Medical Device Link.

MATERIALS

Regulatory demands

The United States Food and Drug Administration (FDA) recommends that device manufacturers describe in detail parameters such as the thickness of individual coating layers, coating uniformity, cohesive and adhesive properties and the overall coating integrity and durability when tested under clinically relevant conditions.² Each of these areas is explored in detail in this article and the effects of surface conditions are considered.

Surface analysis

The coating surface forms the “biointerface” of the device and the characterisation of the surface in terms of drug distribution and contaminants is important for understanding performance. It is not the objective of this article to discuss biocompatibility in depth, however, it is necessary to point out that surface analysis and in vitro testing of microbial contamination and encrustation of implantable devices should be assessed. This is particularly the case for coated devices that are to be implanted into areas potentially containing infectious agents, for example, urinary biomaterials.³

Coating thickness and uniformity analysis

Table I: Technologies for measuring coating thickness on medical devices. (click image to enlarge)

An important part of device coating characterisation is determining the coating thickness and uniformity. The coating thickness of the drug containing layer can affect the drug release characteristics. The coating can also prevent or reduce the corrosion potential of metallic substrates if complete coverage with a sufficiently thick and compliant coating can be ensured. Thickness variations can impair the integrity of the coating and result in the release of particulates or localised delamination, which poses a serious safety risk. This can be particularly acute in areas that experience high levels of load or deformation during device delivery, implantation and post-implantation.

Most techniques to determine coating thickness can be classified into destructive and nondestructive methods. Table I presents a selection of technologies for measuring polymer based coating thickness together with their relative advantages and disadvantages. The most appropriate technology to use depends on several factors, for example, required resolution, coating material, coating thickness, substrate geometry and cost. In general, a nondestructive test method is preferred for the following reasons:

• fewer samples need to be tested because multiple measurements can be performed on the same sample and it is typically less burdensome to validate a nondestructive test method
• result interpretation is easier because the coating integrity is maintained throughout the test.

In this context, spectral reflectometry is a relatively cheap, easy to use and versatile technology that can accurately determine thickness. This proven technology has existed for a long time and is commonly used to measure thin films on wafers in the semiconductor industry. More information on the principles and application of spectral reflectometry is described in Figures 1 and 2.

Figure 1: Light interaction on material boundary layers. (click image to enlarge)

Some commercially available spectral reflectance systems use fibre optics with focusing lenses for small spot size beam delivery. Others can be directly attached to the C-mount of a standard optical microscope. Depending on the magnification of the objective lens, the spot size can be reduced down to a few microns, which makes this technology suitable for reliably measuring the coating thickness on extremely small and complex geometries often found in medical devices.⁴ If the microscope is equipped with a charged coupled device camera, the operator can observe the specimen on a monitor to pinpoint the measurement. With data acquisition rates in the kHz range, this type of measurement system can be combined with a motorised translation stage and sample holder. A coating metrology system of this design can simultaneously analyse multiple coating layers on complex geometries to assess the coating quality (uniformity and thickness) of the final product.

Coating adhesion/cohesion

Figure 2: Reflectance spectrum of a two layer polymer coating on a medical device (left) and the calculated coating thickness of each individual layer (right). (click image to enlarge)

To ensure that the functional coating on a medical device maintains its integrity throughout the life of the product, the adhesive and cohesive strength of the coating needs to be sufficiently high. The device coating must withstand a certain amount of stress and strain without structural failures such as cracks, flaking or delamination. In this context, coating adhesion refers to the strength of attachment of the coating to its substrate and between individual coating layers. Coating cohesion describes the bond strength within a coating layer.

Standardised ISO and ASTM test methods exist, for example, ISO 2409, Cross Cut Adhesion Test. However, they tend to be limited to harder coatings such as paints and adhesives and are less applicable to the softer and more compliant polymer coatings typically found on active coated medical devices. These tests also tend not to be suitable for complex geometries, but instead focus on larger, flat surfaces. Even though flat coupon samples can be made out of the same material as the device (and can potentially be treated in a similar way), it can be extremely difficult to demonstrate equivalence to the real product. Most coating technologies will demonstrate performance related to their geometries or the coupons will not be compatible with the actual production equipment.

Figure 3 : Optical image of a typical teardrop-shaped scratch on a soft coating with some characteristic failure points identified. (click image to enlarge)

One way of assessing the adhesive/cohesive properties of a soft coating is to use Micro/Nano Scratch Testing. A controlled scratch is generated by dragging a probe tip with precise geometry across the coating surface at a controlled rate and under constant, progressive or incremental load (Figure 3). The force normal to the coating surface results in a tangential (frictional) force component, which is continuously monitored with MicroNewton resolution. The penetration depth and sample displacement can also be recorded.

However, it is challenging to express the adhesion and cohesion properties quantitatively, especially for a multilayer coating. The acquired data such as critical loads and penetration depth depend on several test-related parameters, including, probe tip geometry and scratch rate. There are measurement errors, for example, material build-up around the probe tip, sample-to-tip alignment during scratching, sample positioning and elastic coating deformations, which are difficult to control and quantify. Even in the paint industry, which is probably most advanced in this field, the quantitative characterisation of adhesive and cohesive material properties is still regarded as somewhat of a “black art.” The test design and experimental protocol need to be sound and the test performance thoroughly understood to avoid the misinterpretation of results.

Coating integrity and durability

As part of coating performance and safety assessment, manufacturers need to analyse the integrity of the coating on finished products when tested under clinically relevant conditions. Although finite element analysis models are commonly used to identify areas of high stress and strain and can help to predict certain failure modes, polymer based coatings are generally nonstructural and should be assessed with physical test methods. These data are invaluable when trying to predict potential failure modes during in vivo use and to ensure that the coating performs as specified.

In principal there are two different test modalities: acute and chronic. In this context acute refers to the initial implantation of a device and includes device preparation, delivery to the target site and implantation. Chronic refers to a loss of coating integrity after initial implantation and throughout the lifetime of the implant.

To assess acute coating failures, finished products must be prepared as described in the instructions for use. This should be followed by a simulated delivery and implantation procedure in an in vitro model that accurately mimics in vivo physiological and anatomic conditions. To reliably detect coating failures such as cracking or delamination, the devices must be thoroughly examined pre- and post-testing with, for example, optical and/or scanning electron microscopy. The FDA recommends performing all of these tests under worst case conditions. For example, a drug eluting stent (DES) should be delivered through a simulated vessel structure with severe tortuosity and should be expanded to its maximum labelled diameter before analysing the coating.

The characterisation of chronic coating integrity is probably one of the most challenging and time consuming test activities that regulators expect. The coated device is fatigued in a dynamic environment that closely simulates the range of motions and cyclic loads expected in vivo. There are some commercially available durability test systems on the market. However, most of the instrumentation is tailored towards DESs and is not applicable to other medical devices. Even for stents, test systems often need to be customised because motions and cyclic loading in, for example, the femoral artery can be complex. If bespoke instrumentation must be developed, then it is essential to involve experienced physicians during the design and build phase to ensure the clinical relevance of the system and therefore the validity of the test method.

Orthopaedic and intravascular devices are typically tested to simulate a 10 year life. For an orthopaedic device this translates into 5–10 million load cycles; for an intravascular product such as a stent a 10 year life is simulated by 400 million fatigue cycles. The durability test can be accelerated by cycling at a higher frequency providing it can be proved that the increased speed does not affect the way the device would interact with its environment when tested in real time (for example, micro motions between surface and surrounding tissue and tissue compliance). In orthopaedic implants, accelerated wear testing can liberate excessive heat, which damages the lubricating proteins and invalidates the test results. Typically, accelerated durability or fatigue tests run for approximately 2–3 months. Testing should include worst case device configurations and, in the case of the DES, the FDA recommends testing configurations that represent known “off label usage” such as overlapping stents.

The level of damage to the coating as a result of the cyclic fatiguing can also be quantified, often simply by detailed examination of specimen pre- and post-testing. To better understand the device performance over time the analysis should also include periodic sampling or preferably real-time and in-situ measurements. This allows manufacturers to detect and characterise particulate matter that is generated from damage to the coating.

Seek out existing expertise

This article has described some of the testing challenges that must be met when developing a functional coated product. It has also suggested approaches to verification of the finished coating on the device in line with regulatory expectations. As a final remark it is important to emphasise that it is not always necessary for medical device coating developers to start from scratch. It is advised that companies seek out and build on the expertise that already exists in other sectors such as the pharmaceutical formulation, semiconductor and the paint industries.

Angus Forster, Thomas Neudeck and Stephen Blatcher are all Principal Consultants in PA’s Technology and Healthcare Group at PA Consulting Group, Cambridge Technology Centre, Melbourn SG8 6DP, UK, tel. +44 1763 267 492, e-mail: innovation@paconsulting.com, www.paconsulting.com