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Microfluidic Protein Array Shows Promise for Predicting Mucositis During Cancer Therapy


NEW YORK (GenomeWeb) – As part of a larger effort to develop and validate their own microfluidic protein array technology for a variety of applications, researchers from the University of Connecticut have published a report demonstrating that their platform can sensitively and accurately detect a panel of cytokines associated with the risk of oral mucositis, an often debilitating and potentially fatal side effect of oral cancer treatment.

In the study, published last week in the journal Analytical and Bioanalytical Chemistry, a team led by Colleen Krause applied an updated version of its prototype microfluidic electrochemical immunoarray to a panel of targets associated with mucositis, and showed that the technology could measure the four target proteins accurately and quickly with high sensitivity and lower detection limits than ELISA.

Krause told GenomeWeb this week that the study is part of a larger collaboration with colleagues at UConn's department of oral health that aims to produce a multiplex proteomic assay that could be used to better personalize treatment for patients with oral cancer by avoiding this serious side effect.

Oral mucositis is an inflammatory lesion of the oral mucosa caused by high-dose chemotherapy or radiation that is especially prevalent during oral cancer. The ability to predict which patients are at a greater risk of this side effect could give doctors a tool to tailor treatment more appropriately.

Krause has been working for several years on the microfluidic immunoarray detection technology at the heart of the study, and the team has published previously on other work with biomarkers for prostate cancer. The team is still pursuing the prostate cancer work in addition to other clinical areas of interest, she said.

In their new study, Krause and her colleagues set out to adapt the immunoarray platform to the task of identifying a set of four biomarkers associated with the development of oral mucositis.

The study served the dual purpose of advancing development of a mucositis risk assay with their clinical collaborators and simply demonstrating that of the technology can detect low concentrations within a panel of valid biomarkers, Krause said.

Utilizing a more advanced and semi-automated on-line capture format thanpreviously reported, the team's current system includes both a protein capture chamber and a downstream eight-sensor detection chamber.

In the capture chamber, enzyme-antibody-decorated magnetic beads capture each target analyte, in this case the four mucositis-associated proteins, though Krause said the technology could also potentially be applied to other molecules like nucleic acids.

The beads are then washed and delivered to a nanostructured eight-sensor array with a second set of antibodies that recognize and sort the proteins. Finally, the targets are measured simultaneously via chemical activation of the enzyme labels and electrochemical detection.

Electrochemical detection should enable a much more simplified system than other bead-based technologies that have been commercialized using fluorescent detection methods, Krause said. "We are also manufacturing these devices in house, so [this study] shows a lot — that we can build it, use it, and it can be clinically relevant."

The system is also not limited to four targets, Krause added "There is definitely a potential there, and we are hoping to get up to 16 to 32 biomarkers at a time," she said.

In their mucositis marker study, the group focused on four targets, IL-6, IL-1beta, CRP, and TNF-alpha. After optimizing the assay for each target, the researchers set up their system for multiplex detection, attaching primary antibodies for each protein to two of the array's eight sensors.

In a first set of experiments, the investigators found that detection limits for the four analytes were 50- to 1000-fold lower compared to standard singleplex ELISAs.

The team then went on to evaluate a set of serum samples taken at several time points from ten patients undergoing radiation therapy for head and neck cancer. The results showed good correlation with ELISA measurements, the authors wrote.

Overall, the results offer early evidence that the microfluidic array system can rapidly detect four different target proteins simultaneously, a first step toward developing the technology as a clinical tool.

The same approach could also be applied to other small panels of target proteins, the authors wrote, or, as Krause said, to larger panels. The authors reported that their four-protein assay required only 5 microliters of sample volume and a 30-minute processing time, both significantly lower than that required for ELISA.

According to Krause, it's also possible the group could adapt the technology to other types of targets like DNA or RNA.

In the meantime, the investigators' immediate goal is to expand their mucositis work to a larger set of patient samples, hopefully about 100, Krause said, in order to further validate the current mucositis inflammatory biomarker assay.