In a single-use cartridge for the point of care, why use pneumatic control of on-board diaphragm valves in the cartridge when a linear actuator against a flexible layer works just as well?
This question was recently posed by a client as they consider their development path from proof of concept. They envision a couple of different product use environments, one involving a benchtop instrument, and another a portable handheld using battery power.
In some cases, the answer might just boil down to personal preference. But from a development perspective, pneumatically controlled on-board valves offer more flexibility in design of the cartridge.
Consider the following:
On-board pneumatically controlled valves have all the air control lines bused to one edge of the card, and interface through a gasket to a manifold. This makes it simple to create a cartridge carrier that clamps the cartridge in place. With pneumatic control, there is no need to worry about the arrangement of electro-mechanical components above or below the device. A more open instrument architecture is possible with fewer components to get in the way of engineering in optics or heating.
During cartridge development, no engineering of a mechanical actuation interface is required, simplifying parallel cartridge/instrument development and de-risking the final integration of the cartridge into the instrument.
For multiplexing applications, a high density of valves is also easily accomplished with on-board pneumatically controlled valves. Our valves have a 2 x 3 mm footprint, and have been made at densities of 6 valves in a 9 mm2 footprint, arrayed in the standard microtiter plate footprint. Actuation of this many valves would be impossible with a mechanical interface.
Pneumatics also provide positive control of both the opening and closing of the valve. With mechanical actuation there is only one control direction, and that’s to close the flexible layer into the body of the cartridge. If fluid passes through after the mechanical actuation is removed from the flexible layer, the return of the flexible layer to the open position will depend on how long it was closed and may contribute to uncontrolled changes in the pressure drop in the fluid circuit, affecting overall performance.
A rechargeable battery can be used to power a pneumatically controlled cartridge with eight solenoid valves in a handheld system. This has been demonstrated in a commercial handheld that is the size of an iphone 6 and about an inch thick. With pneumatic control, a spike current is needed to actuate from one state to another, but requires very low power to remain in that state. When designed correctly, the pneumatic control like the mechanical actuator, requires intermittent power use. The same is true for the pressure and vacuum pumps. Small pumps, about the size of a fingertip, are used to fill an accumulator to the required vacuum or pressure which is typically no more than 10 psi. The pneumatically controlled valves require very little air flow, so the pumps only cycle on intermittently as well.
Because there are fewer moving parts with the use of pneumatic controls, jostling or even dropping a handheld has less risk of compromising the operation of the cartridge, making it more robust in a field application.
In summary the advantages of pneumatic control of on-board diaphragm valves in cartridges includes:
1. Early collection of performance data with a cartridge operated with a simple mechanical interface.
2. No upfront instrument integration required to achieve semi-automated control of the cartridge.
3. De-couples cartridge optimization from the instrument design.
4. Simplifies the instrument design, reduces the number of mechanical components that interface to the cartridge.
Contact us to learn more about our on-board pneumatically actuated valves, and pneumatic controller, the ADEPT.
Our valves have been incorporated into commercial products. We have technical data on the their performance that we can share under confidentiality.
I am very pleased to announce the appointment of four new members to the Board of Directors: Rob Randelman, Bruce Sargeant, Steve Schaefers, and Joe Stetter. Each person brings a valuable perspective to the board including FDA design control expertise, supply chain management, international business development, and world class scientific expertise in electrochemistry. Each member is distinguished in their respective careers and well regarded within the business communities they serve. Each has been involved in the growth of high tech businesses. Their combined expertise brings a unique strength to the board, and I feel very fortunate to have their support. Their breadth of knowledge and hands-on experience in building technology-based businesses will create synergies and lead to unexpected strategies to build ALine into a world-class microfluidic engineering and contract manufacturing firm. Please go to this link to learn more.
Leanna M. Levine
President and CEO
What happens between a surface and a fluid stream can lead to foul play. That’s why I’m a materials girl. The complex physics and chemistry of surfaces is an important consideration in any product development, and is particularly important for microfluidic systems where the high surface area to volume ‘concentrates’ the effect of the surface. The choice of materials should be taken into consideration during the early design of microfluidic devices to enable applications including cell culture, immunoassays, or nucleic acid amplification.
With sophisticated workflows for immuno-analysis, materials impact assay sensitivity, limit of detection, fluid circuit functional performance, and shelf-life. This is because antibodies stick well to lower energy surfaces, such polystyrene. In cell culture applications, material surface properties can be a matter of life and death, and any leachates from bonding materials can activate cells to begin apoptosis or programmed cell death. For nucleic acid amplification, the issues arise not with the charged nucleic acid molecules being amplified, but, with the reduced activity of the enzyme.
Fluid handling in the device is also impacted by the surface properties. The material surface energy can provide enhanced performance with capillary fill, or create variability if the surfaces have residue from fabrication or do not come from a supplier providing a certificate of conformance. Examples would be the presence of mold release from injection molding, cleaners use to polish machined parts, or debris left from any of a number of cutting tools, including laser cutting, or machining. Hydrophilic surfaces, offered by a few suppliers such as 3M, and Adhesives Research, are frequently used to affect capillary fill and metering of samples or reagents.
Choices for mitigating the effect of surfaces is a tradeoff between cost and complexity. In many cases, the simplest solution is to add other mediators, such as the serum albumins (BSA), or any of a number of polyethylene glycols (PEGs), which when used in excess concentration, effectively foul the surface instead of any active components in the reagent mixture. Likewise, bumping up the concentration of enzymes and active components helps, too. Adjusting the reagent composition is likely the most direct path to increasing performance. Added development will be required if you plan to dry the reagents into the device. In addition, materials that are purchased with their native properties, and for which the design of the fluid functions is insensitive to the surface over a large range of operating conditions, provides the lowest cost, and most robust solution.
In cases where ultra-sensitivity or enhanced functional control and performance is desired, especially for in vivo (e.g. in whole blood where you don’t want platelet activation), or special cell culture applications, imparting chemistry to the surface can be done with covalent linkages created through various methods, including chemical vapor deposition in a vacuum chamber, or plasma treatment with controlled gas mixtures at atmospheric pressure. These processes add cost and complexity to the manufacture, but provide a surface tailored for specific functional attributes. With chemical functional groups on the surface, specific chemical linkages with reagents or secondary surface modifiers can be made with good control. Other methods of controlling surface properties includes the application of a coating and then curing it in place, a common practice in catheter manufacture. Finally, nearly all the methods used to improve the adhesion of bonding materials, whether corona, plasma, or flame, all impart some hydrophilicity to the material. But the shelf life of such treatments is variable, not only due to variations of the treatment conditions, but on the polymer itself. In general, more crystalline polymers will retain surface treatment longer, since the chains have less mobility.
For single-use product applications, avoiding costly treatments to native materials through the design strategy on the fluidics side, and solution modifiers on the reagent side, is the first strategy. If surface treatment is a preferred strategy, then treating the materials before assembly reduces variability. Being able to tailor function by using mixed materials, is also a robust strategy for cartridge development. Using bonding methods that allow assembly of mixed materials facilitates this approach.
This is where being a materials girl comes in handy. Experience with successful products in the marketplace; we stock a well-vetted collection of materials for the most common microfluidics applications. We purchase from qualified vendors with lot control, even in the early development stages. This avoids surprises later during scale up. (Don’t worry, other surprises will crop up). We stock materials which have a track record of performing well in applications ranging from mammalian cell culture to immunodiagnostics. Most of our supplier relationships go back more than 10 years. The table below describes the materials we stock which are commonly used in disposable cartridge development.
It’s a material world, and on the surface, a lot can happen!
The complexity in Microfluidics Product Development originates in the requirement to integrate and optimize the functional performance of a variety of dissimilar components that are coupled together in close proximity. It involves a combination of biological and materials science and engineering to create a robust product solution. Any product that performs tests and measurements is fundamentally an information producing system. The quality of the information depends critically on how well each of it’s disparate components are harmonized to become ‘more than the sum of the parts’.
This is where an understanding of the science is critical to success. In microfluidic systems, the high surface area to volume, shorter diffusion paths, and smaller thermal masses can reduce the time to reach the measurement end point. This is one advantage of microfluidic systems. However, if in performing a multi-step assay, inadequate washes, or an incorrect washing approach is implemented, the opposite will occur. Instead, the system will exhibit degraded sensitivity or dynamic range, or have greatly increased testing times and produce poor quality information. Some poorly designed systems require very high volumes of wash fluid which creates a large mismatch in the fluid components.
Another feature of some more complex tests is to try to translate the exact protocol done in bench top instrumentation or on robotic systems, into a device. This can lead to half a dozen reagent storage packs or more followed by cumbersome mechanical interfaces. Just remember, each component of the system that requires some sort of separate performance validation is adding complexity, and a risk for failure. A better product strategy is to optimize the assay to require no more than three separate reagents.
From an engineering and design for manufacturing perspective, the fewer mechanical parts there are, and the lower the tolerances for the interconnections of these components, the better. Some simple things to remember include taking advantage of the force of gravity…it’s free and it’s dependable! Another simple pointer regarding cartridge alignment is to never design the alignment of the cartridge into the instrument along an edge. This creates constraints on the precision of the disposable component, the very thing you are trying make as inexpensively as possible.
Some of the tougher engineering issues to solve involve the ability to do thermocycling. Here the science, engineering, and system design all need to happen together to ensure that a design feature in one component doesn’t add complexity or risk to another component. Even the nature of the nucleic acid detection test itself can affect the system design and choice of materials, so it’s prudent to map out reasonable specifications on performance of the assay at the outset and chose the disposable design, and interface to the detection and other electro-mechanical components early.
Our approach to supporting systems engineering is to design and develop sub components instruments, such as the ADEPT and ADEPT+, that can be customized and modified to test the integration of each component. Our instruments include cartridge clamping, modules for pneumatic, pumping, and thermal control to provide a means for semi-automated control of the assay being performed. By doing this early in the development program, the overall development risk is lowered and the quality of the final product enhanced.
Learn more about our systems approach by viewing our new Systems Engineering Brochure
ALine’s expertise in microfluidics design and production, integrates custom fluid handling in a single-use device with semi-automated instrument control.
Our toolbox of well characterized on-board valves, pumps, metering, mixing, and de-bubbling strategies perform robustly with manufacture scale up.
Starting with an assay that is performed in a microtiter plate, ALine translates the manual workflow into a semi-automated process in a microfluidic device.
In as little as 60 days, you can be running your target assay in a customized microfluidic device with automated control in an instrument, and begin optimizing the device design and reagents to achieve proof of principle..
SLAS2016 January 25 – 27th, San Diego Convention Center
Learn about our unique solutions to Lab-on-a-Chip products with Instrumentation to support Plug and Play Automation.
SEE the ADEPT Controller with Pressure Sensors, Regulators, and Integrated Thermal control, Vacuum and Pressure Sources
Flexible and Easy to Customize Instrumentation that enables:
ALine is proud to partner with Elveflow to develop custom microfluidic solutions
An ElveFlow pump will be available at the booth. Check it out.
- Droplet Generation
- Cell culture
- Droplet PCR
3D printing lends itself to the manufacture of components which are tailored to specific needs of the end user. For example, an early application of 3D printers was in the manufacture of custom hearing aid shells, designed to fit comfortably into the ear of the individual patient. In dentistry, it has been used to create crowns, mouth guards and braces. Applications in the Life Sciences and Medical Device industry continue to grow as the print resolution, and available materials expand. Exotic applications in tissue engineering, with the goal of producing organs and tissues with defined composition, are being explored.
For applications in microfluidics, ALine has developed a series of 3D printed fluidic connectors that integrate with custom microfluidic devices produced with rapid prototyping techniques such as lamination, or micro-machining. By comparison, commercial connectors, such as luer-locks and hose barbs, have only a limited choice in terms of geometry, require a large footprint for multiple inputs, and introduce dead volume into the fluidic network. Some tubing connectors with compression fittings are available with low dead volume, but are priced so high they often cost more than the device itself.
3D printed fluidic connectors greatly expand the options available to bridge the “chip-to-world” interface. The micro-to-macro interface between the microfluidic chip and the supporting instrumentation has always been a difficult engineering problem. This interconnection issue sometimes leads to the assertion that microfluidics really represents a “Chip in a Lab” rather than a “Lab on a Chip”.
With the development of low cost, high resolution 3D printers, the interface problem can be overcome with simple, easily customized connections. 3D printed connectors with multiple inputs occupy a much smaller footprint and minimize the dead volume. Connectors are customized for the specific device configuration to allow 90 degree of co-planar connections. Hose barbs for flexible tubing connections, as shown in Figure 1) and 2), are a typical application and are readily assembled to the microfluidic using biocompatible pressure sensitive adhesives.
The process to produce these connectors is suitable for rapid prototyping and low to mid-volume manufacturing. The turn-around time is typically a few hours because the process does not involve any machining or production of molds. 3D designs are created using computer automated design (CAD)
software. The printer selectively cures 2D layers of a UV resins, building successive layers which produce 3D objects. Multiple resins are available allowing for choice of color, mechanical properties and biocompatibility. Typical batches include 10-20 connectors per 3D print run with scale-up to 100s and even 1000s easily achieved with no change in equipment.
ALine’s approach of combining 3D printed connectors with our proprietary laminate fabrication technology provides design flexibility in the development of custom microfluidic devices. With the advanced 3D printing tools now available, we solve the problem of the “Chip-to-World” interface with customized connectors, tailored to meet the unique design and functional requirements of each microfluidic application.
For more information contact: Stefano Begolo, Ph.D.; sbegolo(at)alineinc.com
We are pleased to announce that Dr. Stefano Begolo, a recent post doctoral fellow in Rustem Ismagilov’s lab, is joining ALine, in early August 2015.
Stefano was a customer while he was working on the Slip Chip technology at CalTech and he enjoyed interacting with us enough to be interested in being part of the team!
Stefano’s expertise in microfluidics, his familiarity with assay development and PCR, and his interest in working on a variety of client programs will add tremendous depth to our offering.
With his expertise in 3D printing, we plan to offer this capability along with our popular laminate technology.
Click here to learn more about Stefano.
The ADEPT Automates Potentiometric Measurements Using a Microfluidic card connected to an Ion Selective Electrode (ISE) Sensor Array
We combined a low noise multichannel electrometer with the ADEPT pneumatic control instrument for sequential testing of an ISE sensor array to measure Na+, K+, and pH using an external reference. The test system includes an 8-channel ADEPT instrument with the electrometer housed in a shielded box. A slide in port for the microfluidic test card reduce ambient noise and the automated routine for delivering three different analyte solutions of Na+, K+, and pH, provided a controlled environment for the ISE measurements.
Read our latest Newsletter to learn more.
ALine, a leading developer of advanced Fluid Circuit products and solutions is pleased to announce that George Lauro has joined its board. George has 25 years of experience as a technology entrepreneur, operating executive, and venture capitalist. He has built several tech companies from early stage to high value exit (M&A or IPO). George is Founding Partner of Alteon Capital, a Technology Venture Development firm based in Cambridge, MA. He was Managing Director at Wasserstein Perella and head of West Coast technology investing, and was a Partner at Techfarm Venture Capital in Silicon Valley. He led and syndicated 18 private equity financing rounds and control deals, raised over $100M equity financing for portfolio companies and completed over $1 billion in M&A transactions. George will work with ALine’s management team to develop and execute its accelerated growth strategy.
George Lauro added, “I am delighted to be joining ALine’s Board. I believe that the Company’s proprietary functional and material set and strong design and process team positions it for significant growth in the microfluidics and Lab-on-Chip sector. I look forward to helping the Company and team achieve this potential.”
Dr. Leanna Levine, President and CEO commented, “We are very happy that George recognizes the growth potential for our business. His distinguished career and experience in venture capital, operations and entrepreneurship are a tremendous asset to ALine. We are pleased he recognizes ALine’s unique and valuable position in the microfluidics market space.”
ALine is a leading microfluidic and Lab-on a Chip engineering and manufacturing company serving the Life Science, Medical Diagnostics, and Analytical test markets. Over the past 7 years, we’ve designed and brought to volume production several advanced microfluidic solutions for major customers in several industry sectors, including NASA, JPL, Abbott, GenMark, and Iris Diagnostics (Beckman Coulter).
ALine’s array of materials and fabrication processes give us the broadest design space of any Microfluidics company in the world. We provide prototype-to-production solutions and execute all steps of microfluidic solution development from initial design through prototyping up to high volume manufacturing. Our unique processes enable one week turnaround on prototypes of sophisticated microfluidic and Lab-on-Chip devices that are scalable for volume production.
ALine was founded in 2003, and is ISO9001:2008 certified.