The in-vitro diagnostic (IVD) home point-of-care (POC) product landscape will look very different over the coming years as new products to detect the COVID-19 virus are launched. It is driven in part by FDA’s Emergency Use Authorization (EUA), which fast-tracks the traditional 510 (k) process so that COVID testing can be as ubiquitous as measuring your temperature.

And $157 million has already been distributed by the Biomedical Advanced Research Development Agency (BARDA) to support the development of more than 40 COVID-19 diagnostic products. Some of those products are targeted for POC use cases versus laboratory testing. Many new companies entering the market are planning a diagnostic roadmap of capabilities beyond their entry point of COVID-19 testing.

IVD and POC Defined

“In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body” compared with in-vivo products, which perform the same but within the human body as defined by the FDA. According to FDA, “POC testing means that results are delivered to patients in the patient care settings, like hospitals, urgent care centers, and emergency rooms, instead of samples being sent to a laboratory.”

Optical vs. Electrochemical Test Techniques

IVD POC products available today like glucose meters or pregnancy test kits will soon share “shelf space” with start-ups offering novel sensors and meters using nasal swabs, saliva, urine, sweat, and blood. These new IVD products will use the latest in sensor technologies, ultra low power analog, precision mixed-signal, and digital processing, and they will be highly portable, including using biocompatible enclosures for wearable applications. They will also harness the enormous computing power of smart-phones and the cloud.

The two basic measurement techniques for IVD POC home testing are optical and electrochemical (EC). Pregnancy test kits, for example, detect human chorionic gonadotropin (hCG) in urine. Urine is placed on the end of the nitrocellulose strip and flows; hCG binds with dyed mobile antibodies and is captured using fixed antibodies to produce a color line that LEDs and photodiodes will detect. Glucose test strips require a very small drop of blood at the tip of the strip where the chemical enzymes are stored.

An electrical connection is made from the meter to the test zone on the strip to allow a voltage stimulus and measurement, whereas a system using nitrocellulose strips only requires a simple mechanical interface like a light pipe to focus the LED signal on the strip and capture the reflected signal on the photodiode. This article focuses on the more widely used POC electrochemical measurement technique. Future articles will address optical techniques.

EC Measurement Background

In every household, two-terminal batteries are the most common example of a dc power supply. They are used for flashlights, mobile phones, clocks, etc. A well-known EC application is the electrolysis of compounds. A common industrial example is the chlor-alkali process where the salt (NaCl) and water (H 2O) in saltwater are split into chlorine (Cl 2), hydrogen (H 2), and sodium hydroxide (NaOH).

Fig. 1 - Current and potential in a two-electrode system (a) and in a three-electrode system (b), and the schematic of a potentiostat control circuit (c).

The disadvantage of two-terminal EC applications is that it is not possible to investigate a single electrode and thus a single event (see Figure 1). The current flows through the anode (electrode where oxidation happens) and the cathode (electrode where reduction takes place). So, both these electrodes influence the measured current and the current-limiting process cannot be determined. This is especially an issue in analytical chemistry. Another issue is concentration polarization. This is the effect of an electrode changing its environment and thus its potential during an electrochemical reaction. For most electroanalytical methods, a potentiostat is required (see Figure 2). A potentiostat uses three electrodes and a feedback loop to control the potential and measure the current flowing at just one of these electrodes, the working electrode. The potential will be measured to a fixed reference point and thus a lot of information about the event happening at the working electrode can be gathered.

Fig. 2 - Desktop potentiostat (left) from the 1990s and handheld potentiostat (right) from 2020. (Left photo courtesy of University of Rostock – Institute for Electronic Appliances and Circuits)

Why not just two electrodes? One reason is that the potential of the working electrode cannot be measures against a fixed point when there are only two electrodes. Imagine a two-electrode system that consists of the already mentioned working electrode, and the electrode, whose potential should be the fixed reference point, is the reference electrode.

In this case, a certain potential is applied between these electrodes and an electrochemical reaction happens at the working electrode, but since the circuit needs to be closed and current needs to flow, a reaction that is inverse to the reaction at the working electrode must occur; that is, if an oxidation occurs at the working electrode, a reduction must take place at the reference electrode. If a current flows at a constant potential, an electrochemical reaction must happen according to Faraday’s law.

The change of the solution surrounding the reference electrode, due to a flowing current, leads to a change of the potential that is supposed to be the fixed reference point. But the current flow cannot be limited through the reference electrode (RE), because all limitations should be caused by the desired process to investigate; that is, the process at the working electrode (WE).

The solution for this problem is a third electrode. At this counter electrode (CE), also known as auxiliary electrode, the counter-reaction to the working electrode’s reactions takes place. The current is flowing between the working and the counter electrode. The potential is controlled between the working electrode and reference electrode. The potential between the counter electrode and reference electrode is adjusted in such a way that the current flowing through the working electrode at a certain potential between working and reference electrode is satisfied.

Table 1 - Different electrochemical techniques enable precise potential control and current measurement for the detection of many substances.

This technology allows the use of many different electrochemical techniques like cyclic voltammetry, square wave voltammetry, open circuit potential measurements, etc. (see Table 1). The precise potential control and current measurement allow the detection of many substances. This has led to many lab-based quantitative measurements. It is not always possible to wait for a laboratory or to ship samples. On-site POC measurements, especially during the pandemic, have become very important.

Electroanalysis, the detection of substances by electrochemistry, offers many options to quantitatively determine different substances and species, but for many years potentiostats were lab bound (see Figure 3). Now the newest generation of compact potentiostats offered by PalmSens, for example, with expertise in instrument design, including hardware, firmware, and software offer potentiostat systems with high precision, portability, programmability, and low cost.

The compact and ready-to-use potentiostats like the Sensit Smart, are capable of common electrochemical techniques and advanced techniques like electrochemical impedance spectroscopy (EIS). While having the size of a common glucose meter, these devices offer more functionalities and are more versatile.

Fig. 3 - The electrochemistry chip ADuCM355 by Analog Devices is part of the EmStat Pico potentiostat module, which was used to build the handheld, Bluetooth-operated potentiostat Sensit BT.

EIS is a very interface-sensitive technique, which allows among other applications label-free detection of biomolecules for example DNA. 1It is no surprise that in 2021 these compact potentiostats were also used for different SARS-CoV-2 detection systems. 2, 3, 4, 5While the academic world reacted swiftly and developed many new detection methods for SARS-CoV-2, the translation of the proof of principles into a commercial product is a challenging task. Developing a dedicated device including electronics design, firmware, and software requires a team of specialized staff and time.

Fig. 4 - Potentiostat module on a development board (left), modular potentiostat (middle, right). Another reason for long development times is software development. Potentiostat modules often have specialized firmware and software development kits (SDK) which allow writing simple user interfaces in a short amount of time, because the communication with potentiostat itself is simplified. The software developer is in full control without learning the details on a circuitry level.

Commercial solutions that support this translation are available as well. The development can be accelerated by using potentiostat modules. Instead of designing your own potentiostats and firmware, potentiostat modules provide the electrochemical methods of the measurement system. Another option is to use modular potentiostats, which can be changed into an individual product with just a few customizations. The simplest version of such a solution is just exchanging the logo on the device. More advanced solutions allow modification of the electrode connection, as well as offering battery and Bluetooth options and customized keypads. Such turnkey electronic design services allow having prototypes of a reader within a few months (see Figure 4).

IVD System Architecture

Fig. 5 - Block diagram of an IVD system.

Let’s take a closer look at what’s in the box of a typical EC system and the tradeoffs needed when creating a requirements document for a new meter design. System power management is typically a good starting point in any new design (see Figure 5). The number of tests a meter will need to perform, along with the timing, voltages, and currents of those tests and communication (wired/wireless/display/sound) will define the capacity requirements for the battery.

Many home glucose meters on the market today use 3 V CR2032 batteries, as they are small and provide sufficient power of 250 mAHr to support up to a year of daily testing with each test lasting less than 5 seconds. For example, if the system electronics consume 10 mA over 5 seconds (0.00138Hr), then each test draws 0.0138 mAHr, which supports 250 mAHr/0.0138 mAHr = 18,000 tests before replacing the battery. However, if the electrochemical test takes tens of seconds or even minutes and the electrochemical reaction requires higher currents, then much higher capacity batteries must be employed, which increases the enclosure volume, weight, and cost. Rechargeable batteries are an option, but time-sensitive testing to address immediate treatment decisions for home use typically avoids rechargeable batteries.

In such cases, stand-alone potentiostat modules like the EmStat Pico are ideal for the analog front-end function. On-chip sequencers and deep ADC FIFOs allow the analog front end to operate while the processor is shut down, thus saving power. High-speed analog-to-digital conversion enables duty cycling of the front-end measurement system to reduce power consumption. In addition to the battery capacity, it is important to consider the voltage requirements for each block. High-precision, wide dynamic range analog circuits may require boost circuits and LDOs to ensure clean stable supply voltages to the measurement front end.

Conclusion

POC devices to diagnose viruses, joint infections, or nutrient deficiencies, for example, are here to stay. They will become smaller, cheaper, produced in high volume, and more versatile. As competition increases, proven measurement technologies and system design expertise will be a competitive advantage and speed time to market. PalmSens, for example, delivers tested market-ready potentiostats or calibrated potentiostat modules to integrate into hardware, while Tri-Star Design offers turnkey certified product design and development services with expertise in high precision, low-power wireless systems. Both companies are official partners of Analog Devices.

References

This article was written by Paul Errico (This email address is being protected from spambots. You need JavaScript enabled to view it.), Healthcare Senior Account Manager, TriStar Design, Hopkinton, MA, and Ardy van den Berg (This email address is being protected from spambots. You need JavaScript enabled to view it.), Business Developer, and Lutz Stratmann, Head of Applications, PalmSens, Houten, The Netherlands. For more information on TriStar Design, visit here . For more information on PalmSens, visit here .


Medical Design Briefs Magazine

This article first appeared in the June, 2021 issue of Medical Design Briefs Magazine.

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