Drop by Drop and Industry is Transformed

Over the past three decades, the disposable medical market has undergone a variety of changes including the types of devices produced, substrates selected, and sterilization procedures employed. In the early 1970s, device manufacturers were utilizing materials such as glass, rubber and metal to assemble syringes, surgical instruments, and other devices. Such materials were typically assembled and fastened and/or machined or molded in the appropriate configuration. In the 1980s, as medical technology advanced towards intricate and high performance medical device designs, the need for engineering plastics became apparent. During this same period, a shift to single use devices (due to advances in contagious disease) forced design engineers to evaluate engineering plastics such as acrylic, polycarbonate and PVC. With the advent of the 20th and 21st centuries, significant medical and scientific advancements have yielded highly effective and much less invasive devices for a wide range of diagnostic, treatment, and prevention purposes.

Adhesives for the Assembly of Medical Devices

Adhesives have long played an integral part in the assembly of various Class I, II, and III medical devices. Cyanoacrylates, light curing acrylics, epoxies, polyurethane and silicones are used in diverse applications ranging from pre-filled syringes and respiratory masks to blood oxygenators and orthopedic braces. Each application has unique requirements ranging from appearance and bond performance to sterilization resistance. In general, adhesives offer numerous benefits over other medical device assembly methods including:

• Join dissimilar substrates
• Distribute stresses evenly
• Fill large gaps
• Seal & bond
• Offer a neat final appearance
• Easily automated

As with any assembly method, there are several considerations regarding the use of adhesives including: most develop handling strength over time (often referred to as the fixture time), all require a curing process, the majority of adhesives are difficult to disassemble once applied and cured.

Although a variety of adhesives are industrially available, not all possess biocompatibility compliance. The most common types of adhesives selected for device assembly include traditional room temperature and light curing cyanoacrylates, light curing acrylics, room temperature and light curing silicones, epoxies and polyurethanes. In addition to those that meet biocompatibility requirements, non-medical device grades of adhesives can, and are often, selected for less critical applications on Class I devices such as orthopedic braces, stethoscopes, and select surgical instruments. A review of the aforementioned adhesives typically selected for Class II and III devices follows.

CYANOACRYLATE ADHESIVES are polar, linear molecules that undergo an anionic polymerization reaction. A weak base, such as moisture present on essentially all surfaces, triggers the reaction causing the linear chains to form. The products are maintained in their liquid form via the addition of weak acids which act as stabilizers. Several types of cyanoacrylate monomers are produced today including methyl, ethyl, butyl and alkoxy. The most widely used due to high yield and purity production is the ethyl monomer. A wide variety of cyanoacrylate formulations are available with varying viscosities, cure times, strength properties and temperature resistance.

Cyanoacrylates form thermoplastic resins when cured. The initial methylbased cyanoacrylate resins, which were first commercially available in the 1950s from Eastman Kodak, possessed several performance limitations that have since been addressed with formulation modifications. Standard unfilled ethyl monomer based cyanoacrylates typically exhibit low impact and peel strengths, low to moderate solvent resistance, and maximum operating temperatures of 160 - 180°F.

In the late 1970s, rubber was added to standard ethyl cyanoacrylate formulations resulting in significant improvements in peel and impact strengths. A standard ethyl cyanoacrylate tested in peel mode provides an average strength of less than 3 PWI. By comparison, a rubber modified cyanoacrylate exhibits peel strength of approximately 40 PWI. The addition of compounded rubber to the ethyl formulations does have a slight effect on fixture time -- a typical fixture time for a standard ethyl being as low as three seconds on select substrates and a rubber toughened ethyl being between thirty seconds and two minutes.

"Blooming" or "frosting," not necessarily cited as a performance limitation, but nonetheless a potential drawback of cyanoacrylate adhesives, is the presence of a white haze around the bondline.

Blooming/frosting is caused by the reaction of volatilized cyanoacrylate monomer in the air that, because it's heavier than air, falls back to the surface and settles around the bondline. A selection of cyanoacrylate adhesives now use monomers that have a higher molecular weight and lower vapor pressure thus minimizing the potential for blooming/frosting. Users of these types of products should be cautioned, however, since the change in monomer can have an effect on cure speed, physical properties, and operating temperatures. These low bloom products offer the additional advantage of having a reduced odor in the uncured state as compared to traditional ethyl cyanoacrylates.

Traditional ethyl or methyl-based cyanoacrylates can typically withstand maximum temperatures of approximately 180°F. Recent advancements in ethyl cyanoacrylate technology now allow thermally resistant products to withstand continuous exposure temperatures up to and including 250°F. Such thermal resistant materials are usually modified, toughened cyanoacrylate products and therefore share the decreased fixture times. Toughened cyanoacrylate formulations are available in both black and white clear versions.

A new classification of cyanoacrylates was recently introduced: flexible instant adhesives. Such adhesives offer hardness values on the Shore A scale as compared to traditional ethyl cyanoacrylates that are tested on the Shore D scale. In addition, the flexible cyanoacrylates exhibit approximately 4% elongation - double that of standard instant adhesives. Such flexibility properties make these new cyanoacrylates particularly suited for applications where a rapid cure is desired on highly flexible components including various tubing assembly operations.

Besides advancements in ethyl cyanoacrylate technology, there have also been significant advancements in primer and accelerator formulations that not only offer speed of cure but also the ability to bond "hard-to-bond" plastics. The primers are solvent-based systems, which deposit reactive species onto otherwise "dead" substrates. Such reactive species allow for significant increases in bond strength of the majority of difficult to bond materials including polyethylene, polypropylene, fluoropolymer, and acetal homopolymer.

Typical medical device applications involving cyanoacrylates include the assembly of latex balloons and/or stainless steel tips for catheters, and tubeset assemblies.

LIGHT CURING ACRYLICS cure via a free radical reaction to form thermoset resins when exposed to light of the appropriate wavelength and intensity. Like cyanoacrylates, light curing acrylic adhesives are available in a wide range of viscosities from low (~ 50 cP) to thixotropic gels. In addition, light curing adhesives vary in final cured form from hard, glass-like resins to soft flexible resins.

The critical processing key with light curing acrylic adhesives is that light must reach the full bondline in order to cure the adhesive. Adhesive in shadowed areas will not cure. In addition, the maximum depth of cure for the majority of light curing acrylic systems is approximately 0.5." Another consideration when selecting a light cure adhesive is the equipment required for the processing of the product. Light curing adhesives require specific radiant energy (i.e. light energy) in order for the polymerization reaction to occur. It is, therefore, critical that the end user match the adhesive with the appropriate light source. Adhesive manufacturers can recommend the appropriate type of system. Typical low intensity systems can have an average price of $1,000 while high intensity custom systems can run into tens of thousands of dollars.

ew grades of acrylic adhesives that cure solely with higher wavelength visible light (>425 nm) have recently been introduced to medical device manufacturers. The use of such visible light provides significant benefits to design and production personnel including:

• Ability to cure through select colored materials
• Low to no heat output from visible light curing systems
• Minimal personal protective equipment requirements
• Longer life and initial lower cost visible curing systems
• Enhanced cure depths (in excess of 0.5" with proper light source)

Light curing acrylic technology offers the significant benefit of rapid fixture and cure following exposure (as little as 5 seconds for select joints), thus minimizing work in process (WIP). In addition, light curing acrylic formulations have been designed to bond a wide variety of substrates and yield a clear bondline when used in thin sections. Because the final resins are thermoset plastics, thermal, chemical and environmental resistance of light curing acrylics is enhanced versus cyanoacrylate adhesives.

Typical applications involving light curing acrylic adhesives are numerous since it is one of the most selected (if not the most selected) adhesive joining methods employed by device manufacturers. Specific applications include needle assembly, anathesia mask bonding, polycarbonate component assembly (i.e. blood oxygenators, heat exchangers, surgical pumps), and hearing aid molding.

A technology introduced in the United States in 1998 combines the benefits of cyanoacrylate technology and light curing acrylic technology.

LIGHT CURING CYANOACRYLATES are ethyl based products which have photoinitiators added to the formulation. The end result is rapid cure in exposed areas (like that of a traditional light curing acrylic) and cure in shadowed areas. Because the light curing cyanoacrylates are ethyl monomer based, the overall physical performance characteristics are similar to those obtained with a traditional cyanoacrylate. Additional benefits gained with this technology include minimized blooming/frosting since exposed uncured cyanoacrylate can be immediately cured using ultraviolet and/or visible light, increased depth of cure over the traditional cyanoacrylate cure maximum of 0.010 inches, and compatibility with primers for "hardto- bond" plastics. Typical applications for light curing cyanoacrylates would be similar to those outlined for standard cyanoacrylates with the added benefit of rapid cure in exposed areas via exposure to light.

EPOXY ADHESIVES, like the previously mentioned light curing acrylic adhesives, cure to form thermoset plastics. The polymerization reaction occurs via ring openings of an epoxide group initiated by a catalyst such as an amine or mercaptan. Room temperature and heat curing one and two part systems are available. Due to their ability to crosslink, epoxies offer superior chemical, environmental and thermal resistance. The ability to bond a wide variety of substrates and fill large gaps make epoxies useful for deep section potting of medical components and needle assembly. In addition, the superior temperature resistance of this class of adhesives makes them particularly suited for devices requiring multiple autoclave exposures. Because epoxies cure via an exothermic reaction (giving off heat during cure) their use on temperature sensitive components must be closely monitored. A second potential drawback to epoxy use is their rigid nature when cured, thus resulting in potentially low peel strengths.

POLYURETHANE ADHESIVES are similar to epoxies in that one and two part formulations are available. A urethane linkage is formed when the two main formulation components - the polyol and isocyanate - react to form hard and soft segments in the resultant polymer. Such segments contribute to the unique, flexible, yet tough cured materials. Like several previously mentioned chemistries, polyurethane adhesives form thermoset resins when cured, thus exhibiting good chemical and environmental resistance. It is important to note, however, that the overall thermal resistance of cured polyurethanes is less than that of cured epoxies. Polyurethane adhesives are substrate versatile but do, on occasion, require the use of a surface primer to increase the reactivity of the surface to be bonded. Many of the primers require long on-part times in order to effectively prepare the surface for the adhesive. A second potential drawback to the use of polyurethane adhesives is their inherent moisture sen- Adhesives for Medical Device sitivity. Excess moisture on a part or in one of the constituents can cause a reaction resulting in the evolution of carbon dioxide. Thus bubbles are apparent in the finished component. Typical uses of polyurethanes in the medical device market include bonding tips on catheters and optical scopes, sealing oxygenators and heat exchangers and assembly of components requiring flexibility.

SILICONE ADHESIVES are similar to polyurethane adhesives in that they form flexible polymers when cured. Silicones, however, possess no rigid segment and therefore exhibit lower cohesive strengths - the ability of the polymer to adhere to itself. Like previously mentioned epoxies and polyurethanes, silicone adhesives are available in several forms including one part moisture cure, one part heat cure and one part dual moisture and light cure formulations. Although two part silicone systems do exist industrially, the catalysts used in such materials typically cause the system to fail biocompatibility screening

The majority of moisture curing silicones have two primary characteristics that limit their use in the medical device market. The evolution of by-products such as acetic acid coupled with the 24 hour cure time often cause device manufacturers to seek alternate, faster fixturing/curing materials. The use of dual curing systems that react initially to light and subsequently moisture cure provide cure-on-demand fixture strength followed by full cure up to 72 hours later.

Typical silicone applications include coating of highly flexible assemblies such as endotracheal and tracheotomy tubes, and bonding and sealing of silicone based assemblies.

Along with performance issues, medical device manufacturers must also consider regulatory issues. Device manufacturers rely on their component suppliers for assurance that the substrate and/or adhesive will not cause problems with the biocompatibility of the device. In an effort to address such issues, substrate suppliers and adhesive manufacturers began testing their components using tests similar to those used to qualify an enduse device.

Guidelines established by the United States Pharmacopeia (USP), which were initially used to determine the suitability of plastics for use in medical devices, were used by adhesive manufacturers for the same purpose. Adhesives were tested for effect on cells (cytotoxicity), effect on blood constituents (hemolysis), effect following implantation, and overall effect (muscles and system). Exposure temperatures, solvents used for extraction and test durations are factors that varied by supplier. Although several classes of biocompatibility exist, most adhesive suppliers tested to USP Class VI, indicating that the material/device may come in contact with bodily fluids. The results of Class VI testing were typically provided to adhesive users on an as-requested basis in the form of certificates of compliance.

ISO 10993, a globally accepted standard for biocompatibility testing, has replaced Class VI for most component suppliers. The International Standardization Organization (ISO) standard typically involves revised tests, extract solutions, extract temperatures, and test durations that more closely match actual body conditions. For example, under the ISO 10993 standard, most suppliers now conduct extractions at temperatures more closely matched to typical body temperature.

The end user should ask a variety of questions during the adhesive supplier selection process including:

• What biocompatibility standard is the adhesive supplier testing to?
• What qualification tests does the supplier include in the standard?
• How frequently are products retested to verify compliance?
• How were the test specimens prepared? Bonded assemblies or coating?
• What were the extraction conditions?
• What type of documentation can the supplier provide to verify compliance?

Understanding the manner in which test specimens were prepared as well as the testing parameters employed will ensure that the compliance referenced is meaningful to the end user. For example, adhesive suppliers may assemble an actual device, submit the device for test, and receive approval of biocompatibility for the full device. Adhesive suppliers may claim the same such compatibility for the adhesive. However, each device is unique in substrates selected, joint design, and end use. Such a claim, therefore, may be meaningless to manufacturers producing different types and configurations of devices. It is additionally important for device manufacturers to recognize that adhesive biocompatibility compliance is a guideline only and not a guarantee. Should the adhesive be improperly cured, biocompatibility may be sacrificed.

Summary

With pressures from the healthcare community to reduce costs and minimize contagious disease, and from an aging population to offer less invasive procedures, medical device engineers are constantly seeking new and better ways to design and produce devices for a variety of diagnostic, treatment, and prevention purposes. With a significant shift to single use devices, plastics and combinations of plastics with stainless steel, nitinol, and titanium have driven device assemblers to adhesives. Many of these new materials and combinations cannot effectively be assembled and sealed with traditional welding and/or mechanical means. As indicated in the "Engineer's Guide to Plastics" published by Materials Engineering, adhesives are the most versatile assembly method for plastics, capable of joining 36 types of plastics. Mechanical fasteners, which are cited as being capable of joining approximately 28 plastics, are the second most versatile plastic assembly method. Ultrasonic welding, one of the more commonly used welding techniques for medical devices, is referenced as being capable of joining only about eighteen plastics.

The numerous benefits cited coupled with the variety of biocompatible formulations available ensure that the majority of device assembly applications can be quickly, effectively, and safely completed with today's adhesive technology. TMD

Henkel Technologies Corp.
Rocky Hill, CT
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