Determining the Optimal Biomarker Frequency for Biosensors

Thought LeadersChi-En LinMetrohm Young Chemist of the Year AwardPhD Candidate, Arizona State University

An interview with Chi-En Lin Metrohm Young Chemist of the Year, conducted by Alina Shrourou and James Ives

Please give a brief overview of how we currently diagnose and manage complex diseases and their comorbidities. Why is there a pressing need for advancements in this field?

Optical methods, such as ELISA, are considered state of the art. These analyze samples with fluorescent or other signaling labels and yield accurate detection, but the preparation is expensive and complicated, they require trained personnel and hi-tech instruments.

In order to achieve point of care testing for personalized medicine, bio assays need to be able to detect biomarkers at a much faster, cheaper rate without sacrificing accuracy.

Chi-En Lin 2018 Metrohm USA Young Chemist Winner.

Chi-En Lin won Metrohm’s Young Chemist of the Year award for his research into optimal biomarker frequencies, not just the novelty of the research but how it can be applied. Determining optimal biomarker frequencies for multimarker biosensors has wide ranging uses from rapid cancer screening methodologies, dry diagnostics, providing personalized medicine and helping to detect comorbidities before they become a problem.

What is the current gold standard for the development of biomarkers? What are the limits of the current state of the art methods?

The current gold standard assays, besides optical methods like ELISA, include magnetic ones such as magnetic nanotags and beads, and Raman spectroscopy which has recently proved very popular.

These all provide different advantages in terms of detection limits or modalities but they all share limitations on labelling and complicated sample preparation. Raman spectroscopy is good as it can achieve label free detection but it’s still an expensive piece of equipment.

Ideally you want to achieve something similar to a blood glucose meter; easy to produce and very cheap. The test strips used to perform the test are less than one dollar per test strip, usually around five to ten cents.

None of these technologies have the capability to reach down to that scale yet, however electrochemical methods of biomarker detection are much closer to reaching this level than other technologies.

Please give a brief overview of your research that lead you to being named the Metrohm Young Chemist Award winner.

I work in a highly interdisciplinary lab with Dr. Jeffrey La Belle, comprising of three core- subject areas: biosensors, wearable technologies and advanced manufacturing. When I first joined I managed around eight different projects, and while I learned a lot, it wasn’t particularly focused.

Dr La Belle has trained me to think about how to utilize the common themes among these projects as stepping stones to help me wade across the river and achieve a larger goal.

We had a theory about the optimal frequency of a biomarker, which helps you achieve either a single biomarker detection or a multiple marker detection.

I started to grasp this idea and use these projects to develop single or multimarker sensors for certain diseases. I learned what the commonalities and differences are that constitute this optimal frequency and figured out how to exploit these to achieve a better, more sensitive multimarker sensing platform.

The award wasn’t just for the scientific novelty, but that we created applications that can be applied to all kinds of diseases with a focus on commercial ability. Many of our collaborators are industry partners and we design and develop their second-generation products. We also work with doctors to get their inputs during the design process.

How are the electrochemical biosensors produced and customized for complex diseases?

We typically start with a gold electrode to get an idea of how this antibody or this biomarker will behave. Once we get an idea of the reagents we’re working with, we transition toward screen printed electrodes, either gold or carbon.

Depending on the material, we then alter its surface chemistry to achieve good surface coverage and immobilization before trying to characterize and go through a series of designed experiments to find the optimal frequency of this biomarker, then we optimize the surface coating to ensure robustness against interfering species. Eventually we have our disposable test strips for this specific biomarker.

The multimarker part requires a lot more work, because our multimarker approach is actually not a sensor array. In a sensor array you have different working electrodes and each working electrode has a different molecular recognition element.

Our method involves immobilizing different analytes on the same working electrode. We focus on finding the optimal frequency of a specific biomarker, and once we find say two of them, we put both biomarkers on the same surface and monitor them just by looking at the optimal frequencies.

What is electrochemical impedance spectroscopy? How can it be used to create sensitive and rapid biosensors?

Electrochemical impedance spectroscopy (EIS) inputs a sinusoidal signal which consists of a very broad frequency range of one milli hertz to 100,000 hertz. Some of the machines can go up to one megahertz.

When these sinusoidal waves interact with the biomolecules, antibodies or antigens, we can measure the impedance change, the capacitance change and the frequencies.

There is a recognized concept of an optimal frequency, which represents the molecular frequency of interactions between the molecular recognition element and the protein of interest.

Once you find the optimal frequency, the impedance signals generated from that specific frequency can then be used to accurately detect the biomarker.

By finding that frequency there's also an advantage in terms of shortening the assay time as you only need to search for a small frequency range, rather than the entire spectrum of one milli hertz to one megahertz. That would also drastically shorten the assay time.

How do electrochemical biosensors differ from traditional means of detecting biomarkers (i.e. ELISA)? How can they be used to for the diagnosis of complex diseases and comorbidities?

I would say the biggest difference would come from the labeling approach. The electrochemical impedance spectroscopy features a label free option, meaning you don't have to mess with your sample.

You can produce your test strip, then just place the samples on the test strip and let it run, which is very different from ELISA in terms of simple preparation. Another difference is the cost of the meter. ELISA requires very bulky, sophisticated and expensive instruments, whereas the EIS is very capable of developing miniaturized meters, just like blood glucose meters.

We have been working on the EIS portable meters and we find that they are very easy to control, and it is easy to produce a meter cheaper than an iPhone. This, together with the low cost of under a dollar per test strip, will help to achieve personalized biomarker detection in healthcare.

What advantages are there to multimarker platforms of electrochemical biosensors over single biomarker monitoring? What effect will these multimarker platforms have on the evaluation of complex disease states?

Complex diseases often come with a lot of comorbidities, usually chronic diseases, that occur simultaneously. By the time we detect these chronic diseases it’s usually too late, so having a method for early diagnosis is very important.

One reason for the late detection, is that from a patient’s perspective, unless they have a medical emergency or symptoms that drive them to see a healthcare professional, they probably won’t spend hours in a hospital and wait weeks for test results.

If we have a multiplexed biosensor that is easy to administer, can be performed in a primary care setting and doesn’t take too long to produce results, we hope to increase screening rates and in that regard we could get a much more comprehensive view of the state of the disease than with a single marker.

We can enhance that with the rapid multimarker bio assays. In the future, patients may be able to visit their doctor's office, have multimarker tests performed by a nurse and by the time they’re sitting with a doctor, the results would already be available. This would avoid lengthy hospital visits and contribute to a major increase in the efficiency of the healthcare.

What are the limitations of multimarker platforms using electrochemical biosensors?

Every biomarker is quite different. Some biomarkers are very highly concentrated in the body, some are very low, and some of the antibody antigen binding interactions take much longer, for example.

To design a specific biosensor to take into account all these factors is very time consuming. In theory it's doable but in reality, every biomarker would involve a significant amount of work, so we will need sufficient resources to develop them.

What does the future hold for your research?

Right now, we are working with start-up companies to develop their second-generation products, for example, dry eye diagnostics and rapid cancer screening methodologies. Being able to see these go from development to reality is a very good achievement.

For example, with cancer if rapid screening can become available or at least a convenient means for people to test whenever or not they have these biomarkers, will provide people with reassurance and comfort while also catching these diseases early enough that treatment is effective.

Those are all the things that I'd really love to see come to fruition. Career-wise, I hope that this sensor platform can work towards personalized medicine, whether through start-up companies or using my expertise with big companies to further enhance their products.

Regardless of which route is taken, hopefully we can all converge towards personalized medicine through increasing efficiency of healthcare.

About Chi-En Lin

Chi-En is a Ph.D. candidate at Arizona State University where he works under the mentorship of Dr. Jeffrey T. La Belle, Assistant Professor at the School of Biological and Health Systems Engineering.

Chi-En Lin was the 2018 recipient of the Metrohm Young Chemist Award.

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