{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:28:01Z","timestamp":1787128081728,"version":"build-2736575974"},"reference-count":93,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National University Student Innovation and Entrepreneurship Training Program of China","award":["202610719040"],"award-info":[{"award-number":["202610719040"]}]},{"name":"National University Student Innovation and Entrepreneurship Training Program of China","award":["D2025215"],"award-info":[{"award-number":["D2025215"]}]},{"name":"Shaanxi Provincial Natural Science Basic Research Program","award":["2024JC-YBQN-0208"],"award-info":[{"award-number":["2024JC-YBQN-0208"]}]},{"name":"Scientific Research Funding Program of the Department of Education of Shaanxi Province","award":["24JR164"],"award-info":[{"award-number":["24JR164"]}]},{"name":"PhD Student Research Startup Fund of Yan\u2019an University","award":["YAU202303863"],"award-info":[{"award-number":["YAU202303863"]}]},{"award":["YAU202303863"],"award-info":[{"award-number":["YAU202303863"]}],"id":[{"id":"https:\/\/ror.org\/01dyr7034","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>The global fermentation industry faces persistent bottlenecks in scaling laboratory innovations to industrial production, and the integration of synthetic biology (SynBio) and artificial intelligence (AI) within the Design\u2013Build\u2013Test\u2013Learn (DBTL) loop has yielded inconsistent industrial outcomes. This review proposes that transformative impact requires a \u201cscale-up-gated DBTL\u201d framework, in which explicit decision gates constrain every iteration. At the Design phase, scale-down simulation data must inform genetic design choices. At the Test phase, downstream processing compatibility and industrial robustness metrics are enforced as non-negotiable evaluation criteria. At the Learn phase, techno-economic analysis (TEA) and life-cycle assessment (LCA) serve as the convergence criteria, replacing traditional titer plateaus. Through a qualitative cross-sectoral analysis of food, pharmaceutical, agricultural, and energy fermentation, the analysis reveals that workflows incorporating such constraints consistently bridge the valley of death, whereas unconstrained DBTL systematically converges on laboratory optima that are industrially unviable. Five strategic priorities are outlined\u2014embedding TEA\/LCA into DBTL, adopting scale-down simulation, building open fermentation data repositories, harmonizing regulatory frameworks, and fostering cross-disciplinary training\u2014as prerequisites for progressing toward fully autonomous, scale-up-aware biomanufacturing.<\/jats:p>","DOI":"10.3390\/microorganisms14081830","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T07:58:23Z","timestamp":1787126303000},"page":"1830","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Closing the Loop with Gates: A Scale-up-Gated Design\u2013Build\u2013Test\u2013Learn Framework for Industrial Fermentation"],"prefix":"10.3390","volume":"14","author":[{"given":"Xiang","family":"He","sequence":"first","affiliation":[{"name":"Shaanxi Key Laboratory of Research and Utilization of Resource Plants on the Loess Plateau, Engineering Research Center of Microbial Resources Development and Green Recycling of the University of Shaanxi Province, College of Life Science, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Hu","sequence":"additional","affiliation":[{"name":"Shaanxi Key Laboratory of Research and Utilization of Resource Plants on the Loess Plateau, Engineering Research Center of Microbial Resources Development and Green Recycling of the University of Shaanxi Province, College of Life Science, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Shaanxi Key Laboratory of Research and Utilization of Resource Plants on the Loess Plateau, Engineering Research Center of Microbial Resources Development and Green Recycling of the University of Shaanxi Province, College of Life Science, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinli","family":"Li","sequence":"additional","affiliation":[{"name":"Shaanxi Key Laboratory of Research and Utilization of Resource Plants on the Loess Plateau, Engineering Research Center of Microbial Resources Development and Green Recycling of the University of Shaanxi Province, College of Life Science, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenan","family":"Wang","sequence":"additional","affiliation":[{"name":"Shaanxi Key Laboratory of Research and Utilization of Resource Plants on the Loess Plateau, Engineering Research Center of Microbial Resources Development and Green Recycling of the University of Shaanxi Province, College of Life Science, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqing","family":"Dong","sequence":"additional","affiliation":[{"name":"Shaanxi Key Laboratory of Research and Utilization of Resource Plants on the Loess Plateau, Engineering Research Center of Microbial Resources Development and Green Recycling of the University of Shaanxi Province, College of Life Science, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"He","sequence":"additional","affiliation":[{"name":"Shaanxi Key Laboratory of Research and Utilization of Resource Plants on the Loess Plateau, Engineering Research Center of Microbial Resources Development and Green Recycling of the University of Shaanxi Province, College of Life Science, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqin","family":"Liu","sequence":"additional","affiliation":[{"name":"Shaanxi Key Laboratory of Research and Utilization of Resource Plants on the Loess Plateau, Engineering Research Center of Microbial Resources Development and Green Recycling of the University of Shaanxi Province, College of Life Science, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1418-873X","authenticated-orcid":false,"given":"Jianzhao","family":"Qi","sequence":"additional","affiliation":[{"name":"Center of Edible Fungi, Northwest A&F University, Yangling, Xianyang 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0310-4433","authenticated-orcid":false,"given":"Pengfei","family":"Jin","sequence":"additional","affiliation":[{"name":"Shaanxi Key Laboratory of Research and Utilization of Resource Plants on the Loess Plateau, Engineering Research Center of Microbial Resources Development and Green Recycling of the University of Shaanxi Province, College of Life Science, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","unstructured":"(2026, February 23). Fermentation\u2013Biotechnology Market Statistics, 2024\u20132030. Available online: https:\/\/www.grandviewresearch.com\/horizon\/statistics\/biotechnology-market\/technology\/fermentation\/global."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hennigan, J.N., Golovsky, M., Yano, U., Yeo, C., and Lynch, M.D. (2026). Recent advances in systems engineering approaches to integrated strain and bioprocess development. Trends Biotechnol.","DOI":"10.1016\/j.tibtech.2026.03.007"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1016\/j.tibtech.2023.05.002","article-title":"Milligrams to kilograms: Making microbes work at scale","volume":"41","author":"Cordell","year":"2023","journal-title":"Trends Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/s41467-018-03232-w","article-title":"Diverse genetic error modes constrain large-scale bio-based production","volume":"9","author":"Rugbjerg","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e70080","DOI":"10.1002\/elsc.70080","article-title":"Less Genome, More Gain: Genome Reduction Enhances Transaminase-Producing E. coli in a Scale-Down Bioreactor","volume":"26","author":"Avolio","year":"2026","journal-title":"Eng. Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"108889","DOI":"10.1016\/j.biotechadv.2026.108889","article-title":"Dynamic, autonomous gene expression system for self-adaptation and self-regulation in microbial production","volume":"90","author":"Bae","year":"2026","journal-title":"Biotechnol. Adv."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Tran, M.L., Chen, Y.S., and Juang, R.S. (2022). Fouling Analysis in One-Stage Ultrafiltration of Precipitation-Treated Bacillus subtilis Fermentation Liquors for Biosurfactant Recovery. Membranes, 12.","DOI":"10.3390\/membranes12111057"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jankovi\u0107, T., Straathof, A.J.J., and Kiss, A.A. (2024). Process systems engineering perspectives on eco-efficient downstream processing of volatile biochemicals from fermentation. Front. Energy Res., 11.","DOI":"10.3389\/fenrg.2023.1340612"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Rathore, A.S., Mishra, S., Nikita, S., and Priyanka, P. (2021). Bioprocess Control: Current Progress and Future Perspectives. Life, 11.","DOI":"10.3390\/life11060557"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"118152","DOI":"10.1016\/j.foodres.2025.118152","article-title":"Biotechnology meets AI: Accelerating next-generation of microbial breeding for food biomanufacturing","volume":"227","author":"Tan","year":"2026","journal-title":"Food Res. Int."},{"key":"ref_11","first-page":"001628","article-title":"A comprehensive review of genomic-scale genetic engineering as a strategy to improve bacterial productivity","volume":"171","year":"2025","journal-title":"Microbiology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"108741","DOI":"10.1016\/j.biotechadv.2025.108741","article-title":"Accelerated adaptive laboratory evolution: A tool for evolutionary biotechnology","volume":"86","author":"Declerck","year":"2026","journal-title":"Biotechnol. Adv."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Liu, Y., Wang, X., and Wang, M. (2026). Resilience-by-design in engineering Bacillus cell factories. Trends Biotechnol.","DOI":"10.1016\/j.tibtech.2026.02.010"},{"key":"ref_14","first-page":"103380","article-title":"Artificial intelligence\u2013powered biofoundries for protein engineering and metabolic engineering","volume":"96","author":"Chen","year":"2025","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wang, X., Mohsin, A., Sun, Y., Li, C., Zhuang, Y., and Wang, G. (2023). From Spatial-Temporal Multiscale Modeling to Application: Bridging the Valley of Death in Industrial Biotechnology. Bioengineering, 10.","DOI":"10.3390\/bioengineering10060744"},{"key":"ref_16","first-page":"103516","article-title":"From design\u2013build\u2013test\u2013learn cycles to AI-driven digital twins for bioprocess scale-up in the Genesis Mission era","volume":"100","author":"Yuan","year":"2026","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dudeja, C., Mishra, A., Ali, A., Singh, P.P., and Jaiswal, A.K. (2025). Microbial Genome Editing with CRISPR\u2013Cas9: Recent Advances and Emerging Applications Across Sectors. Fermentation, 11.","DOI":"10.3390\/fermentation11070410"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.tibtech.2022.01.004","article-title":"Robustness: Linking strain design to viable bioprocesses","volume":"40","author":"Olsson","year":"2022","journal-title":"Trends Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3890","DOI":"10.1021\/acssynbio.5c00095","article-title":"Model-Based Optimization of a qCRISPRi Circuit for Dynamic Control of Metabolic Pathways","volume":"14","author":"Golla","year":"2025","journal-title":"ACS Synth. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lopez-Barbera, A., Abasolo, N., Torrell, H., Canela, N., and Fern\u00e1ndez-Arroyo, S. (2024). Integrative Transcriptomic and Target Metabolite Analysis as a New Tool for Designing Metabolic Engineering in Yeast. Biomolecules, 14.","DOI":"10.3390\/biom14121536"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ymben.2019.08.004","article-title":"The emergence of adaptive laboratory evolution as an efficient tool for biological discovery and industrial biotechnology","volume":"56","author":"Sandberg","year":"2019","journal-title":"Metab. Eng."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/j.tplants.2021.06.005","article-title":"Microalgae strain improvement strategies: Random mutagenesis and adaptive laboratory evolution","volume":"26","author":"Arora","year":"2021","journal-title":"Trends Plant Sci."},{"key":"ref_23","first-page":"1454","article-title":"Laboratory Evolution: Molecular\u2013Genetic Basis and Phenotypic Plasticity","volume":"90","author":"Dunaevsky","year":"2025","journal-title":"Biochemistry"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kim, K., Choe, D., Lee, D.H., and Cho, B.K. (2020). Engineering Biology to Construct Microbial Chassis for the Production of Difficult-to-Express Proteins. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030990"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100693","DOI":"10.1016\/j.xgen.2024.100693","article-title":"Seed sequences mediate off-target activity in the CRISPR-interference system","volume":"4","author":"Rohatgi","year":"2024","journal-title":"Cell Genom."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1007\/s10295-020-02325-0","article-title":"The future of self-selecting and stable fermentations","volume":"47","author":"Rugbjerg","year":"2020","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Pijpstra, P., Guillouet, S.E., Heidinger, P., Kourist, R., and Gorret, N. (2026). Considerations of Bacterial Robustness and Stability to Improve Bioprocess Design. Fermentation, 12.","DOI":"10.3390\/fermentation12010054"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Najafpour-Darzi, G. (2025). Chapter 4-Fermentation Process Control. Biochemical Engineering and Biotechnology, Elsevier Science. [3rd ed.].","DOI":"10.1016\/B978-0-443-33096-4.00015-6"},{"key":"ref_29","first-page":"362","article-title":"Advances in Transcription Factor-Based Biosensors","volume":"50","author":"Zhao","year":"2024","journal-title":"Food Ferment. Ind."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5294","DOI":"10.1038\/s41467-020-19124-x","article-title":"Exploring the synthetic biology potential of bacteriophages for engineering non-model bacteria","volume":"11","author":"Lammens","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1186\/s12934-024-02523-w","article-title":"Delaying production with prokaryotic inducible expression systems","volume":"23","year":"2024","journal-title":"Microb. Cell Fact."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1002\/bit.28968","article-title":"Physiological Response of Penicillium chrysogenum to Mimicked Local and Global Perturbations of Substrate and Dissolved Oxygen Gradients at Industrial-Scale","volume":"122","author":"Chen","year":"2025","journal-title":"Biotechnol. Bioeng."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"171731","DOI":"10.1016\/j.cej.2025.171731","article-title":"Comparative analysis of hydrodynamic and reactor design effects on performance in bioreactors","volume":"527","author":"Shah","year":"2026","journal-title":"Chem. Eng. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/bit.260320415","article-title":"The design of controllers for batch bioreactors","volume":"32","author":"Cardello","year":"1988","journal-title":"Biotechnol. Bioeng."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Butkus, M., Levi\u0161auskas, D., and Galvanauskas, V. (2021). Simple Gain-Scheduled Control System for Dissolved Oxygen Control in Bioreactors. Processes, 9.","DOI":"10.3390\/pr9091493"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"103493","DOI":"10.1016\/j.copbio.2026.103493","article-title":"Rethinking the loop: Toward integrated strain and bioprocess development","volume":"99","author":"Stoltmann","year":"2026","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"109000","DOI":"10.1016\/j.biotechadv.2026.109000","article-title":"Microbe-specific and product-specific strategies for scalable biomanufacturing","volume":"92","author":"Wang","year":"2026","journal-title":"Biotechnol. Adv."},{"key":"ref_38","unstructured":"Moo-Young, M. (2011). 2.57-The Proportion of Downstream Costs in Fermentative Production Processes. Comprehensive Biotechnology, Academic Press. [2nd ed.]."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1002\/jctb.7690","article-title":"A perspective on downstream processing performance for recovery of bioalcohols","volume":"99","author":"Straathof","year":"2024","journal-title":"J. Chem. Technol. Biotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"146257","DOI":"10.1016\/j.jclepro.2025.146257","article-title":"How does downstream processing influence the sustainability and techno-economics of polyhydroxyalkanoates production?","volume":"521","author":"Thiele","year":"2025","journal-title":"J. Clean. Prod."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.biotechadv.2014.04.002","article-title":"Recovery of carboxylic acids produced by fermentation","volume":"32","author":"Straathof","year":"2014","journal-title":"Biotechnol. Adv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103772","DOI":"10.1016\/j.cis.2025.103772","article-title":"Graphene oxide based membranes for selective ion\/molecule transport in water","volume":"350","author":"Huang","year":"2026","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Yang, Y., Duan, L., and Wu, H. (2025). Challenges Associated with Membrane Separation of Polypeptides and Relevant Solution Strategies. Separations, 12.","DOI":"10.3390\/separations12090238"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"136654","DOI":"10.1016\/j.colsurfa.2025.136654","article-title":"Bare magnetic iron oxides for binding and selective elution of lactoferrin from acid whey","volume":"716","author":"Krolitzki","year":"2025","journal-title":"Colloids Surf. A"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Niazi, S.K. (2025). Continuous Manufacturing of Recombinant Drugs: Comprehensive Analysis of Cost Reduction Strategies, Regulatory Pathways, and Global Implementation. Pharmaceuticals, 18.","DOI":"10.3390\/ph18081157"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Nasuti, C., Solieri, L., and Krogerus, K. (2025). 3.0 Strategies for Yeast Genetic Improvement in Brewing and Winemaking. Beverages, 11.","DOI":"10.3390\/beverages11040100"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"147635","DOI":"10.1016\/j.foodchem.2025.147635","article-title":"From aroma to off-flavor: Metabolomics unveils the metabolic double-sided nature of traditional Chinese fermented foods","volume":"502","author":"Ruan","year":"2025","journal-title":"Food Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"105536","DOI":"10.1016\/j.tifs.2026.105536","article-title":"Interactions of microbiota during solid-state cereal vinegar fermentation","volume":"169","author":"Liu","year":"2026","journal-title":"Trends Food Sci. Technol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1002\/biot.201300305","article-title":"Pichia pastoris secretes recombinant proteins less efficiently than Chinese hamster ovary cells but allows higher space-time yields for less complex proteins","volume":"9","author":"Maccani","year":"2014","journal-title":"Biotechnol. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"20221695","DOI":"10.1098\/rspb.2022.1695","article-title":"Biological control interventions reduce pest abundance and crop damage while maintaining natural enemies in sub-Saharan Africa: A meta-analysis","volume":"289","author":"Ratto","year":"2022","journal-title":"Proc. R. Soc. B"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1002\/jsfa.70160","article-title":"Recent developments in the valorization of agri-food waste and byproducts by fermentation","volume":"106","author":"Tornuk","year":"2025","journal-title":"J. Sci. Food Agric."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s12934-017-0694-9","article-title":"Production of fuels and chemicals from xylose by engineered Saccharomyces cerevisiae: A review and perspective","volume":"16","author":"Kwak","year":"2017","journal-title":"Microb. Cell Fact."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41587-025-02767-w","article-title":"Addendum: Carbon-negative production of acetone and isopropanol by gas fermentation at industrial pilot scale","volume":"43","author":"Liew","year":"2025","journal-title":"Nat. Biotechnol."},{"key":"ref_54","first-page":"102712","article-title":"Artificial intelligence: A solution to involution of design\u2013build\u2013test\u2013learn cycle","volume":"75","author":"Liao","year":"2022","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ymben.2024.07.003","article-title":"Cell factory design with advanced metabolic modelling empowered by artificial intelligence","volume":"85","author":"Lu","year":"2024","journal-title":"Metab. Eng."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"9782","DOI":"10.1038\/s41467-025-65281-2","article-title":"LDBT instead of DBTL: Combining machine learning and rapid cell-free testing","volume":"16","author":"Harrison","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_57","first-page":"103386","article-title":"Recent advances in AI-enabled automation of DNA assembly in biofoundries","volume":"96","author":"Kim","year":"2025","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"108697","DOI":"10.1016\/j.biotechadv.2025.108697","article-title":"Multigene engineering in plants: Technologies, applications, and future prospects","volume":"85","author":"Rajput","year":"2025","journal-title":"Biotechnol. Adv."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s41557-023-01213-1","article-title":"Publisher Correction: OregonFluor enables quantitative intracellular paired agent imaging to assess drug target availability in live cells and tissues","volume":"15","author":"Wang","year":"2023","journal-title":"Nat. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ymben.2025.11.002","article-title":"Engineering artificial biosynthetic pathways for efficient microbial production of psilocybin and psilocin","volume":"94","author":"Guo","year":"2026","journal-title":"Metab. Eng."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4568","DOI":"10.1038\/s41467-025-59753-8","article-title":"Microbial synthesis of branched-chain \u03b2,\u03b3-diols from amino acid metabolism","volume":"16","author":"Wu","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.ymben.2025.10.012","article-title":"Industrial-scale production of Lacto-N-tetraose in engineered Bacillus subtilis via modular pathway optimization","volume":"93","author":"Wang","year":"2025","journal-title":"Metab. Eng."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"133712","DOI":"10.1016\/j.biortech.2025.133712","article-title":"Metabolic flux balancing and enhanced expression of engineered Paeonia lactiflora pinene synthase for high-yield \u03b1-pinene production in Serratia marcescens HBQA7","volume":"442","author":"Zhang","year":"2026","journal-title":"Bioresour. Technol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.synbio.2024.01.004","article-title":"Coupled strategy based on regulator manipulation and medium optimization empowers the biosynthetic overproduction of lincomycin","volume":"9","author":"Cai","year":"2024","journal-title":"Synth. Syst. Biotechnol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"131801","DOI":"10.1016\/j.biortech.2024.131801","article-title":"A comprehensive review on the application of neural network model in microbial fermentation","volume":"416","author":"Huang","year":"2025","journal-title":"Bioresour. Technol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.tibtech.2025.10.005","article-title":"Genome-scale CRISPRi and base-editing libraries for genetic decoding and strain engineering in Shewanella","volume":"44","author":"Chen","year":"2026","journal-title":"Trends Biotechnol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3166","DOI":"10.1177\/0958305X251367113","article-title":"Artificial neural network modelling-coupled genetic algorithm optimization for co-production of bioethanol and xylitol from delignified elephant grass","volume":"36","author":"Aishwarya","year":"2025","journal-title":"Energy Environ."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1016\/j.tibtech.2025.04.003","article-title":"Molecular process control for industrial biotechnology","volume":"43","author":"Treinen","year":"2025","journal-title":"Trends Biotechnol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.procbio.2025.05.023","article-title":"On digital twins in bioprocessing: Opportunities and limitations","volume":"156","author":"Shariatifar","year":"2025","journal-title":"Process Biochem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1007\/s11274-025-04494-5","article-title":"AI-enhanced bioprocess technologies: Machine learning implementations from upstream to downstream operations","volume":"41","author":"Sharma","year":"2025","journal-title":"World J. Microbiol. Biotechnol."},{"key":"ref_71","first-page":"1179","article-title":"Intelligent biomanufacturing: Fermentation process optimization enabled by online monitoring, artificial intelligence, and digital twin technologies","volume":"41","author":"Xia","year":"2025","journal-title":"Chin. J. Biotechnol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Priyadharshini, D., Muthuvel, I., Saraswathy, S., Kavitha, P.S., and Jegadeeswari, V. (2025). Precision to plate: AI-driven innovations in fermentation and hyper-personalized diets. Front. Nutr., 12.","DOI":"10.3389\/fnut.2025.1659511"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1042\/BST20190349","article-title":"Developing synthetic biology for industrial biotechnology applications","volume":"48","author":"Lionel","year":"2020","journal-title":"Biochem. Soc. Trans."},{"key":"ref_74","unstructured":"Exactitude Consultancy (2026, August 09). U.S. Synthetic Biology Market. Available online: https:\/\/exactitudeconsultancy.com\/reports\/50147\/consulting-services."},{"key":"ref_75","unstructured":"Global Growth Insights (2026, August 09). Biopharmaceutical Fermentation Systems Market Size, Share, Growth, and Industry Analysis, By Types (Fermenters, Bioprocess Analyzers, Process Monitoring Devices, Culture & Media Preparation, Culture Media, Buffers & Inducers, Others), By Applications Covered (Biopharmaceutical Companies, Contract Manufacturing Organizations, Contract Research Organizations, Academic Research Institutes, Others), Regional Insights and Forecast to 2035. Available online: https:\/\/www.globalgrowthinsights.com\/market-reports\/biopharmaceutical-fermentation-systems-market-110914."},{"key":"ref_76","unstructured":"Valtus Alliance (2026, August 09). Shaping the Next 25 Years of Pharma, Worldwide. Available online: https:\/\/valtusgroup.com\/2026\/07\/01\/shaping-the-next-25-years-of-pharma-worldwide\/."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Kurata, H., Ishino, T., Ohshima, Y., and Yohda, M. (2022). CDMOs Play a Critical Role in the Biopharmaceutical Ecosystem. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.841420"},{"key":"ref_78","unstructured":"Global Info Research (2026, August 11). Global Microbial Fermentation Technology Market 2025 by Company, Regions, Type and Application, Forecast to 2031. Available online: https:\/\/www.globalinforesearch.com\/reports\/2392647\/microbial-fermentation-technology."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"100606","DOI":"10.1016\/j.jfp.2025.100606","article-title":"Evaluating biosolutions for sustainable food systems: A review of safety, quality, regulatory and sustainability considerations within the European Union","volume":"88","author":"Thomsen","year":"2025","journal-title":"J. Food Prot."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"102685","DOI":"10.1016\/j.mib.2025.102685","article-title":"Emerging governance considerations for the deployment of genetically engineered microbes","volume":"89","author":"Brewer","year":"2026","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_81","first-page":"4200","article-title":"Upgrading microbial strains for fermentation industry","volume":"38","author":"Zhou","year":"2022","journal-title":"Chin. J. Biotechnol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"59","DOI":"10.15302\/J-SSCAE-2021.05.008","article-title":"Development status and prospects of microbial manufacturing industry in China","volume":"23","author":"Bi","year":"2021","journal-title":"Strateg. Study CAE"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4819","DOI":"10.1038\/s41467-026-73835-1","article-title":"Beyond petrochemicals: Challenges and opportunities in industrial-scale biomanufacturing","volume":"17","author":"Kim","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Satnaliwala, K. (2024). Analyzing Barriers to Entry in the Biopharmaceutical Sector: An Entrepreneurial Perspective. Int. J. Multidiscip. Res., 6.","DOI":"10.36948\/ijfmr.2024.v06i05.26638"},{"key":"ref_85","first-page":"19","article-title":"Bridging the Valley of Death: Building a Bio-lndustrial Pilot Plant Network","volume":"121","author":"Starr","year":"2025","journal-title":"Chem. Eng. Prog."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1039\/D5EM00567A","article-title":"Process-based VOC emission characteristics, environmental impact and health risk assessment in typical breweries in Beijing","volume":"28","author":"Zhao","year":"2026","journal-title":"Environ. Sci. Process. Impacts"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s12934-026-02997-w","article-title":"From lab to law: Emerging applications, potential benefits, evolving regulatory framework and challenges for engineered probiotics","volume":"25","author":"Thacharodi","year":"2026","journal-title":"Microb. Cell Fact."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.1021\/jacsau.5c00369","article-title":"Advancing Biocatalysis Education: Sustaining the Future of Industrial Biotechnology","volume":"5","author":"Weise","year":"2025","journal-title":"JACS Au"},{"key":"ref_89","unstructured":"Klein, B., and Benavides, P.T. (2023, January 3\u20137). ABF Past Accomplishments\u2013TEA\/LCA. Proceedings of the 2023 U.S. Department of Energy\u2019s Bioenergy Technologies Office (BETO) Project Peer Review, Denver, CO, USA."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e2811","DOI":"10.1002\/btpr.2811","article-title":"Development of a novel, high-throughput screening tool for efficient perfusion-based cell culture process development","volume":"35","author":"Gagliardi","year":"2019","journal-title":"Biotechnol. Prog."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"107888","DOI":"10.1016\/j.biotechadv.2021.107888","article-title":"Recent advances in fed-batch microscale bioreactor design","volume":"55","author":"Teworte","year":"2022","journal-title":"Biotechnol. Adv."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"116907","DOI":"10.1016\/j.jpba.2025.116907","article-title":"The Pistoia Alliance\u2019s methods database project: Instrument, chromatographic data system, and vendor-agnostic digital transfer of machine-readable high-performance liquid chromatography-ultraviolet methods using the allotrope data format","volume":"263","author":"Aggarwal","year":"2025","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_93","unstructured":"OECD (2026, August 12). Anticipatory Governance for Responsible Innovation in Synthetic Biology. Available online: https:\/\/www.oecd.org\/en\/publications\/anticipatory-governance-for-responsible-innovation-in-synthetic-biology_864dd003-en\/."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/8\/1830\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:14:11Z","timestamp":1787127251000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/8\/1830"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":93,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["microorganisms14081830"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms14081830","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]}}}