{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T07:01:34Z","timestamp":1782975694730,"version":"3.54.5"},"reference-count":16,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002551","name":"Seoul National University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002551","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp;amp; Bioengineering"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Mechanistic models of Chinese Hamster Ovary (CHO) cell cultures are essential for efficient bioprocess development and control, yet parameter estimation remains a critical challenge in model calibration. As model complexity increases, the number of parameters grows and their values become highly system\u2010specific due to biological variability across cell lines and operating conditions. Consequently, estimation requires broad search spaces, leading to inefficient exploration and increased risk of entrapment in local minima during numerical optimization. To address this, a structure\u2010aware optimization framework is proposed that integrates large language model (LLM) reasoning into the parameter estimation loop. The LLM analyzes governing equations and trajectory discrepancies to recommend directional adjustments for parameter boundaries. These insights are combined with correlation\u2010based scaling to adaptively refine the search space, which is explored using stochastic global search methods (Latin hypercube sampling [LHS] and Covariance matrix adaptation evolutionary strategy [CMA\u2010ES]). Applied to fed\u2010batch CHO cell culture data, the framework escapes local minima and resolves complex, nonlinear metabolite dynamics, including lactate and ammonium shifts. Statistical validation across multiple batches and random seeds shows consistent reduction in prediction error and improved optimization robustness. This study demonstrates the potential of integrating structure\u2010aware LLM guidance with numerical optimization to improve the reliability and efficiency of bioprocess modeling.<\/jats:p>","DOI":"10.1002\/bit.70300","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:32:28Z","timestamp":1782970348000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["LLM\u2010Guided Parameter Optimization for Mechanistic CHO Cell Bioreactor Models"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0711-0591","authenticated-orcid":false,"given":"Han Bit","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering Seoul National University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9444-355X","authenticated-orcid":false,"given":"Janghan","family":"Lee","sequence":"additional","affiliation":[{"name":"New Drug Development Center, Osong Medical Innovation Foundation Cheongju Republic of Korea"},{"name":"College of Pharmacy Chungbuk National University Cheongju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7143-3715","authenticated-orcid":false,"given":"Seo\u2010Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"New Drug Development Center, Osong Medical Innovation Foundation Cheongju Republic of Korea"},{"name":"College of Pharmacy Chungbuk National University Cheongju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4514-3330","authenticated-orcid":false,"given":"Jihoon","family":"Kim","sequence":"additional","affiliation":[{"name":"New Drug Development Center, Osong Medical Innovation Foundation Cheongju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2274-5030","authenticated-orcid":false,"given":"Moo Sun","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering Seoul National University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-025-09984-5"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.28922"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.26214"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.1664"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1063\/5.0224297"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/1752-0509-7-91"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.28757"},{"key":"e_1_2_9_9_1","doi-asserted-by":"crossref","unstructured":"Luo X. C.Wang Y.Sun andW.Wang.2025. \u201cHow Do Large Language Models Perform on PDE Discovery: A Coarse\u2010to\u2010fine Perspective.\u201d InFindings of the Association for Computational Linguistics: EMNLP 2025 edited byC.Christodoulopoulos T.Chakraborty C.Rose andV.Peng 2684\u20132697.Association for Computational Linguistics.https:\/\/doi.org\/10.18653\/v1\/2025.findings-emnlp.145.","DOI":"10.18653\/v1\/2025.findings-emnlp.145"},{"key":"e_1_2_9_10_1","unstructured":"OpenAI. 2025. \u201cgpt\u2010oss\u2010120b & gpt\u2010oss\u201020b Model Card.\u201d arXiv.https:\/\/arxiv.org\/abs\/2508.10925."},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2024.03.001"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2025.06.035"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2026.2615475"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-026-35327-6"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty736"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1145\/3786333"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.284"}],"container-title":["Biotechnology and Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.70300","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bit.70300","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.70300","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:32:38Z","timestamp":1782970358000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/bit.70300"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":16,"alternative-id":["10.1002\/bit.70300"],"URL":"https:\/\/doi.org\/10.1002\/bit.70300","archive":["Portico"],"relation":{},"ISSN":["0006-3592","1097-0290"],"issn-type":[{"value":"0006-3592","type":"print"},{"value":"1097-0290","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]},"assertion":[{"value":"2026-04-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"bit.70300"}}