The advent of microfluidics in the 1990s promised a revolution in multiple industries, from healthcare to chemical processing. Deterministic Lateral Displacement (DLD) is a continuous-flow microfluidic particle separation method discovered in 2004 that has been applied successfully and widely to the separation of blood cells, yeast, spores, bacteria, viruses, DNA, droplets, and more. DLD is conceptually simple and can deliver consistent performance over a wide range of flow rates and particle concentrations.Despite wide use and in-depth study, DLD has not yet been fully understood or fully optimised, with different approaches to the same problem yielding varying results. We endeavour here to provide an up-to-date expert opinion on the state-of-art and current fundamental, practical, and commercial challenges as well as experimental and modelling opportunities. Since these challenges and opportunities arise from constraints on hydrodynamics, fabrication and operation at the micro-and nano-scale, we expect this article to serve as a guide for the broader micro-and nanofluidic community to identify and address open questions in the field.

We uncover anisotropic permeability in microfluidic deterministic lateral displacement (DLD) arrays. A DLD array can achieve high-resolution bimodal size-based separation of microparticles, including bioparticles, such as cells. For an application with a given separation size, correct device operation requires that the flow remains at a fixed angle to the obstacle array. We demonstrate via experiments and lattice-Boltzmann simulations that subtle array design features cause anisotropic permeability. Anisotropic permeability indicates the microfluidic array's intrinsic tendency to induce an undesired lateral pressure gradient. This can cause an inclined flow and therefore local changes in the critical separation size. Thus, particle trajectories can become unpredictable and the device useless for the desired separation task. Anisotropy becomes severe for arrays with unequal axial and lateral gaps between obstacle posts and highly asymmetric post shapes. Furthermore, of the two equivalent array layouts employed with the DLD, the rotated-square layout does not display intrinsic anisotropy. We therefore recommend this layout over the easier-to-implement parallelogram layout. We provide additional guidelines for avoiding adverse effects of anisotropy on the DLD.

We investigate the effect of particle volume fraction on the efficiency of deterministic lateral displacement (DLD) devices. DLD is a popular passive sorting technique for microfluidic applications. Yet, it has been designed for treating dilute suspensions, and its efficiency for denser samples is not well known. We perform 3D simulations based on the immersed-boundary, lattice-Boltzmann and finite-element methods to model the flow of red blood cells (RBCs) in different DLD devices. We quantify the DLD efficiency in terms of appropriate "failure" probabilities and RBC counts in designated device outlets. Our main result is that the displacement mode breaks down upon an increase of RBC volume fraction, while the zigzag mode remains relatively robust. This suggests that the separation of larger particles (such as white blood cells) from a dense RBC background is simpler than separating smaller particles (such as platelets) from the same background. The observed breakdown stems from non-deterministic particle collisions interfering with the designed deterministic nature of DLD devices. Therefore, we postulate that dense suspension effects generally hamper efficient particle separation in devices based on deterministic principles.

advances in disease diagnostics, the main culprit for disease manifestation, severity, and death is the hyper-aggressive host immune response in most instances. [1-3] In the example of severe COVID-19 infection, the leading cause of death is sepsis (dysregulated immune response) while existing risk stratification methods based on age and co-morbidity remain challenging and imprecise. [4,5] The status of the patients' immune response can quickly change in a matter of minutes, therefore assays that are able to rapidly inform on the state of the immune system are vital in early triage among patients with acute infection, as well as prediction of downstream deterioration of disease. [6,7] This enables delivery of appropriate medical response, particularly in the emergency department (ED), for timely intervention before immune dysregulation becomes clinically evident and requiring admission to the intensive care unit (ICU). Unlike patients in the ICU who almost always have clear clinical manifestations of disease severity and organ dysfunction (e.g., low blood pressure, decreased oxygenation, jaundice, low urine output), those in the ED frequently show non-specific symptoms and signs, which pose a challenge for physicians to assess the presence of infection and possibility of deterioration into organ dysfunction. Disease manifestation and severity from acute infections are often due to hyper-aggressive host immune responses which change within minutes. Current methods for early diagnosis of infections focus on detecting low abundance pathogens, which are time-consuming, of low sensitivity, and do not reflect the severity of the pathophysiology appropriately. The approach here focuses on profiling the rapidly changing host inflammatory response, which in its over-exuberant state, leads to sepsis and death. A 15-min labelfree immune profiling assay from 20 µL of unprocessed blood using unconventional L and Inverse-L shaped pillars of deterministic lateral displacement microfluidic technology is developed. The hydrodynamic interactions of deformable immune cells enable simultaneous sorting and immune response profiling in whole blood. Preliminary clinical study of 85 donors in emergency department with a spectrum of immune response states from healthy to severe inflammatory response shows correlation with biophysical markers of immune cell size, deformability, distribution, and cell counts. The speed of patient stratification demonstrated here has promising impact in deployable point-of-care systems for acute infections triage, risk management, and resource allocation at emergency departments, where clinical manifestation of infection severity may not be clinically evident as compared to inpatients in the wards or intensive care units.

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Deterministic Lateral Displacement (DLD) is a microfluidic method of separating particles by size. DLD relies on precise flow patterns to deliver highresolution particle separation. These patterns determine which particles are displaced laterally, and which follow the flow direction. Prior research has demonstrated that the lateral array boundaries can be designed to improve the uniformity of the critical size and hence separation performance. A DLD device with an invariant critical size throughout is yet unknown. In this work we propose a 3D design approach. We first represent the flow through the DLD as a 2D lattice of resistors. This is used to determine the relative flow resistances at the boundaries that will deliver the correct flux patterns. We then use the Lattice Boltzmann Method to simulate fluid flow in a 3D unit cell of the DLD and measure the fluidic resistance for a range or typical dimensions. The results of this work are used to create a new equation for fluidic resistance as a function of post size, post height, and post spacing. We use this equation to determine array geometries that should have the appropriate resistances. We then design and simulate (in COMSOL) complete devices and measure fluid fluxes and first flow-lane widths along the boundaries. We find that the first flow-lane widths are much more uniform than in any devices described previously. This work provides the best method for designing periodic boundaries, and enables narrower, shorter and higher throughput DLD devices.

Host immune response plays a critical role in disease manifestation and severity. In article number 2006123, Win Sen Kuan, Jongyoon Han, and co‐workers present a whole blood biophysical immune response profiling tool using deterministic lateral displacement microfluidics. The speed and accuracy of immune response stratification demonstrated in an emergency department has a clear impact in enabling deployable point‐of‐care systems for rapid clinical triage.