|Porous PSAs offer uniform, isolated pore structures to control flow and movement of liquids or gases.|
Component and material suppliers in the in vitro diagnostics (IVD) industry are facing pressure to develop technologies that address the demand for fast-performing, highly sensitive, accurate, and more affordable products in a short development cycle. Understanding the special needs of the IVD industry allows suppliers such as adhesive manufacturers to embrace this challenge through the development of enabling adhesive and coating technologies. This article discusses some of the design challenges related to formulating adhesives for diagnostics and how adhesives can bring added design benefits and enhanced capabilities to device manufacturers beyond simply bonding substrates together.
Pressure-sensitive adhesives (PSAs) have been used for decades in a range of diagnostic device applications. In recent years, technology has evolved to create a more customized adhesive delivering enhanced performance capabilities. Today, PSAs are not only suitable for lateral-flow devices but also for many molecular diagnostic applications, including high-throughput screening, reverse-transcription polymerase chain reaction (PCR), cell culture, and compound storage.
Device manufacturers primarily choose PSAs for their performance characteristics and because their continuous roll format enables efficient manufacturing for batch and in-line processing operations. The adhesives provide an immediate bond without the need for water, solvents, or heat that could potentially damage a device’s sensitive enzymes and reagents. Although several off-the-shelf medical-grade PSA products are currently available, OEMs will benefit most by working with a contract manufacturer that specializes in adhesive formulation and offers custom product capabilities that overcome the challenges of these specialized applications.
Inertness and Compatibility
Formulating adhesives for diagnostic applications is challenging, and adhesive manufacturers must first ensure component compatibility to the biological sample and assay. This responsibility becomes even more complex when considering the variety of available assays and how biomarkers or reagents can be combined as device designs broaden into new fields of disease detection.
When considering adhesive or component materials for any test system, formulators must ensure that the chemistry of all raw materials is inert and remains inert to the chemistries of the device and specimen. The system must be free of residual volatiles (such as solvents; )and monomers, leachable components, and reactive materials to assure chemical compatibility.1 Processing components must also be considered. For example, most PSA systems are manufactured with a release liner to aid in processing. Silicone from the liner’s release coating can potentially be transferred from the adhesive to the IVD device, causing contamination that may affect growth in cell culturing applications.
Environmental contamination, which potentially affects compatibility, can also occur during the handling and manufacturing of the PSA system. Cleanliness during material handling and manufacturing is equally important for maintaining compatibility and component chemistry, particularly in molecular diagnostic applications. Any bacteria, yeast, or fungi that are transferred to test components can introduce biological contamination that may negatively affect results in biotech testing. Because compatibility can change as components age, accelerated and real-time aging studies are required to ensure that the adhesive properties are maintained during the shelf-life of the device.2
Controlling Thickness Tolerance
Tight tolerances for adhesive and substrate thickness control within product rolls and from lot to lot are critical for microfluidic devices and lateral flow applications. Any thickness variations can affect sample volume and test results. PSAs are a proven component in lateral-flow immunoassays that are used in many disposable IVD devices and biosensors. PSAs offer precise and accurate bond lines that improve the reproducibility of these devices, so one or more layers of PSA tape product may be used to bond, laminate, or assemble components within a test strip.
For example, in microfluidic devices and biosensors, a spacer tape defines the height of the microfluidic channels, which are formed by die- or laser-cutting, while the lid of the channel is made of another adhesive tape or a hydrophilic film.3 Adhesive thickness and tight tolerances can be monitored and maintained by integrating sophisticated vision systems and state-of-the-art online coating controls into the manufacturing equipment train to ensure product quality.
Eliminating Cold Flow
Adhesive migration, known as cold flow or creep, is one of the many design challenges adhesives manufacturers must address in IVD device design. The delicate balance of an adhesive’s viscoelastic properties for proper laminating and cutting can have serious effects on manufacturing efficiencies if the formulation is not well-suited for an application’s production processes. During conversion, a roll of adhesive may be processed in a number of ways, including high-speed laminating, slitting, sheeting, guillotining, and laser, rotary, or flatbed die-cutting. Although the PSA format offers many manufacturing efficiency benefits for high-speed conversion, the viscoelastic characteristics can also present challenges. If the adhesive is too hard, it will provide clean cuts but less-than-optimal bonds for laminating. If the adhesive is soft, it will laminate well to other component parts. However, residue may adhere to machinery blades during conversion, affecting the precision of individually cut parts. When adhesive builds up on the blades, the result can be increased cutting cycle time, reducing overall conversion throughput.4 Additional loss of productivity occurs when cutting equipment is shut down and dissembled for manual removal of adhesive buildup on the cutting blades.
Small sample volumes and quantities of biomarkers are influencing the design of devices that use small capillary channels. As a result, the viscoelastic properties of the adhesives used in device designs with large sample flows may not be suitable for smaller-channel designs. In these instances, a dual-stage UV-curable PSA is a good substitute. It cures in less than one second without the risk of damaging sensitive components. Compare that to heat activated-systems, which require pressure and dwell time for bonding. The uniqueness of this tape construction allows it to function like any other PSA for in-line processing with high-tack properties for bonding, laminating, and assembling components within an IVD device.
Once assembled, the laminated construction is briefly exposed to UV radiation, which further cross-links the adhesive and makes it more cohesive to eliminate the risk of cold-flow. The cohesive strength of the UV-cured adhesive prevents cutting blade gumming with low shrinkage. Although the cured adhesive presents increased cohesive strength, the overall system remains flexible.
Strong intermolecular attractive forces exist between molecules to create surface tension. These intermolecular forces create high surface tension in aqueous biological samples. In comparison, the surface energy of a solid substrate is low. The membranes used in IVD devices also have low surface energy and are not compatible with aqueous biological fluids. To achieve lateral flow and, ultimately, wicking of the fluid sample, the difference between the surface energy of the biological fluid, substrates, and membranes used in the diagnostic device must be overcome.5
Two approaches can improve the flow of biological fluids through a diagnostic device. One approach is to increase the surface energy of the substrate with various surface treatments. A second approach is to reduce the surface tension of the biological fluid, which can be accomplished through the incorporation of a hydrophilic PSA.
Adhesives may be formulated with a range of hydrophilic and hydrophobic capabilities to control fluid flow in a device while also providing increased design flexibility using a small biological sample. When an adhesive’s surface is hydrophilic, it reduces a fluid sample’s surface tension, improving wicking consistency and enabling rapid fluid transfer from the inlet port to a remote reactant area for fast test results. Hydrophilic PSAs may also be used as a wicking surface that allows increased separation between the sampling port and test reagents to reduce the risk of chemical interference.
Alternatively, by slowing hydrophilicity to create a hydrophobic surface, device designers can control reaction times as a sample wicks through a device. Surface treatment techniques can be applied to the adhesives or coatings used in a device’s backing material to customize the physical character to include areas with hydrophobic characteristics and reduced surface energy. Fluid wicking through devices that use this approach can be slowed over areas of low surface energy by using a single coating. This approach permits adequate time for the required reaction or complex formulation. The technique also avoids rapid fluid wicking in devices where insufficient reaction times can cause inaccurate test results. It is possible to create a series of reaction zones of various shapes and configurations on a single adhesive film.6
Adhesives with tailorable fluid transfer properties are available in a number of forms, including PSA, heat seal, and film coatings. These forms make them an attractive material choice for lateral flow, microfluidic, microtiter plates, and point-of-care devices that require good bonding to a variety of substrates (see Table I).
|Table I. Hydrophilic adhesives offer tailorable features.|
Optical Transparency and Spectral Properties
PSA manufacturers are faced with a long list of chemical compatibility and physical bonding challenges when formulating products for diagnostic devices. In addition, many biological testing applications rely on diagnostic determination by using fluorescent emissions.
Careful consideration must be given to materials when selecting cover tapes for PCR, real-time PCR, microfluidic, biochip, microarray, and microwell applications. Any interference or background fluorescence from an adhesive coating or accompanying film carrier can affect the detection of optical characteristics. Sealing or cover layers must exhibit little or no spectral emission at the biomaterial detection wavelength (typically 400–800 nm). Low fluorescent film substrates include materials such as polyolefin (PMP), cyclic polyolefin (CPO), polyacrylates (PMMA), polycarbonate (PC), polystyrene (PS), and polyethylene terephthalate (PET) (see Figure 1). From an adhesive standpoint, chemistries with high levels of acrylic acid should be avoided, and low coat weights should be used.
Going with the Vertical Flow
The availability of a porous PSA technology that provides the ability to bond multiple layers while enabling the free exchange of fluids or gasses is a relatively new concept.7 The technology was originally developed for applications requiring secure containment of fluids while providing ventilation for gas exchange, such as in microtiter plates or microarrays. Now it is being considered for IVD devices where a conventional, impermeable PSA was not previously a viable component. This customizable adhesive technology offers open pores or cells of relatively uniform size and distribution to create a low-density, highly permeable structure. The pores are isolated channels that control flow and movement of aqueous-based fluids and gases. They typically range in diameter from approximately 200 to 500 µm and have 30–50% porosity. They enable flow from one substrate to the next through the z-direction of the adhesive, while acting as a gasket seal in the x-y direction.8
Pore Structure: A Microscopic View
The porous adhesive’s ability to provide bonding capabilities while allowing the free transport of fluids and gases across the two surfaces of the adhesive film could create new PSA application areas in IVD. The adhesive forms instant bonds to join film substrates, membranes, pads, filter elements, or plastic parts without the need for curing or clamping during production of the finished product. The typical pore size of 200 µm is large enough to allow the passage of a whole blood sample. Alternatively, the adhesive may be laminated to a porous membrane to filter red blood cells. For example, the porous PSA can enable the construction of a stack of filtration membranes for cost-effective sample preparation. In vertical flow or combination lateral flow IVDs, the adhesive layer can provide a physical separation between materials while enabling the rapid passage of fluids through the adhesive.9
|Figure 1. The effect of excitation energy on the fluorescence of various substrates.|
Assay developers are evaluating ways to reduce cost by improving assay stability and yields of expensive reagent-laden components, and aqueous-based dissolvable films. At the same time, a related technology to PSAs that uses similar coating and processing approaches is gaining attention as a viable means for incorporating reagents into diagnostic devices such as lateral flow test strips, microfluidic devices, and microplates. These films provide a means for containing, storing, transporting, and processing reagents in a simple solid-state form. The reagents are made available by simply redissolving the film in an aqueous medium. Dissolvable films can be tailored to meet the specific needs of an application and offer significant formulation flexibility for achieving physical properties such as film thickness, dissolution rate, surface characteristics (texture), and mechanical properties (film strength). 10
Conventional preparation techniques for test strips, such as spraying, coating, or striping, can result in the costly loss of reagent. They can also limit the effective distribution of active components throughout a membrane or conjugate pad. Dissolvable films are formulated as a homogeneous mixture of a film former and reagent(s), so consistent dispersion of the active component is an inherent benefit of the film technology, translating to increased yield and reduced costs for device manufacturers.11 The film is provided in a continuous reel and may be cut into any size or shape to fit the end product design. Each precisely die-cut film component is a premeasured single dose that is easier and safer to handle than aqueous solutions of reagents. Higher dose concentrations can be obtained by increasing the loadings within the film itself or by increasing the film’s overall mass and thickness. Reagent-loaded dry films do not require refrigeration or preservatives. Increased stability of the reagent when it is integrated into a film format results in less waste and requires fewer resources for device manufacturers to properly store and handle the sensitive and fragile reagents.
For diagnostic applications that require a controlled and timed reaction, dissolvable films may be incorporated as isolation barriers formulated with longer disintegration rates. Alternatively, the films may be used in multiple-layer constructions and vertical flow devices that contain or separate one or more reagents for their controlled release when exposed to an analyte within a device.
PSAs provide custom bonding with added performance benefits in electrochemical sensors, such as blood glucose or lactose test strips, or biofeedback devices that incorporate an electrical current or potential for diagnosis. Electrically conductive PSAs enable small and thin effective bonds because they not only bond components together, but also provide the added functionality of supplying pathways for electrical signals. By eliminating the need for other conductive elements, electrically conductive PSAs present options for simplifying electronic component designs.
When uniformly dispersed within an adhesive, conductive particles create pathways within the adhesive matrix to make contact from one surface to another. The conductive fillers may be comprised of a number of materials, such as nickel, silver, and carbon or a combination of these materials. The adhesive matrix may be formulated from silicone, acrylic, or rubber polymers to ensure the maximum flexibility and compatibility with metal, film, and potentially low surface–energy substrates.12
Depending on the application, a number of adhesive or film formulations can be created in combination with the carbon particles, including
- Carbon-filled adhesive matrix.
- Carbon- and metal-filled adhesive matrix.
- Carbon and silver compound adhesive.
- Adhesive-embedded composites for x-y versus z-conductivity control.
- Conductive films and laminates.
A number of factors are driving IVD manufacturers to reduce the cost of their current products and develop next-generation devices for current and new applications. As device manufacturers maneuver through shortened product development cycles, they turn to their material suppliers for the latest technologies for enhancing product performance and value.
Suppliers face many technological challenges in developing innovative new products and efficient and reliable manufacturing processes that produce high-quality products that meet or exceed regulatory requirements. Custom adhesives manufacturers are uniquely positioned to develop and implement technologies that provide reliable bonding for a multitude of IVD testing platforms, and deliver enabling technologies to address the challenges IVD manufacturers are facing today and in the future.
1. WG Meathrel and J O’Mahoney, “Customized Adhesive and Coating Technologies Enable Drug Delivery Methods,” Pharma, September (2009): 20–23.
2. WG Meathrel and R Malik, “Advanced Pressure-Sensitive Adhesives Enable Advent of Next-Generation IVD Products,” European Medical Device Technology 2, no. 1 (2011): 19–21.
3. P Hilfenhause and T Meigs, “Pressure-Sensitive Adhesive Tapes for IVD Applications, 16.2” IVD Technology (2010): 33–38.
4. E Lakitosh, “Die-Cuttable Adhesive Development,” Internal company document. Adhesives Research, Glen Rock, PA.
5. H Hand and W Meathrel, “The Effect of Hydrophilicity on the Flow Properties of Biological Fluids in Diagnostic Devices,” IVD Technology (2001); available from Internet:
6. W Meathrel et al., 2002, Hydrophilic diagnostic devices for use in the assaying of biological fluids, U.S. Patent 7,476,533, filed April 19, 2002, and issued Feb 25, 2004.
7. R Malik, R and K McKinney, Porous pressure-sensitive adhesives and tapes, U.S. Patent 60/978,591, filed October 8, 2008, and issued April 9, 2009.
8. R Malik, “Porous Adhesive Technology for Diagnostic Applications,” IVD Technology 15, no. 2 (2009): 27–32.
9. R Malik, “Porous Pressure-Sensitive Adhesives,” European Medical Device Technology 1.2, (2010): 41–43.
10. W Meathrel and C Moritz, “Dissolvable Films and Their Potential in IVDs.” IVD Technology 13, no, 9 (2007): 53-58.
11. W. Meathrel et al., Disintegrable films for diagnostic devices, U.S. Patent 7,727,466, filed Nov. 21, 2008, and issued June 1, 2010.
12. D Hariharan, “Electrically Conductive Adhesives Charge Forward,” Design Fax 4 (2009); available from Internet: www.designfax.net/news/archive/04-28-2009/stories/feature-1.asp#.
William G. Meathrel, PhD, is senior scientist at Adhesives Research Inc. (Glen Rock, PA). Ranjit Malik, PhD, is group leader of core technology at the company.