking (dislodging?), and is the strain-relief sufficient to prevent future interfacial damage?

Stress-cracking may result in particle generation. Loose chips of coating may enter the blood-stream of a patient and cause blockage of small arteries or veins, and there is the risk of thrombus formation around the chipped-off coating particles. Stress-cracking may also result in increased drug release if it concerns a drug-loaded hydrogel. However, effects due to stress-cracking are generally not that enormous, but cracking is often an indicator for coating dislodgement. The latter not only gives rise to sometimes massive production of (often large!) coating particles but also results in loss of device functionality. One might say that there is a battle between forces in the coating and between the coating and the underlying surface. This may eventually result in break-down of functionality and give rise to increased patient risk. The following paragraphs address (1) causes of stress and strain in coatings, (2) detection, (3) long term effects (aging), and (4) methods to artifically accelerate aging of coatings and devices.

There are several causes of stress or strain forces in coatings, for example:

• Shrinkage due to drying
• Shrinkage due to cross-linking and crystallization-like regrouping (setting)
• Temperature-induced shrinkage or expansion
• Expansion due to re-hydration
• Shrinkage or expansion of the coated device as result of temperature change
• Shrinkage or expansion of the coated device as result of mechanical forces (pull, push, bending)
• Shear, e.g. between packaging and coating, or shear during device application
• Oxidation-induced expansion

Shrinkage due to drying and setting generally happens shortly after application of the coating to the device, due to loss of solvent (drying). The thicker the coating, the greater the forces within the coating and the higher the chance of stress-cracking or dislodgement from the device. Stress-cracking is a force-relief mechanism. Temperature-induced stress and strain, as well as mechanically induced forces, generally affect the coating during transportation (e.g. aeroplane). These effects come on top of the forces that were already induced by drying and setting of the coating. Some coatings may give way much easier after transportation than before. Some hydrogel coatings adhere extremely well while dry, but eventually give way when re-hydrated upon use. Internal forces then already caused chain scission and interfacial breakdown during transportation and storage, but adhesion is maintained by the hydrophilic groups. However, these groups will start gathering water molecules around them upon re-hydration, thus letting go of each other: The coating weakens and may even completely fall apart. Depressing....

Most manufacturers of coatings are well aware of these effects, and engineer stress-relief mechanisms. Think of addition of molecules that make the coating more flexible. Another solution that I have even seen concerned a coating that litterally cracked up into thousands of small coating-islands. These islands were too small to build up any significant amount of stress compared to the interfacial forces. Sometimes it suffices to keep the coating thin and homogeneous (for optimal force distribution). It will be of no suprise that most difficulties are encountered with hydrogel coating-design and little or no difficulty with molecular grafts, silicone gels (that do not dehydrate), and flexible polymer layers (e.g. polyethylene lining).

Illustration of stess-induced dislodgement of a hydrogel coating inside a catheter (picture left).
No dislodgement will occur when the hydrogel is applied to the outer surface (picture right).
Some resulting forces are illustrated by the arrows.

There exists a variety of methods to detect stress and strain in coating layers. Indirect methods address investigation of the presence of cracks and local dislodgement. Direct methods involve force measurement. Examples are:

• Mechanical wear testing, e.g. repeated bending or stretching of the substrate and see how the coating responds
• Microscopy, especially scanning electron microscopy (SEM), searching for cracks
• Tape peel tests - trying to remove the coating with help of adhesive tape
• Scraping - the scraping profile (e.g. sharp edged versus a soft edged profile) generally reveals the state of cracking and adhesion
• Coating-on-thin-film test. The thin film will bend because of the forces within the coating and across the interface
• In-vitro simulation of device application, combined with visual inspection. Think of particulate matter testing (e.g. USP-788)

Adhesion of polyethylene lining can be evaluated with help of a simple peel test, utilizing a pull bench. Many coatings are hard to see and thus require some sort of staining method. Congo Red is often used for hydrogel coatings, but it tends to increase coating stress. Refer to the note on staining of hydrogels for illustration of this effect. Toluidine blue O is preferred for heparin-containing coatings.

The bottom line of all these tests is to assess the risk (chance and impact) of dislodgement of the coating from the device during clinical application. The biggest difficulty is found in change of performance over time: Aging. Please read on....

Illustration of strain-induced bending of a thin-film. Some resulting forces are shown.

Basic aging mechanisms are, for example:

• Chain scission - molecular break-up in the bulk of the coating
• Cross-linking by slow reactions (e.g. oxidizing or similar effects, sometimes light-activated)
• Re-alignment of molecules near the interface, either improving or undermining adhesion
• Slow hydration (humidity) - this can greatly affect biodegradable coatings

The underlying causes were listed two paragraphs ago. Especially setting of the coating (molecular re-alignment) and temperature-induced stretching or shrinking of either the coating or the device are ongoing effects. They may slowly deteriorate the coating or its adhesion to the medical device. The rate of aging thus also depends on the storage method and environment. Storage near fluorescent tubes is not a good idea! Humidity is generally not appreciated by biodegradable coatings, whereas some hydrogel coatings remain compliant (read: tough) provided the air is not too dry. Places with lots of mechanical vibration or temperature fluctuation are hardly ever appreciated by medical devices, and in the end something must give. The aging effects are almost never reversible.

The basics of artificial acceleration of aging related to medical coatings and medical devices are found in doing everything you shouldn't do according to the previous paragraph. Think of running temperature and humidity cycles on the sterilized finished product. Repeated bending or elastic stetching of the coated product will also work. But how much should the coating be abused before one can tell that it passed the accelerated aging test? The answer to that is not always simple, since it strongly depends on the functionality of the coating and patient risk. The general approach must include aspects of the real-time life cycle of the product:

• Sterilization
• Transportation simulation (transport test)
• Storage simulation
• Application simulation (i.e. simulation of clinical use).

It is best to evaluate functionality and safety of the coating after each of these four steps. The first step is easiest to implement: Sterilization is just the real thing - no simulation. The second step can also be the real thing. I remember sending some samples around the world just for transportation testing! Simulation is not too hard either: Combine some temperature and humidity cycles with prolonged mechanical vibration - a few days should suffice. Storage simulation is where you want to gain time. One can think of accelerating the day and night cycle for temperature and add some accelerated seasonal humidity changes to it. Think of 1100 temperature cycles of 2.4 hours (1.2 hours high temperature, 1.2 hours low) combined with 3 humidity cycles of 1.2 months (0.6 months dry and 0.6 months humid) in order to accelerate the aging by factor 10. This whole cycle thus lasts 3.6 months, representing 3 years of real-time aging. Higher acceleration is possible, so long as the aspects of coating and device aging are well understood. Accelerated aging must completely relate to real-time aging and that may require some insight and testing for proof of principle. The weak aspects and definitely the risk apects of the coating form a good starting point. Note that the ISO-10993 series allows thermal acceleration, according to the Arrhenius or van 't Hoff rule for chemical reaction speeds. It is up to the engineer, however, to validate the accelerated aging process in the light of product-risk assessment.