principles of operation. [10][11][12] However, the effective separation of micron-scale components from biological matrices using these conventional techniques is often constrained by low throughput, biofouling, and incompatibility with the need for continuous and automated processing. [3,6,7,9] In addition, biological particles such as cells are often susceptible to damage or degradation due to the application of high forces during centrifugal or membrane based separations, presenting a further obstacle to achieving time-and cost-effective isolation of biological targets. [3,[13][14][15][16][17][18] Microfluidic-based separations based on both active and passive techniques have been investigated as promising approaches to continuous-flow isolation of micron-scale particles from fluid suspensions. Active separation methods utilize external forces including electric, [19] magnetic, [20] and acoustic forces, [21] whereas passive separation methods utilize hydrodynamic forces induced by microstructure-fluid interactions and fluid dynamic phenomena. [22][23][24] Passive separations are particularly attractive as they do not require external actuation beyond the application of bulk fluid flow through the system, thereby minimizing instrumentation requirements and system complexity. Microfluidic filtration is a straightforward strategy for particle separation utilizing sizebased retention, with an integrated membrane, micropillar array, or other porous structure able to selectively pass particles smaller than the pore size while retaining other larger particles. [25][26][27] However, as with its macroscale counterpart, filtration presents inherent challenges when handling large sample volumes, including membrane biofouling, limited throughput, high pressure requirements, and limited scaling. [26,[28][29][30] While passive hydrodynamic separation techniques such as inertial focusing, [24,31] deterministic lateral displacement, [32,33] pinched flow fractionation, [34] and Dean flow focusing [22,35,36] can overcome these constraints and are well suited to continuous flow operation, throughput remains fundamentally limited since relatively low Reynolds number flows must be employed in these systems to maintain force balance during microfluidic separations. [23,30,37] At the macroscale, hydrocyclone technology has evolved as a powerful and simple solid-liquid separation technology traditionally used in large-volume industrial processes including mineral dewatering [38,39] and desliming, [40] heavy metal recovery, [41,42] and water treatment. [43][44][45] Hydrocyclones enable Hydrocyclones are a simple and powerful particle separation technology, widely used in macroscale industrial processes, with enormous potential for miniaturization. Although recent efforts to shrink hydrocyclones to the centimeter scale have shown great promise for passive and high-throughput microparticle separations, further miniaturization is constrained by limited understanding of the impact of device size scale and design on separation performance,...