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Sep 20, 2012

Litmus-Like Test for Liver Toxicity

  • Scientists have developed a low-cost, paper-based microfluidic point-of-care test that they claim can can identify drug-induced liver toxicity from a fingerprick of blood in just 15 minutes. The multiplex, postage stamp-sized test semiquantitatvely measures levels of the serum transaminases aspartate aminotransferase (AST) and alanine aminotranserase (ALT), and provides the results as a color-change reaction akin to that of a litmus paper test for measuring pH.

    The Beth Israel Deaconess Medical Center (BIDMC) team say the platform could form the basis of a cheap, easy-to-use assay that could be used routinely in any POC or field setting to monitor for liver status in patients with underlying liver disease, or those receiving potentially heptatotoxic drugs for diseases such as tuberculosis or HIV. Moreover, the test format could be adapted to measure a diverse range of analytes.

    Monitoring for hepatotoxicity in resource-limited settings is often hampered by expense, as well as logistic and practical issues, explain Nina R. Pollock, M.D., George M. Whitesides, and colleagues. Such testing, where available, requires venipuncture, which patients may object to strongly, and the testing procedure is also often carried out in centralized laboratories, which delays results. Consequently many patients receive little monitoring during treatment for HIV or tuberculosis.

    Unlike paper-based lateral-flow assays that can only run multiple tests if they use compatible reagents, paper-based microfluidic devices can be designed to direct the flow of sample within channels, and split a single, low-volume sample into multiple sections, for assaying using completely different reagents. One of the major benefits is that, like lateral-flow tests, paper-based microfluidic assays require no external pumps, instrumentation or power, are portable and disposable.

    These factors make such technology ideal for POC testing, particularly in resource-limited settings. However, while proof-of-principle studies have confirmed that paper-based microfluidics can be harnessed for clinical chemistry, enzymatic, immunoassay, and ELISA tests on patterned paper, “there has been minimal validation of paper-based microfluidic devices using actual clinical specimens, and a field-ready clinical test for monitoring hepatotoxicity has yet to be demonstrated,” the investigators write.

    Working with Diagnostics for All, the BIDMC investigators have now developed and tested a paper-based microfluidic device that they claim can rapidly provide clinicians with an on-the-spot visual indication of AST and ALT levels concurrently from a fingerprick of blood. The device is constructed in three dimensions using layers of patterned paper printed with microchannels, and overlaid with a plasma separation membrane to prevent the passage of cells from the sample into the channels. The construct is then laminated to prevent contamination and evaporation. The blood sample is applied to a hole in the lamination, and the fluid drawn up along the paper channels is split and directed into  two separate zones, one of which contains dried reagents for measuring AST, and the other the reagents for ALT. The device also contains three control zones to confirm performance. Fluid passing into the test zones essentially reconstitutes the reagents, and the reaction can proceed. Both reactions have been designed to generate a strong color result. Importantly, the color readouts in the test zones correspond to the transaminase concentrations cutoffs currently used when monitoring TB patients.

    Testing the device on hundreds of whole blood and serum specimens, the team found that it performed at over 90% accuracy when compared against the gold standard automated platform test. Encouragingly, the assays performed well at different ambient temperatures, and the tests themselves remained stable for at least a few months when sealed in foil-lined packages.

    “Our platform offers several technical advantages over other platforms developed with paper-based microfluidic technology,” Dr. Pollock et al claim in their published paper in Science Translational Medicine. “The 3D, multilayered design of our platform allows it to split a single 30 to 35 mL sample of whole blood into five separate streams of plasma, which are tested with five independently optimized assays in parallel, in 15 min, at ambient temperature.”

    Another key benefit is that neither sample preparation steps nor additional instrumentation is needed. “We anticipate that our device will ultimately simplify and reduce the cost of detection and monitoring progression of hepatotoxicity, making extremely inexpensive, minimally invasive, and accurate transaminase testing available at POC for all who need it and thus providing distinct advantages over standard-of-care automated methods using venipuncture,” the investigators conclude. Their published paper is titled "A Paper-Based Multiplexed Transaminase Test for Low-Cost, Point-of-Care Liver Function Testing."

    The team is now working with the non-profit organization PATH, to design a preliminary field study of the paper-based test in Vietnam, but foresees widespread application beyond AST and ALT analysis. “Successful development of this paper-based platform could facilitate the development of similar POC clinical assays for monitoring other clinically important analytes,” the authors write. 


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