Chip–NMR biosensor for detection and molecular analysis of cells

Abstract

Rapid and accurate measurement of biomarkers in tissue and fluid samples is a major challenge in medicine. Here we report the development of a new, miniaturized diagnostic magnetic resonance (DMR) system for multiplexed, quantitative and rapid analysis. By using magnetic particles as a proximity sensor to amplify molecular interactions, the handheld DMR system can perform measurements on unprocessed biological samples. We show the capability of the DMR system by using it to detect bacteria with high sensitivity, identify small numbers of cells and analyze them on a molecular level in real time, and measure a series of protein biomarkers in parallel. The DMR technology shows promise as a robust and portable diagnostic device.A number of new diagnostic platforms have been developed to measure biomolecule abundance with high sensitivity 1 , enable early disease detection 2 and gain valuable insights into biology at the systems level 3 . Some examples include nuclear magnetic resonance (NMR) with hyperpolarized gas 4 , nanowire 5 and nanoparticle 6 sensors, surface plasmon resonance devices 7 and mass spectrometry 8 . Many of these devices and techniques, however, requiring time-consuming purification of samples typically followed by a set of amplification strategies 6 , may lack the ability for the multiplexed measurements that are desirable in identifying complex diseases 1,9 or may not be amenable for easy point-of-care translation.Here we report a chip-based DMR system for rapid, quantitative and multichanneled detection of biological targets. Using readily available magnetic nano-and microparticles as a proximity sensor to amplify molecular interactions 10 , the DMR system can perform highly sensitive (up to 1 × 10 −12 M) and selective measurements on small volumes of unprocessed biological samples. As proof of concept, we show sensitive detection of bacteria, profiling of circulating cells and multiplexed identification of different cancer biomarkers. If implemented with standard microfabrication technology, the DMR system will be a high-throughput, low-cost and portable platform for large-scale sensing.The DMR sensor strategy is based on a self-amplifying proximity assay using magnetic nanoparticles 10 . When a few magnetic nanoparticles bind their intended molecular target Correspondence should be addressed to R.W. (rweissleder@mgh.harvard.edu). Note: Supplementary information is available on the Nature Medicine website.Author Contributions: H.L. designed the device, built the DMR prototype, obtained measurements, analyzed data and wrote the manuscript. E.S. performed all chemical modifications of magnetic nanoparticles and assisted in measurements and data analysis. D.H. collaborated in the development of the NMR electronics of discrete components. R.W. conceived the project, provided overall guidance, designed experiments and targeted nanoparticles, analyzed the data and wrote the manuscript with contributions from all authors.Competing Interests Statement: The authors declare competing financial i...

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