In membrane-based IVDs, hydrophilic constructions can improve test performance while maintaining manufacturing efficiencies.
|William G. Meathrel, PhD, is group leader for medical research and development, Herbert M. Hand Sr. is a medical product development scientist, and Li-Hung Su is a medical product development chemist at Adhesives Research Inc. (Glen Rock, PA). The authors wish to thank David Schaefer and the Department of Physics, Astronomy, and Geoscience at Towson University (Towson, MD) for technical assistance and for the atomic force microscopic imaging of hydrophilic adhesive coatings.|
Lateral-flow test strips are routinely used in clinical and other applications to provide convenient and simple analysis of many important chemicals.1–5 IVD devices incorporating such strips are used to detect such analytes as nutrients, hormones, therapeutic drugs, drugs of abuse, and environmental contaminates. In clinical test devices, biological fluids such as whole blood, plasma, serum, nasal secretions, sputum, saliva, urine, sweat, transdermal exudates, and cerebrospinal fluid may be analyzed for specific components that are important for diagnosis and monitoring. In addition, microbiological suspensions and tissues may be homogenized in compatible liquids and the fluid analyzed for specific components. Typically, the specimen fluid is deposited at the inlet port of a suitable IVD test strip and the sample fluid is drawn into the device by mechanical means such as vacuum or by capillary flow.
In aqueous biological fluids such as blood, urine, and sputum, strong intermolecular attractive forces create high surface tension.6 By comparison, the surface energy of solid substrates commonly used to make IVD devices is low. To achieve lateral flow and wicking of the liquid, the differential between the surface energies of the biological fluid and the solid substrates needs to be overcome—preferably without any mechanical assistance.
Two approaches can be used to 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.
This article provides information about novel hydrophilic coatings and adhesive constructions for IVD test devices. Hydrophilic constructions reduce the surface tension of biological fluids, thus enhancing the lateral flow and wicking of such fluids. Adhesives are formulated using polymer resins and surfactants to provide multifunctional bonding properties. Hydrophilic adhesives are formulated to be thermally bonded or pressure sensitive. The hydrophilicity of the surface is controllable through the chemical composition and the structure, concentration, and distribution of the surfactant in the adhesive coating.
The Flow of Sample Fluids
Figure 1. Schematic diagram of a typical lateral-flow diagnostic device.
Lateral-flow devices typically incorporate an inlet for receiving the biological fluid (see Figure 1). The sample inlet area or port may be proximal to a conjugate pad that holds reagents specific to the analytical test method. As the sample specimen flows from the inlet area through a reagent area, specific chemical reactions or a complex formation occur. The reaction product or complex continues to flow to a detection area where the analyte is monitored. Specimen fluids may continue to flow and be collected in an absorbent pad. Adhesive backings are typically used in the construction of such lateral-flow devices to support their various components, including the conjugate pad, the microporous membrane containing specific reagents, and the absorbent pad.
The time required for determining the concentration of a specific analyte is dependent on the flow rate of the fluid and the reaction rate between the analyte and a specific test reagent. The flow rate of the sample fluid is typically controlled by capillary flow through the microporous membrane.
Figure 2. Capillary rise in a cylinder or channel.
Controlling Surface Tension to Affect Flow. The surface tension of a fluid is the energy parallel to its surface that opposes extending that surface. Surface energy is the energy required to wet a surface. To achieve optimum wicking, wetting, and spreading, the surface tension of a fluid must be decreased so that it is less than the surface energy of the surface to be wetted.
The wicking movement of a biological fluid through the channels of a diagnostic device occurs via capillary flow. Achievement of capillary flow is a function of cohesion forces among liquid molecules and forces of adhesion between the liquid and the walls of the channel (see Figure 2). The Young/Laplace equation states that fluids will rise in a channel or column until the pressure differential between the weight of the fluid and the forces pushing it through channel are equal, as follows.7
In the equation, Dp is the pressure differential across the surface, g is the surface tension of the liquid, q is the contact angle between the liquid and the walls of the channel, and r is the radius of the cylinder. If the gravitation force is g, capillary rise is h, and the density of the liquid is r, then the weight of the liquid in the column is pr2ghr or the force per unit area balancing the pressure difference is ghr. Therefore,
For maximum fluid wicking through the channels of a membrane, the radius of the channel r and the contact angle q should be small, and the surface tension of the fluid g should be large.
Figure 3. Wetting of a fluid on a smooth, flat surface.
Wetting is the adhesion on contact between a liquid and solid.8 Figure 3 illustrates surface wetting of a fluid on a flat smooth surface. The theoretical explanation of this phenomenon can be described by the classic model known as Young's equation.9
gSV = gSL + gLV cosq
The diagram illustrates the relationship between the contact angle q and the surface tension of liquid gLV and solid gSV.8 When the contact angle q between liquid and solid approaches zero, the liquid will spread over the solid. For maximum wetting, the surface tension of the liquid must be less than or equal to the surface tension of the solid surface. This is the critical wetting tension of the solid.
The spontaneous process of wetting can also be derived from the differential between the work of adhesion and cohesion by substitution of the Dupré equation, as follows.8
WA – WC = gSV + gLV – gSL – 2gLV = gSV – (gLV + gSL)
This equation, where WA is the work of adhesion and WC is the work of cohesion, implies that spontaneous spreading will occur if the work required to separate the liquid-solid interface is greater than liquid separation itself. The Dupré equation can therefore be further derived by introducing the initial spreading coefficient S defined by Harkins, as follows.10
S = WA – WC = gSV – (gLV + gSL)
Since gSL is relatively small in comparison with gLV, the initial spreading coefficient term becomes:
S = gSV – gLV
Spreading is the movement of liquid across a solid surface. Contact angle is a measure of wettability. Spreading increases as the contact angle decreases until wetting is complete. Hence, spreading will occur spontaneously when S is greater than zero, which also indicates that the surface tension of the solid must be greater than that of the liquid, as shown in the above equation. From this initial spreading coefficient equation, it follows that wettability can be increased either by increasing the surface tension of the solid or decreasing the surface tension of the liquid.
Surface Treatments for Solid Phases
Surface treatments to increase the surface energy of a solid include both physical and chemical methods. Physical treatments used to increase surface energy include corona discharge, mechanical abrasion, flame, and plasma treatment.11 Chemical surface treatments include cleaning, priming, coating, and etching.
Corona discharge is the most widely used technique for surface treatment of plastics. During the treatment, the plastic surfaces are heavily bombarded with oxygen radicals at high-energy radiation levels. Consequently, the plastic surface undergoes either electret formation or chemical structural changes.12–15 Either result will improve the wettability of plastics.
Another commonly used method is wet chemical treatment. This treatment involves oxidizing the plastic surface through exposure to oxidizing acids such as a mixture of chromic acid and sulfuric acid.16
Effects of Corona Discharge and Chromic Acid Treatments. To quantitatively demonstrate the effects of corona discharge and chromic acid treatments on the surface energy of solid substrates, a study was conducted employing these techniques on six commonly used industrial plastics. The corona discharge treatment involved exposing the surface of each plastic to an electric discharge of 10,000–50,000 V at a frequency of approximately 500 kHz for approximately 5 seconds. The chromic acid treatment required the plastic surface to be flooded for 15 seconds with chromic acid, which was then removed by washing with distilled water; the surface was then rinsed with isopropanol and wiped dry. In each case, the contact angle was measured immediately after treatment.
Figure 4. Effect of surface treatments on contact angle.
As measured by the water contact angles for untreated and treated samples, both corona discharge and chromic acid treatments were effective in improving the wettability of the surfaces (see Figure 4). The decreased water contact angles indicate an increase in the surface energies of the treated plastics that would similarly enhance their wettability for biological fluids.
Chromic acid was most effective on plastics with functional groups, such as polycarbonate and polyester panels. Corona discharge was most effective in increasing the surface energy of the polyolefin films (polypropylene and high-density polyethylene). The corona discharge treatment method could improve the water contact angle by orienting surface electrical charges or by introducing oxygen on the surface. Either mechanism will increase the polarity of the plastic and thereby increase its surface tension. Consequently, the contact angle q will be smaller due to reduced difference in surface tension between the plastic gSV and the water gLV. A disadvantage of corona discharge treatments is the instability of the treatment. Corona treatment substrates should be coated soon after treatment.
Surfactants in Adhesives
The use of surfactants to lower the surface tension of a fluid is well known.17–19 A variety of anionic and nonionic surfactants can be used to lower the surface energy of an aqueous fluid (see Table I).
|Sodium 2-ethylhexyl sulfate||Branched||Anionic||232|
|Sodium lauryl sulfate||Linear||Anionic||288|
|Sodium nonylphenol ether sulfate||Aromatic||Anionic||498|
|Polyalkyeneoxide modified heptamethyltrisiloxane||Linear siloxane||Nonionic||600|
Table I. Physical properties of selected surfactants.
To determine the properties needed for an adhesive with both bonding and hydrophilic attributes, a substantial amount of research was conducted to understand the interrelationships between polymers and resins used to make adhesives. As described below, the use of surfactants in coatings and adhesives was studied to determine their effects on wettability, fluid flow rate, and adhesive properties. Each surfactant was formulated into a base adhesive at different concentrations. The water contact angle was measured to determine the effect of the surfactant on reducing the surface tension of the water.
This research has resulted in the development of proprietary technology that meets the need for a hydrophilic adhesive to reduce surface tension of fluids and improve flow rate in diagnostic devices.
Preparation of Hydrophilic Adhesives. Hydrophilic coatings and heat-sealing and pressure-sensitive adhesives were prepared in the laboratory. Dissolution of polymeric resins occurred in organic solvents and was followed by measurement of solution solids and viscosity over a period of several hours of mixing.
The surfactant was introduced into the liquid polymer mixture after dissolution of the resin. Gentle agitation for several minutes was sufficient to achieve homogeneity. Hydrophilic pressure-sensitive formulations were prepared by the introduction of a surfactant into liquid acrylic adhesive solutions and emulsions followed by gently mixing until dispersed or dissolved.
Film Preparation. Hydrophilic films were prepared in the laboratory using coating apparatus. The dried coatings had an approximate thickness of 0.0005 to 0.001 in. The hydrophilic adhesive coatings were protected with a film release liner of low surface energy.
Effect of Surfactant Type on Water Contact Angle
Various surfactants were formulated into emulsion pressure-sensitive adhesives. These hydrophilic coatings were tested for surface wetting using deionized water. The sessile drop method was employed to measure the contact angle of liquid water on the surface of the hydrophilic thin film.
A further study of surface wetting was conducted for two hydrophilic heat seal adhesives, HY-5 and HY-10, which were formulated using polyester resins and the anionic surfactants sodium nonylphenol ether sulfate and sodium dioctylsulfo succinate, respectively. Water was dropped onto the surface of the adhesives and the contact angle was measured as a function of time.
Figure 5. Effect of surfactant concentration on contact angle.
Results. With increasing surfactant concentration, most test samples exhibited a similar trend of decreasing contact angle (see Figure 5).
Sodium nonylphenol ether sulfate exhibited the most effective reduction of water surface tension at all three surfactant concentrations used in this study. Of the surfactants evaluated, it had the highest molecular weight among the anionic surfactants. It is proposed that the lower molecular weight anionic surfactants have better solubility into the adhesive matrix so that there is less surfactant concentrated at the water-adhesive interface.
The nonionic surfactant nonylphenol ethoxylate exhibited little effect on the contact angle of deionized water. This may be due to its higher molecular weight and the lower water affinity of the hydrophilic group compared with anionic surfactants. In addition, the nonylphenol group enhances its absorption onto the polymer surface.
Polyalkyeneoxide-modified heptamethyltrisiloxane (PMHS), also a nonionic surfactant, reduced the water contact angle on the adhesive surface compared with nonylphenol ethoxylate. PMHS has a siloxane polymer backbone rather than a hydrocarbon backbone, which accounts for its lower surface energy. In addition, PMHS also has a lower molecular weight than nonylphenol ethoxylate, which enhances its mobility within the adhesive matrix.
The linear structure of sodium lauryl sulfate would improve its solubility into the adhesive so that its effect on the adhesive surface is less than that of sodium 2-ethylhexyl sulfate.
Figure 6. Plot of water contact angle surfactant concentration for hydrophilic heat-seal systems.
The effect of surfactant concentration on the surface wettability of the coatings prepared using different polymeric resins is shown in Figure 6. Polyamide, ethylene vinyl acetate, and polyester resins were formulated with sodium dioctylsulfo succinate. The contact angle is high when no surfactant is present in the coatings since the polymeric resins are hydrophobic. By increasing the surfactant concentration, the surface becomes more hydrophilic and lower water contact angles are observed, indicating significant surface wetting. At very high surfactant concentrations the wetting effect can be enhanced or attenuated depending on the surfactant and its compatibility with the polymer matrix.
The spreading behavior of water on the surfaces of the HY-5 and HY-10 coatings is as follows. Initially there is rapid spreading of the drop as it contacts the surface of the film. The contact angle decreases quickly to less than 10º. Equilibrium is established within 30 seconds to one minute. This spreading behavior is typical of hydrophilic coatings, heat-seal adhesives, and pressure-sensitive adhesives.
Flow Rate in Microfluidic Channels
Experiments were conducted to determine the effects of hydrophilic coatings and adhesives on the flow rate of distilled water in a microfluidic channel. Following a screening of the effects of different types of surfactants on contact angle, the most effective surfactants were formulated into adhesive tapes used as a cover for a microfluidic device. For this set of experiments, a hydrophilic pressure-sensitive adhesive was formulated using concentrations of sodium nonylphenol ether sulfate ranging from 0 to 6%.
Figure 7. Diagram of test device with a microfluidic channel formed using hydrophilic adhesive tapes.
The microfluidic channel, measuring 20 cm x 10 µm x 30 µm, was molded into a polystyrene device (see Figure 7). The hydrophilic tape was used to close the channel to create the microfluidic device. Distilled water was placed in one of the terminal wells and the time for the water to flow through the channel was measured.
Results. When no surfactant was added to the adhesive, water did not flow through the channel. With increasing concentrations of surfactant, however, the rate of water flow through the microchannels increased while the contact angle decreased.
The increased flow rate of water can be attributed to the reduction of water surface tension, in accordance with the principle of capillary rise. The water will advance farther when its surface tension is close to that of the capillary material, which is now determined by the hydrophilic adhesive cover. At surfactant concentrations greater than 4%, however, the rate of flow ceases to increase because the concentration exceeds the critical level. Additional surfactant on the surface of the adhesive does not further reduce the surface tension of the fluid and may become autophobic.20
To investigate the distribution and mobility of surfactants in hydrophilic coatings, chemical surface analysis of the hydrophilic coatings was performed using infrared spectroscopy via attenuated total reflectance (ATR). The FTIR-ATR spectra of the hydrophilic heat-seal adhesive HY-10, which contains sodium dioctylsulfo succinate, were recorded.
Results. Primarily absorption peaks for sodium dioctylsulfo succinate were observed in the fingerprint region of the spectrum at wavelengths which correspond to the methyl stretch at 2967 cm–1 and sulfur-oxygen vibration at 1049 cm–1 (see Figures 8 and 9).21 The HY-10 film surface was then washed and dried and another spectrum of the washed surface was taken in proximity to the original measurement. The disappearance of the 2967 cm–1 methyl stretch and the S-O vibration at 1047–1049 cm–1 confirmed the loss of surfactant as a result of the washing procedure.
Figure 8. FTIR absorption spectrum of the hydrophilic coating HY-10 (C-H stretch region from 2980 cm–1 to 2840 cm–1).
|Figure 9. FTIR absorption spectrum of HY-10 (S-O region from 1065 cm–1 to 1025 cm–1).|
Infrared spectra of the coatings confirm the increase in surfactant concentration on the surface (see Figure 10). The prominent peak at 2958 cm–1 in the ATR is assigned to the C-H stretch of a CH3 group on the surfactant in the hydrophilic adhesive and is used to monitor surfactant accumulation on the surface. A plot of absorbance of the C-H stretch as a function of concentration of surfactant at 0%, 1%, 5%, and 10% shows a flattening resulting from the surface saturation by the surfactant (see Figure 11).
Figure 10. Infrared spectrum of HY-10 (C-H stretch region from 3000 cm–1 to 2800 cm–1).
|Figure 11. Methyl absorption versus surfactant concentration for the hydrophilic coating HY-10.|
Surface Topography by Atomic Force Microscopy
The surface topography of the hydrophilic coatings was observed using atomic force microscopy (AFM). Hydrophilic tapes were mounted onto 1-cm-diam metallic stubs and imaged in the tapping mode. This mode of imaging has several advantages over direct-contact-mode imaging. Lateral forces that are prevalent during contact-mode scans are eliminated. Additionally, the tapping mode provides a nondestructive method for the imaging of soft samples. Importantly, phase images obtained using the tapping mode can give additional information concerning the mechanical and adhesive properties of the sample surface.22
All samples were initially scanned in air. The hydrophilic coating HY-10 was rinsed with deionized water for 10 seconds, then wiped dry with a paper tissue. The sample dried overnight and was imaged the next morning.
Figure 12. Atomic force microscopy images of hydrophilic coatings formulated with various percentages of the surfactant sodium dioctylsulfo succinate. Coatings shown have 0% (a), 5% (b), and 10% (c) surfactant.
Results. The AFM images show enrichment of the film surface at the film/air interface with increasing amount of surfactant introduced to the adhesive formula. The AFM image of the coating containing no surfactant shows a relatively smooth, flat surface (see Figure 12a). Transformation is observed when 1% surfactant has been incorporated into the adhesive coating, where raised features are observed on the film surface. Surface topography is increased with 5% surfactant (see Figure 12b). With 10% surfactant, the surface appears to be smoother due to saturation (see Figure 12c).
Figure 13. Effect of surfactant on surface properties.
A comparison of surface peak height and contact angle as a function of surfactant concentration is shown in Figure 13. When no surfactant is present the surface of the coating appears to be smooth with little topography. At 0% additive, the corresponding effect of surfactant concentration on the water contact angle of the film surface shows that the contact angle is 70–80°, which indicates that the surface is hydrophobic. With increasing surfactant in the adhesive formulation, surface roughening was observed. At 1% surfactant additive, the height of the cross-sectional features increased from 0 nm to approximately 5 nm. The cross-sectional analysis reveals a build-up of the surface features related to increased additive. With the addition of surfactant comes amelioration of surface wetting and the contact angle decreases in a nonlinear fashion until total wetting of the surface is achieved at concentrations of 5% and 10%.
AFM images were recorded before and after water washing of the hydrophilic coating containing 10% surfactant to observe the effect on the surface topography. The images showed the surface topography of the unwashed hydrophilic coating with surfactant concentrated on the surface. After washing with distilled water, surfactant is solubilized and removed from the surface leaving a more rugged topography.
When it comes to the adhesives used in their products, IVD manufacturers are requiring high performance, quick dynamic wettability, and good durability. Adhesive manufacturers must control and balance these factors to achieve hydrophilic adhesives that lend themselves to ease of manufacturing.
However, when choosing an adhesive for use in an IVD device, it is important to consider all of the following: the components to be bonded and the surface energies of those components, the type of fluids to be wicked and the surface tensions of those fluids, chemistry of the reagents, compatibility of adhesive with all components, use conditions, shelf life, and packaging.
Membranes used in lateral-flow devices are typically hydrophobic polymers with low surface energy. Consequently, these components are not compatible with aqueous biological fluids. To overcome the low surface energy of such membranes, surface-active agents are often added to increase their wettability and consequent wicking ability. However, the addition of such surface-active agents may decrease the ability of the membrane to bond or to retain proteins that are critical to the performance of the device. In addition, surfactants added to the membrane can reduce test sensitivity by causing extensive spreading of reagent bands.
The use of hydrophilic coatings formulated by mixing surfactants with a polymer resin can enhance the wicking of biological fluids into or through an IVD device. These constructions bond device components and provide a hydrophilic surface that can reduce the surface tension of a biological fluid. Reduced surface tension allows rapid transfer of the fluid from the inlet area to the reagent area of an IVD, thus reducing the time for analysis. More-efficient transport of fluid to reagent also allows for use of smaller sample volumes, thereby enhancing design flexibility and making it possible to employ alternative collection sites for increased patient comfort. Finally, these products can reduce the risk of chemical interference by providing a wicking surface that allows increased separation between the sampling port and test reagents. All of these benefits allow for more-efficient manufacturing processes with the potential for reduced product cost.
Hydrophilic coatings and pressure-sensitive and heat-sealable adhesives may be used in a variety of IVD products, including capillary-flow, lateral-flow, microfluidic, and electrophoretic devices.
The unique proprietary technology developed for hydrophilic coatings and heat-seal and pressure-sensitive adhesives can be custom-formulated to provide bonding surfaces that enable wetting and spreading of fluids into IVD devices. The selection of adhesive and surfactant additive and its concentration are critical to device performance.
The experimental results provide evidence of hydrophilic enhancement of adhesive tape constructions that can be used for IVD devices. To ensure compatibility, however, different polymer systems will require judicial selection of surfactant. Surfactant properties such as molecular weight, charge type, and chemical structure must be considered in selecting the best hydrophilic adhesive construction.
Hydrophilic coatings formulated with surfactants have proven effective in improving wicking and increasing flow rates in IVD devices. The properties of the adhesive and surfactant are selected to be compatible with the diagnostic device and its reagent chemistry. As with any application, the suitability of a tape construction must be determined by the device manufacturer.
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