Detecting Biomarkers with Lab-on-a-Chip

What is a biomarker?

A biomarker (biological marker) is an indicator of a particular biological state or condition that can be measured in serum, urine or other samples obtained from patients or experimental subjects. Most commonly, biomarkers are associated with the assessment of disease state or severity. Modern use of the term generally refers to molecular biomarkers including nucleic acids, proteins, peptides, metabolites and other small molecules. Others include so-called imaging biomarkers, which are features that can be detected in images such as CT or MRI scans. Optimal biomarkers are consistent and can be measured inexpensively.

Well established clinical biomarkers include PSA (prostate-specific antigen), a protein often elevated in men with prostate cancer, beta-amyloid and tau proteins found in cerebrospinal fluid of Alzheimer’s patients, and fasting blood glucose, which indicates a diabetes diagnosis at values of 126 mg/dL or higher.

Biomarkers can be highly valuable for both basic and clinical research and facilitate diagnosis, prognosis, evaluation of disease stage, monitoring of response to treatment, and, importantly, prediction of appropriate candidates for specific treatments.

Lab-on-a-chip Systems for Biomarker Detection

Conventional methods for biomarker detection such as polymerase chain reaction and immunoassays can be expensive and time-consuming. With this in mind, lab-on-chip biomarker detection technologies have been developed to allow the inexpensive and straightforward measurement of biomarkers; limited volumes of patient samples, such as blood, can now be analyzed on chip-scale devices with fluidic microchannels. In addition, such platforms offer the possibility of automation and analysis of multiple biomarkers simultaneously ¹. Accordingly, there has been growing interest in the application of microfluidics for biomarker development and clinical analysis in the last several years.

The field of oncology, in particular, has benefited immensely from the advancement of biomarker research. Lab-on-chip immunoassays have been developed for the multiplexed detection of protein cancer biomarkers in a highly sensitive and efficient manner²⁠, for example, employed a microfluidic electrochemical immunoassay to simultaneously measure PSA and interleukin-6 in the serum of prostate cancer patients in only 75 minutes. Aside from diagnostics, microfluidic biomarker detection can also aid in the optimization of personalized therapies. A recent study aimed at improving revolutionary anti-tumoural T cell transfer therapy employed a microfluidic device equipped with a Chemyx Fusion 200 two-channel syringe pump to evaluate and thereby enhance the quality of transferred T cells³⁠. Cells were stimulated then fixed or lysed at precise time points for analysis, with the purpose of measuring various dynamic biomarkers following stimulation. In this manner, T cell “age” and thus function was predicted to select optimal cells for adoptive transfer.

The applicability of lab-on-chip biomarker analysis is certainly not limited to cancer research. Another area of interest is the cardiovascular disease (CVD), a leading cause of death worldwide that in fact shares common risk factors with cancer, such as chronic inflammation. As such, it has been suggested that cancer and CVD may share common diagnostic biomarkers, and microfluidic platforms have been developed to detect markers such as C-reactive protein (CRP), a biomarker of inflammation, by modified immunoassay or label-free surface acoustic wave (SAW) biosensors⁴⁠. For example,⁴⁠ designed a microsystem incorporating the latter to detect multiple CVD markers on the same sensor, without cross-contamination or signal interference. Due to the multifactorial nature of the disease, it is highly desirable to have the capability of probing several biomarkers for accurate diagnosis. Lab-on-chip technology for this purpose is rapidly evolving in the hopes of facilitating the early diagnosis of CVD and cancer, in addition to many other diseases, for successful treatment and recovery.

Future Biomarker Research

Without a doubt, biomarkers are powerful tools that will have a major influence in the future of translational and personalized medicine. In view of their benefits, the US Food and Drug Safety Administration (FDA) has introduced a Biomarker Qualification Program in order to facilitate drug development using validated biomarkers. Efforts to identify novel, more accurate biomarkers will surely persist.

Microfluidic technology is uniquely poised to overcome current challenges and address untapped opportunities in the discovery and development of biomarkers. Lab-on-chip platforms offer enhanced sensitivity and specificity as well as the possibility of multiplexed biomarker analysis. Furthermore, reduced sample and reagent requirements will permit reduced cost and time to complete discovery studies and clinical trials.

References

1. Nahavandi, S., Baratchi, S., Soffe, R., Tang, S. Y., Nahavandi, S., Mitchell, A., & Khoshmanesh, K. (2014). Microfluidic platforms for biomarker analysis. Lab on a Chip, 14(9), 1496-1514
2. Chikkaveeraiah, B. V., Mani, V., Patel, V., Gutkind, J. S., & Rusling, J. F. (2011). Microfluidic electrochemical immunoarray for ultrasensitive detection of two cancer biomarker proteins in serum. Biosensors and Bioelectronics, 26(11), 4477-4483.
3. Rivet, C. A., Hill, A. S., Lu, H., & Kemp, M. L. (2011). Predicting cytotoxic T-cell age from multivariate analysis of static and dynamic biomarkers. Molecular & Cellular Proteomics, 10(3), M110-003921.
4. Wu, J., Dong, M., Santos, S., Rigatto, C., Liu, Y., & Lin, F. (2017). Lab-on-a-Chip Platforms for Detection of Cardiovascular Disease and Cancer Biomarkers. Sensors, 17(12), 2934.
5. Mitsakakis, K., & Gizeli, E. (2011). Detection of multiple cardiac markers with an integrated acoustic platform for cardiovascular risk assessment. Analytica chimica acta, 699(1), 1-5.