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Here, we present an integrated droplet microfluidic workflow for high-throughput screening and isolation of antibody-producing ExpiCHO-S cells using a FRET-based secretion assay. The FRET assay was developed and optimized for picodroplet-based screening by evaluating probe configuration, donor-to-acceptor ratio, antibody concentration range, and signal saturation behavior. The platform enables picodroplet-based detection of secreted antibodies, sequential enrichment of antibody-producing cells, and image-verified single-cell isolation. Application of this approach yielded image-verified monoclonal antibody-producing clones that maintained consistent antibody production during the stability assessment performed in this study, including in the absence of selection pressure. By reducing the early clone-identification phase from DNA transfection to validated 96-well antibody-producing clones to approximately 5 weeks, this workflow addresses key limitations of conventional approaches and provides both a practical FRET assay-development framework and a scalable strategy for streamlining early CLD workflows in biomanufacturing.<\/jats:p>","DOI":"10.1007\/s00449-026-03406-7","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T06:05:25Z","timestamp":1787119525000},"page":"2703-2719","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Streamlined stable CHO cell line development using droplet microfluidics with image-based monoclonality assessment"],"prefix":"10.1007","volume":"49","author":[{"given":"Kumar Vishven","family":"Naveen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akanksha","family":"Tyagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omnia Mohammed Hamid","family":"Ibrahium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer E. 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