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However, conventional inertial focusing techniques are limited by particle size dependency, hindering effective 3D central co-focusing of particles with varying sizes. In this study, we introduced a novel microfluidic method based on an inertial-viscoelastic-secondary flow synergistic effect (INVEST) within a composite microchannel (CMC), enabling high-efficiency 3D co-focusing of multi-sized particles. The CMCs incorporated height-varying horizontal and vertical semicircular obstacles to modulate inertial and secondary flows, while hyaluronic acid (HA) was introduced to enhance the viscoelastic effect and balance the force disparities among particles. Comprehensive numerical simulations were conducted to analyze the main flow field, secondary flow vectors, and shear-rate distributions. A novel metric, equilibrium zone width (EZW), was first proposed to theoretically assess the focusing performance. The simulation results indicated a minimal EZW of 15.58\u2009\u03bcm. Moreover, experimental validations across various HA concentrations, obstacle configurations, and particle sizes demonstrated focusing widths below 20.5\u2009\u03bcm and efficiencies exceeding 95% for particle mixtures with diameters from 10 to 20\u2009\u03bcm. Further testing using white blood cells confirmed a focusing efficiency of 96.14%. These findings verified that the CMCs successfully integrated inertial migration, viscoelastic effects, and enhanced secondary flows to realize the INVEST mechanism within a single microchannel, effectively addressing the issues of size dependency of traditional inertial focusing and the corner attraction effect of viscoelastic focusing. The developed microfluidic platform enables robust 3D central co-focusing of multi-sized particles and heterogeneous cells, providing a promising solution for high-throughput microflow cytometry and single-cell analysis.<\/jats:p>","DOI":"10.1038\/s41378-026-01254-9","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T06:53:25Z","timestamp":1776236005000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Coupling inertial, viscoelastic, and enhanced secondary flow in a composite microchannel: achieving high-precision multi-sized particle 3D central co-focusing"],"prefix":"10.1038","volume":"12","author":[{"given":"Tianwei","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenchen","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanming","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6374-8020","authenticated-orcid":false,"given":"Gaobin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xichen","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0452-4114","authenticated-orcid":false,"given":"Jianguo","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"1254_CR1","doi-asserted-by":"publisher","first-page":"134033","DOI":"10.1016\/j.snb.2023.134033","volume":"390","author":"S Soares","year":"2023","unstructured":"Soares, S. et al. 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