For the label-free detection, enumeration, imaging, and sizing of nanoparticles and viruses, electron microscopy constitutes the gold standard despite its high capital cost, limited field of view, and specialized sample preparation requirements. Alternative nanoparticle detection and sizing methods, such as dynamic light scattering, do not provide individual particle sizes as well as the location and spatial distribution information that is offered through imaging techniques. On the other hand, standard optical imaging techniques, such as brightfield microscopy, typically do not provide strong enough signal-to-noise (SNR) and signal-to-background ratios to observe individual nanoparticles. To overcome these various limitations in label-free nanoparticle and virus detection and quantification, we use an alternative imaging approach based on lensfree holographic on-chip microscopy. This approach provides the advantages of ultra-large fields of view >20 mm2 (>100 fold larger than conventional microscopes with comparable resolution), as well as compatibility with field-portable and cost-effective implementations. However, lensfree on-chip holographic microscopy has traditionally been limited in SNR, hampering its ability to detect individual nanoparticles.
To boost the sensitivity of this computational microscopy modality, we have created a vapor-deposition approach to form tunable liquid polyethylene glycol nanolenses that self-assemble around the target nanoparticles . These nanolenses greatly enhance the holographic optical signatures, enabling the detection of spheroids with diameters smaller than 40 nm and rod-shaped particles with diameters below 20 nm. The signal enhancement provided by these nanolenses agrees well with theoretical predictions based on the simultaneous numerical modeling of the liquid lens interface shape and the optical diffraction through the system. We demonstrate that this procedure is compatible with specific component detection in heterogeneous mixtures through the use of functionalized surface capture. One important application is virus detection, where we have used self-assembled nanolenses to enable the imaging of single viral particles in lensfree holographic optical microscopy . In order to facilitate easy application of this approach in field settings, we have combined the nanolens self-assembly and imaging into a single portable device prototype device that monitors the nanolens formation in situ. Such a device is particularly well-suited for point-of-care or limited-resource settings where nanoparticle or virus detection and sizing are required, e.g. in medical diagnostics (viral load measurements) or environmental monitoring.  E. McLeod, C. Nguyen, P. Huang, W. Luo, M. Veli, and A. Ozcan, “Tunable vapor-condensed nanolenses,” ACS Nano, under review.  O. Mudanyali, E. McLeod, W. Luo, A. Greenbaum, A. F. Coskun, Y. Hennequin, C. P. Allier, and A. Ozcan, Nature Photonics, 7 247-254 (2013).
University of California, Los Angeles, University of California, Los Angeles
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