Medical Device Development’s quarterly dinner discussion took place at the Savoy Hotel in Limerick, where the hot topic of the evening was hydrophilic coatings. Keith Edwards, CEO of Biocoat, and Dr Tofail Syed from the University of Limerick led talks about advances in material science and the considerations to be made when selecting hydrophilic coverings for various medical devices.
On the evening of the 20 August 2014, medical device delegates from companies including Boston Scientific and Cook Medical sat down in the Savoy Hotel, Limerick, Republic of Ireland, for a three-course dinner and to discuss innovations in coatings science.
Leading the discussion after the starters were served was Keith Edwards, president and CEO of US-based coatings business Biocoat. Founded 23 years ago, the company provides solutions for the cardiovascular, neurovascular and peripheral vascular markets. It also has an ophthalmic market presence.
A keen traveller, it was clear Edwards enjoys meeting members of the medical device manufacturing community and hearing their coating challenges. "We pride ourselves as chemists, so if it’s out there, we can probably coat it," he revealed.
That bold statement was followed by an even bolder image as Edwards kicked off his presentation with a picture of a new funnel, a disruptive technological device that delivers relatively pain-free breast implants for female patients that have undergone mastectomies for cancer removal. Coatings are essential to the mechanism of this equipment.
"The funnel has a hydrophilic coating on it," Edwards explained. "And you squeeze it just like confectionery sugar [in a piping bag]. It squeezes a very large breast implant into a small orifice."
Hydrophilic coatings exhibit water-loving characteristics and participate in dynamic hydrogen bonding with surrounding water. Chemically, they rely on this surface interaction with water to provide an extremely lubricious surface. Lubricity describes the slipperiness of a surface, and can be defined by its coefficient of friction (CoF), or the ratio of the force of friction between two bodies and the force pressing them together. The lower the CoF, the more lubricious the surface. Other, more obvious applications for lubricious coatings include disposable medical devices such as catheters and guidewires, where the slippery surface treatment reduces the insertion force, allowing them to traverse the vasculature more smoothly. An additional benefit of such a coating when these devices are used is its potential to reduce thrombosis.
There are two significant technologies in biomedical device coatings: polyvinylpyrrolidone (PVP) and hyaluronic acid (HA). PVP is a well-studied stable platform with a similar performance to soap: it’s very slippery when wet, but in demanding applications there is a risk of degradation. HA coatings are something different entirely, with an interesting chemistry. They’re not lubricous when dry, but instantaneously hydrate when exposed to body fluids to form a hydrogel.
Some suitable coating substrates are polyesters, polyamides, polyethers and polyurethanes. But there are others that require additional plasma and surface treatment. That’s extremely important because the establishment of a strong bond is necessary for a coating to function, to have a low particle count and, perhaps most essentially, to stay in place. Edwards also revealed that his company is developing an advanced coating that might prove a low-cost alternative to other materials.
"Our goal (if you decide to bring coatings in-house) is to have one coating that works for everything, and we’ll work the chemistry around that," he said. "You don’t want to commingle coatings. You don’t want to have a process you need to modify significantly."
Primed and ready
Most systems involved in coating catheters or guide wires require the application of a primer layer or a base coat. This primer adheres to the substrate through mechanical adhesion and, depending on the type of substrate, there may be some covalent bonding in action too. Edwards referred to the company’s own base coat as essentially "a very flexible super glue". It’s designed to keep the coating on the substrate, but also to provide a chemical basis for the top coat to bond to.
For its coatings, Biocoat uses long-chain molecules of HA. When HA chain molecules are exposed to liquid, they trap water, and the resulting hydrogel is so flexible it can go through a very calcified artery and still remain very much intact, Edwards said.
Responding to a delegate who asked what should be their primary concern when looking for a coating today, Edwards explained that the most pressing question should be how much lubricity a medical device requires. "You want to look for the lowest coefficient you can get and how you can maintain that up to 30 cycles or more," he said.
"We have a Japanese firm that tested us out to 500 cycles," revealed Edwards. "Really, the number we do is your call because you’re the ones that know how much your device is getting used."
He went on to explain that the company performs several tests on the coatings including irritation, cytotoxicity, systemic toxicity and haemolysis.
Edwards also revealed that the FDA has become increasingly concerned with particulates in recent years. The association has pointed out that particulate matter can be generated from the breakdown of a device’s coating. If these particles enter the bloodstream during use, they increase the risk of an embolism. Thickness is important here too because if you choose a thicker coating, you run the greater risk of more particulates.
"When we visited with the FDA recently we had a very important dialogue," said Edwards. "They did ask extensively about particulates, and we test them. We have low particulates, but you can’t say you’re going to have low particulates if you’re testing a polyester rod but the coating’s going on a nylon rod. You have to test on all types of substrate."
When choosing a substrate, you need to examine the surface energy and the contact angle, so the chemistry of the surface will be adequate to have those strong bonds. Biocoat looks for unreacted monomers and plasticisers that might bloom to the surface in the form of colourants or materials specific to nylons and silicones.
"If you’ve got dye blooming to the surface, that’s going to cause weak boundary layers," Edwards added.
Medical device manufacturers then have to elucidate what sort of cure system to use. Engineers will discover significantly different manufacturing set-ups for a UV cure system compared with a heat one. If a company provides Biocoat with a substrate medical device, the surface will be prepared and cleaned. The base coat will be applied and then dried for around 20 minutes in an oven. When it’s out of the oven, a top coat is immediately applied and that’s where curing comes in.
Advantages to UV curing include a shorter timeframe. However, batch size can prove problematic. The number of devices a UV chamber can hold is pretty limited, typically around 10-20, whereas heat cure systems can accommodate batch sizes as big as your company’s drying oven will handle.
"If you’re looking for a cost comparison between UV and thermal, it’s very difficult to say there’s a big saving in one over the other," Edwards said. "However, what I can tell you is that there’s a difference in the chemistry."
Biocoat has found that a thermal cure of two hours produces extraordinary uniformity through the coating surface, whereas UV cure tends to give some degree of variability.
The coating itself is a dip process, Edwards explained, and the withdrawal speed is very important.
"The slower we withdraw, the thinner the coating is," he said. "[Devices are] going to stay in the humidity-controlled oven for about two hours. They’ll come out and then, as you can imagine, handling is a big issue. When they come out of that oven, they’re dry, but while they’re being brought into the oven they have to be kept separately as you don’t want the two wires touching each other."
A sample of the devices are then inspected. The parameters are the same for both the base coat and the top coat processes.
"There are three critical things: the withdrawal rate, the oven temperature and drying time. And typically, what we’ll do is make sure we test a few drying times," Edwards explained.
As delegates tucked into their main courses, Dr Tofail Syed took to the lectern to discuss the work he is conducting. Syed is a researcher and lecturer at the University of Limerick. He studied in his native Bangladesh before undertaking a PhD at the University of Limerick, where he has been based for the past 13 years.
His research group uses first principle and phenomenological modelling techniques to design nano and biomaterials with specific desired properties. They carry out synthesis and processing of carefully selected model systems and characterise them to determine the efficacy of the designed materials in providing the targeted physical property.
The group makes extensive use of the state-of-the-art modelling, synthesis and processing, and custom-made characterisation techniques available at the university. With a passion for turning scientific principles into innovations for device applications, the group has been granted three patents so far, with 31 in process. It has 23 projects in the pipeline and strong links with industry.
Key projects in development include a nanoscope that, among other applications, will allow the screening of patient cells for Alzheimer’s disease. The prototype developed will be easy to use and flexible, and allow direct imaging of the chemistry and the structure of very small features. The technique uses infrared radiation as a source of detection, but breaks away from its physical diffraction limit so that features as small as 70nm in lateral dimension can be seen, which is comparable to the size of a virus. The technique is also capable of seeing buried features without the need for destroying the surface of a cell or a material. The University of Limerick is leading the 11-member European Label-free Nanoscopy Using Infrared (LANIR) team, which is undertaking this research.
Tricks of the trade
As dessert was served, Edwards returned to the lectern to introduce delegates to the ‘pinch friction test’ – essentially a good measure of coating performance over time. Most device manufacturers have some form of this examination.
"If you ask an R&D engineer about the method, the answer will likely be: ‘That’s the way we’ve always done it’," revealed Edwards. "We have one client that uses sand paper, one client that uses water, and another that uses PBS [phosphate buffer saline solution]."
He presented data from Biocoat’s own pinch test. Typically, clients present the company with a new substrate and a device. Biocoat makes multiple coatings of that device, and put it in a pinch tester. The machine fixes the tube to be tested onto a mandrel, while a bath of PBS is placed below at 37°C. The tube is pushed down into the saline solution and pulled up again 30 times.
"Or if you tell us to do it 50 times, we will," Edwards pointed out.
He said the use of PBS was important "because if you’re comparing performances in PBS, it’s going to be different than it is in water – I’ll tell you that right now".
PVP coatings fare well in water, and test poorly in PBS, whereas the reverse is true for HA coatings.
Edwards showed an example readout of the company’s pinch tester, before showing three instances of coatings that worked and three that failed. A graph displayed the gram-force of friction against the rod length. "A good coating will have an even and low gram-force all the way along that tube. That’s a coating that is successful," he explained.
But the failed coating example exhibited a wide variety of gram-force all the way along the length of the device. Degradation in the durability of the coating was also observed, while the friction went up as the number of cycles increased.
"What’s going on there? Well it could be any number of things," Edwards explained. "The base coat was not adequate; the top coat could’ve been applied poorly; there was an inadequate bond; there was something going on so that that substrate was not compatible with that coating. That’s the detail that we sweat before we give you a coating."
But how do you know your coating is there in the first place? Edwards introduced attendees to a dye test where the dye binds to HA pretty well to give an indication of lubricity. He showed a slide of an uncoated tube (white) compared with its coated counterpart (sapphire blue).
Testing for performance over time is also a critical measure of coating success, so accelerated aging is another useful trick that Biocoat performs for clients.
However, Edwards said: "Over time, we believe in our coating’s ability to maintain its durability and lubricity characteristics."
Lastly, Edwards spoke about the costs associated with coatings, and whether it is better to outsource or to coat in house.
The cost of coating application, including staff labour, equipment, facilities etc., can be anywhere from $6-50 a device, he revealed. But if you choose to outsource, you don’t have to worry about the cost of the reagents, while higher volume orders can reduce the unit cost.
"We don’t have a tremendous amount of data here," Edwards admitted, "but it seems for companies with fewer than 30,000 devices a year, a contract coatings service is a good idea. In other words, let somebody else do it.
"And if you’re one of little guys, have somebody else do your coatings, so you don’t have to invest in expensive machinery," the costs of which can be up to $1 million.
Navigating the coating cost maze is a complex task, said Edwards. Most medical device firms are loath to pay royalties, a model that in the past kept the reagent costs low and tied the success of a product to the coating vendor revenue. Royalties are common, however, and may amount to 0.5% of sales, while unit royalties of $0.25-15.00 per device are also common. Some coating vendors offer programmes of free reagents, but a per-device charge, he revealed.
Licence fees are another way a coating supplier recoups the significant costs of getting your facility up and running with a validated process.
One critical question to ask a coating vendor, however is: ‘What about the waste?’ Even if the amount of coating per device is low, if you’re disposing of many litres of reagent, there will be nasty and expensive surprises. Edwards said Biocoat is dedicated to making sure that the amount of waste in the process is kept to a minimum.
Ultimately, though, however you decide to go about coating your device, the most important concern is whether it will stand the test of time.
"What you want to know is that the coating you have today, you can use ten years from now on a third, fourth, fifth-generation device," Edwards concluded.
All in all, he provided a thorough undertaking of informing the guests about the most important medical device coating considerations. And after a productive evening of scientific discussion and fine dining, delegates left the Savoy with much food for thought.