PCR

As part of bi-weekly meetings of the SEMI Environment, Health, Safety and Sustainability (EHSS) community to share information on the impacts of the pandemic, the EHSS COVID-19 Working Group recently revealed that companies are offering PTO to employees to get vaccinated.

The recent global pandemic redefined well-established paradigms in healthcare. The classic model involving frequent hospital visits is no longer viable due to the risk of contagion. The focus is now on remote and pervasive vital sign monitoring solutions and automated data processing for health assessment. Social-distancing-friendly technologies, such as wearables, implantables, insertables and ingestables that enable long-term monitoring, can help detect medical abnormalities both in individuals and large populations. SEMI spoke with Carlos Agell, program manager and principal member of Technical Staff at imec, about remote vital sign monitoring using innovative form factors and methodologies. imec’s healthcare technology vison for remote care systems will be the focus of Agell’s presentation at the SEMI MedTech Forum, 19 February, as part of the SEMI Technology Unites Global Summit, 15-19 February 2021, online event. Join us to meet experts from imec and other key industry influencers. Registration is open. SEMI: What is driving innovation in diagnostics and what is the role played by the semiconductor industry? Agell: There is a clear need for remote diagnostics triggered by the COVID-19 pandemic. Two examples are respiration monitoring and SARS-CoV2 testing technologies. The fact that some of the more obvious symptoms of COVID-19 are respiratory has revealed a big gap in medtech: the need for low-friction, ambulatory, continuous and pervasive respiratory monitoring solutions. At imec we have been working on bioimpedance-based technologies (from chipsets to smartphone-enabled sensing devices) that can provide feasible solutions in that space. Hence, novel sensing modalities from the semiconductor industry can make a difference when it comes to remote ambulatory respiratory monitoring. On the other hand, SARS-CoV2 diagnostic technologies have become paramount during the health crisis. In this space there is a clear need to simplify, speed up and lower the cost of testing. Additionally, from a practical perspective society needs to prevent virus spreading. imec is spearheading an innovative semiconductor-based solution aimed at simplifying SARS-CoV2 testing by collecting aerosols from subjects’ breath using a silicon-based solution for analysis using the polymerase chain reaction (PCR) method, the gold standard in COVID-19 testing. Determining viral load in exhaled breath is a clear indicator of infectiousness, and detecting subjects with a high viral load is key when developing these rapid tests to facilitate economic recovery. A cost-effective and speedy though reliable SARS-CoV2 testing solution opens up possibilities for its use as gating mechanism (such as testing to allow access to facilities and prior to boarding a plane) to help jump-start some of the hardest-hit sectors in the economy, such as travel and hospitality (hotels and restaurants) by enabling more in-person interactions. SEMI: Please share more about imec’s commitment to improving the healthcare sector. Agell: imec R D is active in the field of remote unobtrusive respiration solutions, which are vital in treating respiratory system conditions such as asthma, chronic obstructive pulmonary disease (COPD) and COVID-19. These solutions rely on a combination of silicon chipsets, sensor integration and algorithms to interpret sensor data. As part of our effort to understand biological fundamentals, imec’s multi-electrode array (MEA) platform for heart-on-chip applications offers unparalleled capabilities to acquire high-density information (4444 electrodes/mm2) to enable extra- and intracellular recordings, electrical stimulation and impedance gauging to study patient-derived cardiomyocytes, cells that make up the heart muscle. imec is developing a rapid, low-cost SARS-COV2 test based on breath analysis (aerosol capture) aimed at a 5-minute analysis. Such tool is a key to economic recovery, and imec is planning large-scale testing of the prototype device at Brussels Airport later in 2021. imec has recently supported spinoffs and external companies that develop social distancing tools for usage during the pandemic. Healthcare is a key strategic area at imec, with multiple departments working on complementary topics, ranging from cell-sorting technologies and multi-electrode arrays, through sensors and systems for non-invasive cardiorespiratory and neurological monitoring, all the way to advanced processing of medical data and tooling for trials. SEMI: How is the pandemic impacting remote diagnostics? What’s new in that field? Agell: The pandemic has accelerated advances in remote diagnostics for healthcare – for example making remote doctor visits possible and launching telehealth into a successful sector. But in my opinion, this is just the starting point. Telehealth doctors will soon need to collect health data points such as body temperature, weight, or blood pressure remotely, the same information they collect during an office visit. Soon thereafter though, doctor’s will need more and more data, sparking the next stage of advances in remote diagnostics as algorithms are developed to analyze sizeable amounts of data. All in all, it will result in a big move from doctor-centric paradigms to more patient-centric solutions. Hopefully that jump will also drive a more proactive approach to health, enabling prevention and keeping people healthy, and leaving behind the era of curing the sick. imec research tools for respiratory monitoring will come in the form of a health patch. SEMI: Besides infectious disease diagnostics, what solutions will enable a paradigm shift? Can you name two global market trends related to the rising need for remote diagnostics? Agell: The paradigm shift in healthcare will be largely fueled by the hyperconnectivity trend. Communications are fast and far-reaching. The pandemic has proven that healthcare, similar to retail, banking, trading and business in general, can also be done partly remotely through a communications line. The need for proof of performance in the case of diagnostics has been proven challenging, due to the highly regulated medical field and the general conservativeness of this market. There is a clear trend underway in which algorithms and automated diagnostics are slowly gaining the trust of the medical community. Trials and regulatory submissions will help here, but the clear proof will be the general trust of the medical community (and general population) in solutions that have been on the market for a while. Similar to what happened with GPS navigation technologies back in the day, it would require a critical mass to reach general acceptance. As far as the healthcare market is concerned, there is a forecast bounce back from telehealth into hybrid models (a mix between in-office visits and telehealth) as a first post-pandemic scenario. Although this is perceived as the best of both worlds, its effectiveness and survival within the market is still to be proven. A clear market trend accelerated by the pandemic is the commoditization of health and wellness features in consumer electronics. A glimpse into consumer electronics venues reveals that watches, smartphones, weight scales and even your office chair or mattress will soon be collecting healthcare information. imec MultiElectrode Array (MEA) chipset SEMI: What is imec’s role in addressing the challenges and trends in healthcare? Agell: As an R D organization, imec offers expertise in the semiconductor, integration, data interpretation, data management and health-specific application domains. Thanks to our experience in horizontal technology and multiple application domain verticals (including healthcare), imec provides solutions to partners that push the boundaries of performance in health-tangential fields such as communications, consumer electronics, automotive and energy. imec is part of big European initiatives aiming to tackle the challenges of the pandemic. For example, we recently started working on the Digipredict project, which aims at early intervention in infectious diseases. We’re working with key players in the research domain within the EU such as École Polytechnique Fédérale de Lausanne, University of Twente and Eidgenössische Technische Hochschule Zürich. Additionally, imec has worked for market leaders in the healthcare sector such as Philips and Biotelemetry (recently integrated in Philips) and can help partners make the next health solution a reality. SEMI: How can technology unite us? What do you expect from your participation at SEMI Technology Unites Global Summit? Agell: I am a big optimistic on this pandemic. I believe technology has played a key role in putting boundaries around damage caused by the global health crisis. Technology does not only unite us, but it arguably saves lives! My personal expectation for the SEMI Technology Unites Global Summit is for us to get a better understanding about how the semiconductor industry reacts to a pandemic and upcoming post-pandemic scenario. I am curious to see if health-related trends emerge, and whether this is a transitory effect. During the last global pandemic, the semiconductor industry was not even existing, so there is no clear precedent for the current situation. Carlos Agell, program manager and principal member of Technical Staff at imec, where he oversees the development of projects and sets strategy directions for research topics. He has a background in wearable device development, having taken leadership roles in development of two FDA-approved medical devices in the field of wearable cardiology. He is member of the Dutch chapter of the standardization committee, which develops next-generation international standards for active medical devices. Carlos Agell holds two MSc degrees in Electronics Engineering and EECS from the Polytechnical University of Catalonia (Spain) and the University of California in Irvine (Irvine, CA, USA). Serena Brischetto is senior manager of Marketing and Communications at SEMI Europe.

While the world awaits a working vaccine to protect us from COVID-19, we need to employ all available tools to help curb the spread of this novel virus. On the one hand, it’s remarkable that we’re relying on the same low-tech tools that our forebears used to moderate the pandemic of 1918 — social isolation, mask-wearing and hand-washing. On the other, we have access to numerous technologies that hadn’t even been invented a century ago. Among the most important is molecular diagnostics for advanced testing.While we continue to face a scarcity of test kits in the U.S., the majority of commercially available genetic tests for COVID-19 are reliable, so accuracy is rarely the problem. We’re hampered instead by the timeliness of getting the results and by the level of detail the tests provide.To save more lives and reduce the burden on our healthcare system, we need point-of-care genetic tests that deliver accurate results rapidly, telling us right away who’s positive and who’s negative. We also need pertinent test data shared as quickly as possible via secure networks to improve our ability to track surges in infections. These are two of the challenges that emerging biotech companies are pivoting to embrace. RT-PCR: The Gold Standard in Accuracy, Not SpeedWhen I read about some of the high-quality COVID-19 tests on the market – such as Abbott’s, which detects positive results in as little as five minutes — I am awed by how far we’ve come since the last global pandemic. The core enabling technology in test platforms such as Abbott’s uses the molecular genetics technique real-time reverse polymerase chain reaction (RT-PCR). The vast majority of rapid tests administered today in hospitals and other clinical settings use RT-PCR.While accuracy is high for RT-PCR tests, getting tests results to patients is slow because test samples are sent to the lab for analysis. That lab could be located in a hospital, in a doctor’s office, or in an urgent care facility run by a large company such as Quest Diagnostics. Regardless of location, each lab must have an RT-PCR machine to read the test results. Plus each RT-PCR machine costs thousands of dollars, and requires a technician to read the results, , factors that have limited the proliferation of these machines.New COVID-19 cases are still surging in parts of the U.S., India and Brazil, and in some areas, we’re seeing instances of inundated labs, with test results coming back in one to two weeks. That’s not fast enough for a virus this contagious. We need to get accurate tests results to healthcare providers, public officials, and patients as close to real-time as possible. To meet this goal, we need to apply molecular-diagnostic techniques to new types of biosensors that deliver test results at the point of care in minutes through platforms that send that data in near real-time to the cloud. This essential information will allow public health institutions, states, cities and other key stakeholders to identify and mitigate emerging hot spots of disease.Over the past seven months, we’ve had the privilege of working with a handful of biotech companies that have pivoted to develop rapid point-of-care molecular diagnostics that target COVID-19. One of these, HEMEMICS, is developing a handheld molecular diagnostic test platform that could be administered by healthcare workers in triage settings such as ambulances, emergency rooms, community clinics and makeshift hospitals. As a true point-of-care test platform, it would deliver results onsite, without requiring the transfer of test samples to a lab. “We’re aiming to redefine point-of-care testing for COVID-19,” said John Lehman Warden, Jr., CEO and co-founder, HEMEMICS. “Unlike the most common type of on-site test — the lateral flow monitor — our test isn’t waiting for osmotic reactions to occur. We place the sample from a quick nasal swab or a drop of blood right on-chip, and binding takes place within a standing drop of fluid. That makes our platform fast, delivering results in about 60 seconds. Plus it simplifies sharing test results with other communities of interest, such as public health departments and municipalities, because it’s Bluetooth-enabled and supports cloud-based management networks.”As its foundry partner, we’re collaborating with HEMEMICS as it continues to refine its biochip’s sensitivity for both antibody and antigen testing of SARS-CoV-2. Once HEMEMICS is satisfied, it will move forward with the U.S. Food and Drug Administration’s (FDA’s) emergency use authorization (EUA), which it hopes will bring the HEMEMICS platform into the hands of the millions of people who stand to benefit.As we head into the fall and winter months, we’ll need both rapid, connected point-of-care biosensor test platforms such as HEMEMICS’ and high-accuracy RT-PCR tests to fight COVID-19 effectively. And at their root, we’ll have MEMS and biosensors to thank. For more information on Rogue Valley Microdevices’ biosensor solutions, please contact the company at [email protected] or visit its website. As founder and CEO of Rogue Valley Microdevices, Jessica Gomez has created a world-class precision MEMS foundry in the heart of Southern Oregon. Integral to her role as CEO, Gomez practices a business philosophy of offering best-in-class process technology and R D expertise to customers to help them achieve the highest quality and reliability in their products. Gomez plays an active leadership role within and beyond the technology industry. She is a board member of the prestigious SEMI Board of Industry Leaders, she was the first executive selected for Spotlight on SEMI Women, and she is chairman of the Oregon Institute of Technology Board of Trustees.Rogue Valley Microdevices is a longtime member of MEMS Sensors Industry Group (MSIG), a SEMI technology community that enables the MEMS and sensor industry to address common challenges, innovate and accelerate business results.

On Saturday, March, 21, 2020 the U.S. Food and Drug Administration (FDA) gave emergency authorization to Cepheid, a California company, to sell a new test for rapid detection of the pandemic coronavirus SARS-CoV-2, which causes COVID-19. Cepheid’s Xpert® Xpress SARS-CoV-2 test gives healthcare workers results in just 45 minutes, with less than a minute of hands-on time for sample preparation.Cepheid, founded by Kurt Petersen, M. Allen Northrup and five others in 1996, is well known in the MEMS community for commercializing microfluidic chip-based polymerase chain reaction (PCR) analysis machines. This is not the first time Cepheid has responded quickly to a biological threat; after the 2001 terrorist attacks in the USA, Cepheid was the first to provide rapid anthrax detection capabilities to the U.S. Postal Service, and it still does today.At the heart of all COVID-19 test protocols (see the WHO protocol and U.S. CDC protocol) is the real-time reverse transcription polymerase chain reaction (RT-PCR) analysis technique. In a very simplified description, PCR uses thermal cycling to amplify the DNA present in a patient’s swab sample, and then using fluorescence optical detection, searches for the virus’s specific DNA. The test requires knowing the virus’s genome in the first place; the crucial work to sequence the full genome of SARS-CoV-2 was first published by Chinese scientists for public use on January 10, 2020.While traditional PCR machines take many hours to thermal cycle and reach a result, MEMS-based PCR systems can work much faster. Featuring scale heaters and reaction chambers that have a tiny thermal mass, they create a significantly faster heat-cool cycle, enabling a rapid result in minutes.The first MEMS silicon PCR chip, developed by Northrup et. al. at Lawrence Livermore National Laboratory and licensed to Cepheid (left) and the Cepheid test cartridge today (right). (Source: Northrup MA, Ching MT, White RM, Watson RT, “DNA amplification in a microfabricated reaction chamber,” Transducers 1993, Yokohama, Japan. pp. 924–926.) Research on MEMS-based PCR systems has continued steadily since the early 1990s. Today, researchers have been focusing on developing highly integrated, low-cost systems specifically for point-of-care use. One example of recent research: a team at Korea’s ETRI and Genesystem have developed a prototype low-cost, handheld PCR system having a polyimide chamber and microheater and an integrated CMOS detector for optical readout of results (figure below). Cross-section schematic of the chamber, heating module and integrated optical detector in a portable PCR prototype (left) and integrated test cartridge (right). (Source: DS Lee, OR Choi, and YJ Seo, “A Handheld and Battery-Powered Realtime Microfluidic PCR Amplification Device,” Transducers 2019, Berlin, Germany pp. 1063-1065.) Korea’s quick recruitment of its biotech companies and creation of novel drive-through testing sites helped it to successfully pinpoint its COVID-19 outbreak and to implement control measures. Let’s hope the Cepheid test can be similarly effective.Based on successive epidemics of SARS, MERS and now COVID-19, rapid PCR test machines, enabled by MEMS technology, are becoming essential medical tools in the fight against viral outbreaks. As continued development lowers the cost of such critical equipment, let’s hope we may soon have a PCR machine in every doctor’s office.Alissa M. Fitzgerald, Ph.D., founded A.M. Fitzgerald Associates, LLC (“AMFitzgerald”), a MEMS and sensors solutions company based in Burlingame, CA, in 2003. She has over 25 years of engineering experience in MEMS design, fabrication and product development.Prior to founding AMFitzgerald, Fitzgerald worked at the Jet Propulsion Laboratory, Orbital Sciences Corporation, Sigpro, and Sensant Corporation, now part of Siemens. She received her bachelor’s and master’s degrees from MIT and her doctorate from Stanford University, in Aeronautics and Astronautics. Fitzgerald has numerous journal publications and holds eight patents. She served on the Governing Council of MEMS Industry Group from 2008-2014 and was inducted into the MIG Hall of Fame in 2013. Fitzgerald serves on the Board of Directors of both Rigetti Computing and the Transducer Research Foundation.AMFitzgerald is a longtime member of MEMS Sensors Industry Group (MSIG), a SEMI Strategic Association Partner. For more information on AMFitzgerald, please visit: https://www.amfitzgerald.com.Interested in learning more about this topic? Read Alissa M. Fitzgerald and Farzad Khademolhosseini’s article in EE Times, MEMS in the Fight Against Covid-19.