Encoded nano-structures/particles have been used for barcoding and are in great demand for the simultaneous analysis of multiple targets. Due to their nanoscale dimension(s), nano-barcodes have been implemented favourably for bioimaging, in addition to their security and multiplex bioassay application. In designing nano-barcodes for a specific application, encoding techniques, synthesis strategies, and decoding techniques need to be considered. The encoding techniques to generate unique multiple codes for nano-barcodes are based on certain encoding elements including optical (fluorescent and non-fluorescent), graphical, magnetic, and phase change properties of nanoparticles or their different shapes and sizes. These encoding elements can generally be embedded inside, decorated on the surface of nanostructures or self-assembled to prepare the nano-barcodes. The decoding techniques for each encoding technique are different and need to be suitable for the desired applications. This review will provide a thorough discussion on designing nano-barcodes, focusing on the encoding techniques, synthesis methods, and decoding for applications including bio-detection, imaging, and anti-counterfeiting. Additionally, associated challenges in the field and potential solutions will also be discussed. We believe that a comprehensive understanding on this topic could significantly contribute towards the advancement of nano-barcodes for a broad spectrum of applications.

Nanoparticles have been widely implemented for healthcare and nanoscience industrial applications. Thus, efficient and effective nanoparticle separation methods are essential for advancement in these fields. However, current technologies for separation, such as ultracentrifugation, electrophoresis, filtration, chromatography, and selective precipitation, are not continuous and require multiple preparation steps and a minimum sample volume. Microfluidics has offered a relatively simple, low-cost, and continuous particle separation approach, and has been well-established for micron-sized particle sorting. Here, we review the recent advances in nanoparticle separation using microfluidic devices, focusing on its techniques, its advantages over conventional methods, and its potential applications, as well as foreseeable challenges in the separation of synthetic nanoparticles and biological molecules, especially DNA, proteins, viruses, and exosomes.

HIGHLIGHTS• A well-organized and thorough discussion on the fundamental principles and recent progress in deterministic lateral displacement (DLD) is provided.• The most updated designs and applications of DLD techniques for particle separation and detection are reviewed.• The current limitations of DLD and its potential solutions for clinical and commercial applications are discussed.ABSTRACT The separation and detection of particles in suspension are essential for a wide spectrum of applications including medical diagnostics. In this field, microfluidic deterministic lateral displacement (DLD) holds a promise due to the ability of continuous separation of particles by size, shape, deformability, and electrical properties with high resolution. DLD is a passive microfluidic separation technique that has been widely implemented for various bioparticle separations from blood cells to exosomes. DLD techniques have been previously reviewed in 2014. Since then, the field has matured as several physics of DLD have been updated, new phenomena have been discovered, and various designs have been presented to achieve a higher separation performance and throughput. Furthermore, some recent progress has shown new clinical applications and ability to use the DLD arrays as a platform for biomolecules detection. This review provides a thorough discussion on the recent progress in DLD with the topics based on the fundamental studies on DLD models and applications for particle separation and detection. Furthermore, current challenges and potential solutions of DLD are also discussed. We believe that a comprehensive understanding on DLD techniques could significantly contribute toward the advancements in the field for various applications. In particular, the rapid, low-cost, and high-throughput particle separation and detection with DLD have a tremendous impact for point-of-care diagnostics.

Deterministic lateral displacement (DLD) method for particle separation in microfluidic devices has been extensively used for particle separation in recent years due to its high resolution and robust separation. DLD has shown versatility for a wide spectrum of applications for sorting of micro particles such as parasites, blood cells to bacteria and DNA. DLD model is designed for spherical particles and efficient separation of blood cells is challenging due to non-uniform shape and size. Moreover, separation in sub-micron regime requires the gap size of DLD systems to be reduced which exponentially increases the device resistance, resulting in greatly reduced throughput. This paper shows how simple application of asymmetrical Deterministic lateral displacement (DLD) method for particle separation in microfluidic devices has been extensively used for particle separation in recent years since it was first published by Huang et al.1,2 Due to its high resolution and robust separation, DLD has shown versatility for a wide spectrum of applications for sorting of microparticles such as parasites 3 , blood cells [4][5][6][7] , circulating tumor cells 8,9 , bacteria 7,10 , spores 11 , and more recently, nanoparticle separation 12 and DNA isolation 13,14 . While the DLD empirical model is well established in current research, its scope is restricted to spherical particles, cylindrical pillars and uniform gap-size across all adjacent pillars 15 . Thus, it has been challenging to separate non-spherical particles such as red blood cells (RBCs), bacteria and DNA. Many groups have worked on changing pillar shapes and device gaps to effectively separate these particles 16,17 . However, this will greatly increase fabrication complexity and restrict throughput by reducing gap-sizes in a DLD pillar array.The DLD method uses rhombic or rotated square pillar arrays to redirect fluid laminar flow streams and each array arrangement would have a distinctive critical separating diameter. Particle larger than the critical cut-off diameter (D c ) will be displaced laterally from its flow from the sample streamline while smaller particles flow unhindered in the pillar array by flowing within the fluid streamlines. Based on current DLD empirical model, DLD separation cut-off size and resolution depends on the array rotation angle or slant and lateral gap-size between pillars 6 : ε = .. D g 1 4(1) c 0 48

Disease diagnostics requires detection and quantification of nano-sized bioparticles including DNA, proteins, viruses, and exosomes. Here, a fluorescent label-free method for sensitive detection of bioparticles is explored using a pillar array with micrometer-sized features in a deterministic lateral displacement (DLD) device. The method relies on measuring changes in size and/or electrostatic charges of 1 µm polymer beads due to the capture of target bioparticles on the surface. These changes can be sensitively detected through the lateral displacement of the beads in the DLD array, wherein the lateral shifts in the output translates to a quantitative measurement of bioparticles bound to the bead. The detection of albumin protein and nano-sized polymer vesicles with a concentration as low as 10 ng mL−1 (150 pM) and 3.75 μg mL−1, respectively, is demonstrated. This label-free method holds potential for point-of-care diagnostics, as it is low-cost, fast, sensitive, and only requires a standard laboratory microscope for detection.

Real‐time particle detection is an integral part of microfluidics for diagnostics. The detection method is typically performed with the use of bulky and expensive instruments including a bench‐top microscope, high‐speed camera, and fluidic pump. This limits the practical applications of microfluidics for real‐time point‐of‐care detection. Here, a portable and low‐cost smartphone microscopy platform is developed for real‐time particle detection in microfluidics based on a polydimethylsiloxane (PDMS) lens, modular 3D printed accessory, plug‐and‐play paper pump, and a novel particle counting algorithm. The PDMS lens is developed using a new method based on the PDMS precuring and hydrophobic modification on a pillar template to allow for fabrication of various lens shapes with high reproducibility and broad range magnification ratio from 30× to 100×. The modular 3D printed smartphone accessory allows for easy imaging setup to cater for different size of microchannel and the paper pump design provides a convenient single‐step process to drive the fluid. The platform is implemented to count the moving particles in the outlet of microfluidics deterministic lateral displacement with 94% counting accuracy. This platform provides huge potential applications for real‐time point‐of‐care detection that can be integrated with various microfluidic techniques.

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