The COVID-19 crisis has been unprecedented, and in manufacturing this has put the medical device sector under compressed development timelines never before seen in peacetime.  Companies across America and around the globe have retooled and ramped up manufacturing of personal protective equipment and critical devices such as medical ventilators.

From the beginning, however, testing has been recognized as the key to pandemic control and while the methodologies are well established, tests that accurately targeted COVID-19 were only recently developed and not yet available in sufficient quantities.  Much medical testing is an in-vitro chemical reagent driven process—swab, analyze in a laboratory, then generate results for interpretation by a physician.

This is fine under normal circumstances, but during a global pandemic event it is simply not fast enough for a virus as virulent and dangerous as COVID-19.

A better solution would be a small, low-cost handheld device capable of point-of-care testing and which generates accurate, repeatable results that don’t require a physician or lab technician to interpret. The result would be the kind of flexibility that front-line healthcare workers need: the ability to identify and isolate cases quickly, without the need to quarantine or examine COVID-free individuals.

What does it take to engineer devices with these tough specifications?

One company that has prioritized manufacturing support for companies working to develop solutions for this problem is Parker. Reggie Stotts, Global Market Development Manager, Diagnostics for the company describes the current systems. “What we're seeing right now are organizations scrambling as quickly as possible to come up with different assays that will either test for presence of the virus in the patient currently, or coming up with assays to determine if there are antibodies in patients that will signal that they've been infected previously. There's a real scramble going on right now to come up with assays that work on existing platforms, as well as some in this space who are trying to develop new detection techniques.”

With two basic testing methodologies, the problem would seem to be simple. However, there is an important difference between determining if a patient is currently infected, and determining if a patient was once infected, but is now virus free.

Don McNeil, Strategic Marketing Manager, Clinical Diagnostics at Parker, explains, “Often you'll hear about rapid tests or RNA tests. These are called molecular diagnostics tests. These tests look for the RNA that is present in the COVID virus in the patient. If the patient sample has COVID RNA in it, that means they're infected. Those are the tests that are being used for the rapid determination if a patient is sick with COVID or not, and constitute the vast majority of the testing going on right now.”

“The next type of testing is key and will become more and more important as we try to open the country again and get people back to work and out in public. It’s called antibody immunochemistry testing. This is where the test, instead of looking for the DNA of the coronavirus, looks for patient-created antibodies against the coronavirus. It is believed that the antibody test proves that the patient will not be reinfected. This allows us to decide, ‘Okay, this patient now has immunity. It's safe for this person to go back out. They won't be infecting other people, and they are not at risk of being infected themselves,’" says McNeil.

In a sense, these two testing methodologies represent a tactical and strategic approach to the COVID-19 problem. Tactically, healthcare workers need a yes/no determination of patient infection to move forward with treatment and isolation. Strategically, healthcare workers and public health authorities need a test that certifies individuals as COVID-free and able to return to normal life without the risk of infecting others. With the current state of understanding of the COVID-19 virus, it’s unclear whether a positive test for the presence of antibodies in a patient prevents them from becoming re-infected, but it does suggest that their transmission risk is low.

Automating Point-of-Care Testing

The automation of medical testing has been ongoing for decades, but much of it has been focused on replacing human labor within the standard laboratory model. Getting away from the need to move samples to a central testing location, then send data back to physicians is a serious technical challenge.

In the current environment, there simply isn’t time to spend years developing new systems, and multiple medical device manufacturers are rushing equipment into the field. The U.S. Food and Drug Administration (FDA) is doing its part with a greatly accelerated approval program, but safety is not the same as accuracy and repeatability. At least one manufacturer has developed a point-of-care testing machine that the FDA has determined to be unreliable.

That machine, developed by a major medical device manufacturer, was not unreliable because of poor engineering, but because of the complexity of the testing process, which is based on in-vitro lab technologies developed in the early 1990s.

Much current testing uses a technology called singleplex PCR. It uses a technique called polymerase chain reaction to replicate a tiny sample of a specific DNA sequence millions or billions of times to create a mass large enough for detectable activity with reagents. By testing one sequence in one tube, it’s possible to get definitive results for a very narrowly defined DNA sequence.

An alternative is multiplex PCR, where multiple DNA fragments are amplified and tested with reagents that can discriminate between sequences. This is analogous to multiplexing in signals electronics, with one reaction performing several tests simultaneously. A patient with a persistent cough and fever for example, may be tested with singleplex PCR for COVID-19 and test negative. The patient is still ill, but with something other than the COVID-19 virus. A multiplex test could be designed to also test for other viruses, allowing the physician to definitively identify what has made the patient sick, such as a common seasonal flu.

Running a large “panel” is obviously a preferred strategy, and current technology has brought automation to the process.

“When we talk about the large automated machines that are in the laboratories, these are usually referred to as in-vitro diagnostics (IVD) machines. These are great and they're designed for high throughput, but the challenge is that they can't be placed close to the patient, so there's a delay in getting the sample to the machine,” says McNeil. “Then there is often a delay queuing up the sample to go through the machine because there are thousands of other samples being run. Once the result comes out, then the answer has to get back to the patient. That can frequently take a day or more, especially if the samples are being shipped to a clinical laboratory. When you add up all these delays, the high throughput of these IVD machines is totally lost. These machines are very good for routine testing because they can run the samples at a lower cost per sample than a point-of-care machine.”

“Where point-of-care shines, where it's really needed, is in a more urgent situation,” McNeil adds.

While the current pandemic has redefined the notion of urgency in point-of-care testing, there are multiple ways that an automated, low-cost solution can improve patient care. ER and OR environments both need quick answers for sick patients who may require isolation. Besides public health and patient wellness enhancement, system costs can be reduced as well, as McNeil describes:

“Hospitals measure what they call patient turnaround time—the time from when the patient checks in to when they are discharged and they check out. It's like turns in a manufacturing environment. The faster they can turn those patients around, the more patients that the hospital can serve. Right now, there's a shortage of about 7 million healthcare workers worldwide, and that number is expected to get worse, rising to about 12 million in 2030. So, hospitals are trying to function with fewer personnel. If you can increase the turnaround time, you can care for more patients with the current staffing levels.”

A small, low-cost and easy solution is an obvious money saver, but there are other benefits for patients and public health in general. A system that operates without the need for trained lab technicians, or clinicians to interpret the results, could open testing to public venues such as walk-in clinics, schools or pharmacies. A small footprint device can be issued to paramedic services and individual EMT technicians. A low-cost and ubiquitous system could also eliminate the need for billing through medical insurance, encouraging individuals to purchase a low-cost but definitive test before presenting at a clinic or hospital.

According to McNeil, although the proportion of the total cost of diagnostics in hospitalization is in the low single-digit percent range, almost three-quarters of the decisions that doctors make about patient care are based on those tests. More data upfront means better care with lower costs as the output.

The medical device manufacturing industry is perhaps the most highly regulated discipline in engineering. Testing devices must be safe to use for patient and testing personnel, and generate definitive results with a highly controlled and very low rate of false positives or false negatives. Much of medical testing operates by statistical processes and probabilities. There is always a possibility of error, however small, and this makes the engineering of machines with simple “go/no-go” presentation of results challenging.

According to McNeil, “there are very strict requirements. An organization called CLIA manages clinical laboratories and in order for one of these machines to be working outside of a laboratory, away from very highly trained laboratory personnel, it needs to have a CLIA waiver. The manufacturer has to be able to prove that the system is so easy to use that a user with minimal training and reading through a small manual of instructions can operate it.”

Even handling test result data adds technical challenges. The Health Insurance Portability and Accountability Act requires healthcare providers to protect and secure patient information. A simple Bluetooth connection is an easy, low-cost way to move data from a point-of-care testing machine to a smart phone or tablet, but robust encryption is necessary. The COVID-19 crisis has spurred the FDA to issue waivers to device manufacturers, but testing accuracy and repeatability must still be similar to in-vitro testing devices. It’s a tough technical challenge.

What Form Will a Compact Point-of-Care Device Take?

In essence, new generation point-of-care testing devices will follow the path of computers and consumer electronics: do what big machines do faster, cheaper and in a smaller footprint. This miniaturization will make the I/O, data processing and communications functions single-board PCB solutions, but the chemistry is little different from testing in laboratory glassware. Patient samples will be inserted into a small presterilized and preloaded resin cartridge containing the necessary reagents and the machine will pump reagents to small reaction chambers for the actual testing.

The chemistry is the same as that of larger IVD machines, but miniaturizing the volumes of liquids and moving them through very small channels creates its own set of engineering problems. Surface tension and liquid viscosity, for example, are much more important in microfluidic or small channel fluid handling, with associated complexity in pumping and fluid transfer.

“A point-of-care testing machine generally moves liquids in a different way than an IVD machine. IVD machines tend to use liquid pumps and valves. They'll have precision syringe pumps and piston pumps, rocker valves, and everything is moving liquid,” says McNeil. “On point-of-care testing systems, most of them use pneumatic energy or vacuum to move things through the cartridge. The cartridge is inserted, the machine interfaces to that cartridge and applies the correct pressure to move liquid from chamber A to chamber B and then add reagent C and do mixing.”

Pneumatics are provided with a miniaturized self-contained piston or diaphragm pump and operate at pressures that are typically under 10 psi, although some newer devices operate at 100 psi pressures in the same small form factor.

Getting the sample into several reaction chambers in a cartridge that may be no bigger than a deck of cards is one challenge, but how can the electronics interpret the results?

In the process industries, testing usually involves chemical changes that are readily measurable, such as pH, temperature, viscosity, color or the presence of a precipitate. Advanced point-of-care testing technology often takes advantage of chemiluminescence. A chemiluminescent reagent bonding to a target DNA fragment will emit photons which can be detected by chip scale sensors using off-the-shelf technology. Alternately, a specific frequency of laser light can be passed through an optical window in the cartridge and onto the detector.

A key element to this strategy is the containment of the test sample and reagents in the disposable resin cartridge. With pneumatics moving fluids, it’s possible to segregate the machine from possible contaminants, eliminating the need to sterilize the equipment between tests. If sterilization is required, it’s a simple process with commonly available cleaning and disinfection agents.

What Can Engineers Do to Speed Development?

Most medical device manufacturers in the diagnostic testing segment understand the chemistry well. Their capability in machine design, system development and integration is normally a secondary skillset for most teams, and as a result they typically rely on their vendor engineering team in a similar way to the OEM/Tier One relationship in the auto and aerospace industries. 

“It depends a lot on the OEM that we’re interacting with,” McNeil explains. “Some have fluidic engineers, and some have hired people to figure how to make these machines. They may come to us to say, ‘We need a pump and a valve that will do X, Y and Z for us. And here's the space you have. Can you put twelve valves and a pump in that space? Yes or no?’ Others may not have as much fluidics expertise in-house, and they don't want to invest in that expertise if they can work with a partner like Parker. They may come to us and say, ‘This is how much liquid I have to move. Here are the different chambers I'm thinking about. How many pumps and valves do I need?’”

McNeil relates an example regarding a specific customer developing a point-of-care testing device that needed a footprint no bigger than an eight-and-a-half by eleven sheet of paper, or smaller.  Parker developed a very compact high-speed pneumatic pump capable of 100 psi pressure specifically for the application. The key for device manufacturers is to understand their in-house capabilities in fluidics and reach out to experts like Parker early enough to develop workable solutions before a design is locked in. Design changes are always expensive, but in the compressed time-to-market environment of a pandemic, the costs can be astronomical.

Stotts agrees. “They want to focus on their chemistry. They see that as their core competency, and the machine building to a lesser extent, so they tend to lean on companies like Parker to do a lot of the engineering. But even if the company regards the whole device as their expertise, they're going to want something designed for manufacturability. Something that, in a perfect world, is off-the-shelf, that can be easily manufactured and uses readily available components. Often, they typically want to be able to alternatively source, so that they always have a supply of that part.”

When should an engineer working on a point-of-care testing technology reach out to experts like Parker? Stotts states simply, “As soon as possible. The earlier they approach us, the more value that Parker adds. We already make a lot of the solutions that Don [McNeil] mentions, so the sooner we're brought in, the more we can help steer the conversation to areas or avenues that will help ensure success of the application overall.”

With capabilities ranging from EMI touchscreen and thermal management solutions, to filtration and polymer-based assay consumables, Parker’s engineering expertise is the trusted core competency.

During the COVID-19 crisis, Parker has prioritized medical device industry engineering support.  For more details visit the Parker website.