{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:21:44Z","timestamp":1789478504463,"version":"build-2803163510"},"reference-count":99,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2025A1515012380"],"award-info":[{"award-number":["2025A1515012380"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2023A1515010243"],"award-info":[{"award-number":["2023A1515010243"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["202301-314"],"award-info":[{"award-number":["202301-314"]}]},{"name":"Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People\u2019s Hospital","award":["2025A1515012380"],"award-info":[{"award-number":["2025A1515012380"]}]},{"name":"Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People\u2019s Hospital","award":["2023A1515010243"],"award-info":[{"award-number":["2023A1515010243"]}]},{"name":"Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People\u2019s Hospital","award":["202301-314"],"award-info":[{"award-number":["202301-314"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Brain organoid technology has revolutionized in vitro modeling of human neurodevelopment and disease, providing unprecedented insights into cortical patterning, neural circuit assembly, and pathogenic mechanisms of neurological disorders. Critically, human brain organoids uniquely recapitulate human-specific developmental processes\u2014such as the expansion of outer radial glia and neuromelanin\u2014that are absent in rodent models, making them indispensable for studying human brain evolution and dysfunction. However, a major bottleneck persists: Extended culture periods (\u22656 months) are empirically required to achieve late-stage maturation markers like synaptic refinement, functional network plasticity, and gliogenesis. Yet prolonged conventional 3D culture exacerbates metabolic stress, hypoxia-induced necrosis, and microenvironmental instability, leading to asynchronous tissue maturation\u2014electrophysiologically active superficial layers juxtaposed with degenerating cores. This immaturity\/heterogeneity severely limits their utility in modeling adult-onset disorders (e.g., Alzheimer\u2019s disease) and high-fidelity drug screening, as organoids fail to recapitulate postnatal transcriptional signatures or neurovascular interactions without bioengineering interventions. We summarize emerging strategies to decouple maturation milestones from rigid temporal frameworks, emphasizing the synergistic integration of chronological optimization (e.g., vascularized co-cultures) and active bioengineering accelerators (e.g., electrical stimulation and microfluidics). By bridging biological timelines with scalable engineering, this review charts a roadmap to generate translationally relevant, functionally mature brain organoids.<\/jats:p>","DOI":"10.3390\/biom15081118","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T09:41:17Z","timestamp":1754300477000},"page":"1118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Navigating Brain Organoid Maturation: From Benchmarking Frameworks to Multimodal Bioengineering Strategies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5417-4530","authenticated-orcid":false,"given":"Jingxiu","family":"Huang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China"},{"name":"Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8987-4673","authenticated-orcid":false,"given":"Yingli","family":"Zhu","sequence":"additional","affiliation":[{"name":"Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiong","family":"Tang","sequence":"additional","affiliation":[{"name":"Singapore Bioimaging Consortium, Agency for Science Technology and Research (A*STAR), Singapore 138667, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4243-2330","authenticated-orcid":false,"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Lu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211116, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7893-2006","authenticated-orcid":false,"given":"Alfred Xuyang","family":"Sun","sequence":"additional","affiliation":[{"name":"Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/s41586-024-08172-8","article-title":"An integrated transcriptomic cell atlas of human neural organoids","volume":"635","author":"He","year":"2024","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nature12517","article-title":"Cerebral organoids model human brain development and microcephaly","volume":"501","author":"Lancaster","year":"2013","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.stem.2016.07.005","article-title":"Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons","volume":"19","author":"Jo","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.neuron.2013.10.044","article-title":"The cerebellum and cognitive function: 25 years of insight from anatomy and neuroimaging","volume":"80","author":"Buckner","year":"2013","journal-title":"Neuron"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.3415","article-title":"Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture","volume":"12","author":"Pasca","year":"2015","journal-title":"Nat. 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