{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:09:16Z","timestamp":1791356956869,"version":"4.3.1"},"reference-count":106,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T00:00:00Z","timestamp":1774742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF)\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/013aysd81","award":["RS-2023-00278088"],"award-info":[{"award-number":["RS-2023-00278088"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gels"],"abstract":"<jats:p>Human induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as powerful three-dimensional (3D) platforms for modeling human neurodevelopment and neurological disorders. However, the absence of a functional vascular network remains a critical limitation, restricting oxygen and nutrient delivery, impairing metabolic stability, and constraining long-term maturation. Conventional extracellular matrix (ECM) mimetics, such as Matrigel and other static synthetic hydrogels, provide biochemical support but fail to recapitulate the dynamic remodeling that characterizes the developing neurovascular niche. Recent advances in stimuli-responsive hydrogels offer spatiotemporal control over matrix stiffness, degradability, viscoelasticity, and biochemical cue presentation. In this review, we discuss dynamic hydrogel systems within a structure\u2013property\u2013function framework, highlighting how network chemistry and architecture may regulate endothelial sprouting, lumen formation, vascular stabilization, and neurovascular unit maturation in vascularized brain organoid models, based on evidence from both organoid studies and related biomaterial or vascular systems. Photoresponsive, enzyme-cleavable, thermo-responsive, supramolecular, bio-orthogonal click-based, and bioprinted platforms are discussed with emphasis on mechanotransduction, angiocrine signaling, and barrier specialization. Functional outcomes, including trans-endothelial electrical resistance, selective permeability, transporter expression, electrophysiological integration, and sustained perfusion, are discussed alongside translational challenges such as cytocompatibility, oxidative stress, scalability, and regulatory feasibility. Collectively, dynamic hydrogels provide a versatile biomaterial strategy for improving vascularization and aspects of functional maturation in brain organoid models with enhanced physiological relevance. Ultimately, stimuli-responsive hydrogel systems may serve as enabling platforms for engineering vascularized brain organoids and advancing human-relevant neurovascular disease modeling.<\/jats:p>","DOI":"10.3390\/gels12040287","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T08:22:36Z","timestamp":1774858956000},"page":"287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Structure\u2013Property\u2013Function Relationships in Stimuli-Responsive Hydrogels for Brain Organoid Vascularization"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2864-790X","authenticated-orcid":false,"given":"Minju","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1806-9458","authenticated-orcid":false,"given":"Hoon","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo Sub","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Jung","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12929-017-0362-8","article-title":"3D brain Organoids derived from pluripotent stem cells: Promising experimental models for brain development and neurodegenerative disorders","volume":"24","author":"Lee","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Costamagna, G., Andreoli, L., Corti, S., and Faravelli, I. (2019). iPSCs-Based Neural 3D Systems: A Multidimensional Approach for Disease Modeling and Drug Discovery. Cells, 8.","DOI":"10.3390\/cells8111438"},{"key":"ref_3","first-page":"e55372","article-title":"Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders","volume":"122","author":"Gabriel","year":"2017","journal-title":"J. Vis. Exp."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s13365-023-01133-3","article-title":"iPSC-derived three-dimensional brain organoid models and neurotropic viral infections","volume":"29","author":"Swingler","year":"2023","journal-title":"J. Neurovirol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1093\/stcltm\/szad089","article-title":"Establishment and Validation of a Model for Fetal Neural Ischemia Using Necrotic Core-Free Human Spinal Cord Organoids","volume":"13","author":"Shin","year":"2023","journal-title":"Stem Cells Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e5493","DOI":"10.21769\/BioProtoc.5493","article-title":"Generation of 3D Human iPSC-Derived Multi-Cell Type Neurospheres for Studying Neuron, Astrocyte, and Microglia Crosstalk","volume":"15","author":"Wendt","year":"2025","journal-title":"Bio Protoc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e04913","DOI":"10.1002\/advs.202504913","article-title":"One-Step Drug Screening System Utilizing Electrophysiological Activity in Multiple Brain Organoids","volume":"12","author":"Shin","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1351734","DOI":"10.3389\/fncel.2024.1351734","article-title":"Brain organoid protocols and limitations","volume":"18","author":"Zhao","year":"2024","journal-title":"Front. Cell. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1002\/acn3.51820","article-title":"Engineered extracellular matrices facilitate brain organoids from human pluripotent stem cells","volume":"10","author":"Topal","year":"2023","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4730","DOI":"10.1038\/s41467-021-24775-5","article-title":"Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids","volume":"12","author":"Cho","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"20417314251319475","DOI":"10.1177\/20417314251319475","article-title":"Strategies to overcome the limitations of current organoid technology-engineered organoids","volume":"16","author":"Fan","year":"2025","journal-title":"J. Tissue Eng."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"165","DOI":"10.3390\/organoids2040013","article-title":"Matrigel Tunes H9 Stem Cell-Derived Human Cerebral Organoid Development","volume":"2","author":"Estridge","year":"2023","journal-title":"Organoids"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1038\/s41592-024-02393-5","article-title":"Unleashing the power of biomaterials to enhance organoid differentiation and function","volume":"21","author":"Musah","year":"2024","journal-title":"Nat. Methods"},{"key":"ref_14","first-page":"144","article-title":"Dynamic hydrogel mechanics in organoid engineering: From matrix design to translational paradigms","volume":"55","author":"Zhang","year":"2026","journal-title":"Bioact. Mater."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bar-Kochba, E., Carneal, C.M., Alphonse, V.D., Timm, A.C., Ernlund, A.W., Rodriguez, C.L., Morales Pantoja, I.E., Smirnova, L., Hartung, T., and Merkle, A.C. (2025). Advancing next-generation brain organoid platforms for investigating traumatic brain injury from repeated blast exposures. Front. Bioeng. Biotechnol., 13.","DOI":"10.3389\/fbioe.2025.1553609"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"876","DOI":"10.7150\/thno.123243","article-title":"AI and organoid platforms for brain-targeted theranostics","volume":"16","author":"Ye","year":"2026","journal-title":"Theranostics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6012","DOI":"10.1021\/acsapm.3c00710","article-title":"Photocrosslinked Gelatin Methacryloyl (GelMA)\/Hyaluronic Acid Methacryloyl (HAMA) Composite Scaffold Using Anthocyanidin as a Photoinitiator for Bone Tissue Regeneration","volume":"5","author":"Lin","year":"2023","journal-title":"ACS Appl. Polym. Mater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20417314241230633","DOI":"10.1177\/20417314241230633","article-title":"Human induced pluripotent stem cell-derived planar neural organoids assembled on synthetic hydrogels","volume":"15","author":"Majumder","year":"2024","journal-title":"J. Tissue Eng."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.actbio.2023.09.040","article-title":"Bioactive and chemically defined hydrogels with tunable stiffness guide cerebral organoid formation and modulate multi-omics plasticity in cerebral organoids","volume":"171","author":"Isik","year":"2023","journal-title":"Acta Biomater."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1039\/D2LC01109C","article-title":"Vascularized human brain organoid on-chip","volume":"23","author":"Tan","year":"2023","journal-title":"Lab A Chip"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8162","DOI":"10.36922\/or.8162","article-title":"Generation of vascularized brain organoids: Technology, applications, and prospects","volume":"1","author":"Mei","year":"2025","journal-title":"Organoid Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"tkae039","DOI":"10.1093\/burnst\/tkae039","article-title":"Mechanical strategies to promote vascularization for tissue engineering and regenerative medicine","volume":"12","author":"Wang","year":"2024","journal-title":"Burn. Trauma"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s10020-025-01131-7","article-title":"Effects of hydrogel stiffness and viscoelasticity on organoid culture: A comprehensive review","volume":"31","author":"Lai","year":"2025","journal-title":"Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1002\/term.3225","article-title":"Vascularization strategies in tissue engineering approaches for soft tissue repair","volume":"15","author":"Tayebi","year":"2021","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e08734","DOI":"10.1002\/advs.202508734","article-title":"Rethinking Matrigel: The Complex Journey to Matrix Alternatives in Organoid Culture","volume":"12","author":"Wolff","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/s41578-020-0199-8","article-title":"Synthetic alternatives to Matrigel","volume":"5","author":"Aisenbrey","year":"2020","journal-title":"Nat. Rev. Mater."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1038\/s41467-022-29279-4","article-title":"Tissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids","volume":"13","author":"Kim","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Urrestizala-Arenaza, N., Cerchio, S., Cavaliere, F., and Magliaro, C. (2024). Limitations of human brain organoids to study neurodegenerative diseases: A manual to survive. Front. Cell. Neurosci., 18.","DOI":"10.3389\/fncel.2024.1419526"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhao, X., Xu, Z., Xiao, L., Shi, T., Xiao, H., Wang, Y., Li, Y., Xue, F., and Zeng, W. (2021). Review on the Vascularization of Organoids and Organoids-on-a-Chip. Front. Bioeng. Biotechnol., 9.","DOI":"10.3389\/fbioe.2021.637048"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ehab, S., Gaser, O.A., and Dayem, A.A. (2025). Hypoxia and Multilineage Communication in 3D Organoids for Human Disease Modeling. Biomimetics, 10.","DOI":"10.3390\/biomimetics10090624"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"C146","DOI":"10.1152\/ajpcell.00195.2010","article-title":"Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces","volume":"300","author":"Krishnan","year":"2011","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ursini, O., Grieco, M., Sappino, C., Capodilupo, A.L., Giannitelli, S.M., Mauri, E., Bucciarelli, A., Coricciati, C., de Turris, V., and Gigli, G. (2023). Modulation of Methacrylated Hyaluronic Acid Hydrogels Enables Their Use as 3D Cultured Model. Gels, 9.","DOI":"10.3390\/gels9100801"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1021\/mz300366s","article-title":"Photo-selective delivery of model therapeutics from hydrogels","volume":"1","author":"Griffin","year":"2012","journal-title":"ACS Macro Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2300918","DOI":"10.1002\/adhm.202300918","article-title":"Facile Synthesis of Highly Stretchable, Tough, and Photodegradable Hydrogels","volume":"12","author":"Fonseca","year":"2023","journal-title":"Adv. Healthc. Mater."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/s41467-024-54880-0","article-title":"Visible light-responsive hydrogels for cellular dynamics and spatiotemporal viscoelastic regulation","volume":"16","author":"Lu","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8307","DOI":"10.1038\/s41467-023-43768-0","article-title":"Hydrogels with tunable mechanical plasticity regulate endothelial cell outgrowth in vasculogenesis and angiogenesis","volume":"14","author":"Wei","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e01932","DOI":"10.1002\/adhm.202501932","article-title":"Using High-Throughput Screening to Identify Crosslinking Peptides That Control Cell-Mediated Matrix Degradation","volume":"14","author":"Wu","year":"2025","journal-title":"Adv. Healthc. Mater."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1039\/D3LP00057E","article-title":"Matrix metalloproteinase responsive hydrogel microplates for programmed killing of invasive tumour cells","volume":"1","author":"Cook","year":"2023","journal-title":"RSC Appl. Polym."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/acs.biomac.9b01675","article-title":"Conversion of an Injectable MMP-Degradable Hydrogel into Core-Cross-Linked Micelles","volume":"21","author":"Najafi","year":"2020","journal-title":"Biomacromolecules"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"134493","DOI":"10.1016\/j.ijbiomac.2024.134493","article-title":"Structurally decoupled hyaluronic acid hydrogels for studying matrix metalloproteinase-mediated invasion of metastatic breast cancer cells","volume":"277","author":"Goodarzi","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/jbm.a.35534","article-title":"Temperature responsive hydrogels enable transient three-dimensional tumor cultures via rapid cell recovery","volume":"104","author":"Heffernan","year":"2016","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Zhang, K., Xue, K., and Loh, X.J. (2021). Thermo-Responsive Hydrogels: From Recent Progress to Biomedical Applications. Gels, 7.","DOI":"10.3390\/gels7030077"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101073","DOI":"10.1016\/j.reth.2026.101073","article-title":"A thermo-responsive sol-to-gel phase transition hydrogel for sustained delivery of mesenchymal stem cell-derived exosomes","volume":"31","author":"Liu","year":"2026","journal-title":"Regen Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nmat4474","article-title":"Supramolecular biomaterials","volume":"15","author":"Webber","year":"2016","journal-title":"Nat. Mater."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1038\/nprot.2017.053","article-title":"Shear-thinning and self-healing hydrogels as injectable therapeutics and for 3D-printing","volume":"12","author":"Loebel","year":"2017","journal-title":"Nat. Protoc."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"eadr3209","DOI":"10.1126\/sciadv.adr3209","article-title":"Synthetic, multi-dynamic hydrogels by uniting stress-stiffening and supramolecular polymers","volume":"10","author":"Rijns","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1021\/acsabm.9b00253","article-title":"Comparison of Bioorthogonally Cross-Linked Hydrogels for in Situ Cell Encapsulation","volume":"2","author":"Zhan","year":"2019","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_48","first-page":"386","article-title":"Recent advances in defined hydrogels in organoid research","volume":"28","author":"Gan","year":"2023","journal-title":"Bioact. Mater."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"042003","DOI":"10.1088\/1758-5090\/ade47a","article-title":"3D bioprinting in tissue engineering: Current state-of-the-art and challenges towards system standardization and clinical translation","volume":"17","author":"Agarwal","year":"2025","journal-title":"Biofabrication"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e2200653","DOI":"10.1002\/adma.202200653","article-title":"A Print-and-Fuse Strategy for Sacrificial Filaments Enables Biomimetically Structured Perfusable Microvascular Networks with Functional Endothelium Inside 3D Hydrogels","volume":"34","author":"Ryma","year":"2022","journal-title":"Adv. Mater."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Maggiotto, F., Bova, L., Micheli, S., Pozzer, C., Fusco, P., Sgarbossa, P., Billi, F., and Cimetta, E. (2025). 3D bioprinting for the production of a perfusable vascularized model of a cancer niche. Front. Bioeng. Biotechnol., 13.","DOI":"10.3389\/fbioe.2025.1484738"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"120294","DOI":"10.1016\/j.biomaterials.2020.120294","article-title":"A sequential 3D bioprinting and orthogonal bioconjugation approach for precision tissue engineering","volume":"258","author":"Yu","year":"2020","journal-title":"Biomaterials"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.actbio.2020.12.041","article-title":"Phototunable interpenetrating polymer network hydrogels to stimulate the vasculogenesis of stem cell-derived endothelial progenitors","volume":"122","author":"Crosby","year":"2021","journal-title":"Acta Biomater."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"eadh8313","DOI":"10.1126\/sciadv.adh8313","article-title":"Tunable hydrogel viscoelasticity modulates human neural maturation","volume":"9","author":"Roth","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/jbm.a.37662","article-title":"Vascularization of PEGylated fibrin hydrogels increases the proliferation of human iPSC-cardiomyocytes","volume":"112","author":"Vanderslice","year":"2024","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"122050","DOI":"10.1016\/j.biomaterials.2023.122050","article-title":"A combination of matrix stiffness and degradability dictate microvascular network assembly and remodeling in cell-laden poly(ethylene glycol) hydrogels","volume":"295","author":"Friend","year":"2023","journal-title":"Biomaterials"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"41524","DOI":"10.1038\/s41598-025-25381-x","article-title":"3D endothelial network formation in hydrogels improved by stromal cells and specific growth factors","volume":"15","author":"Acimovic","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.mattod.2025.01.019","article-title":"Enabling 3D printability and vascular morphogenesis with double network dynamic hydrogels","volume":"84","author":"Xu","year":"2025","journal-title":"Mater. Today"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Falandt, M., Bernal, P.N., Longoni, A., Buchholz, M.-B., Quilis, P.C., Widmann, K., Barrera-Roman, M., Malda, J., Vermonden, T., and Rios, A. (2025). Hybrid supramolecular-covalent bioresin promotes cell migration and self-assembly in light-based volumetric bioprinted constructs. bioRxiv.","DOI":"10.1101\/2025.01.06.631505"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Son, J., Li, S., and Jeong, W. (2025). Bioprinting Vascularized Constructs for Clinical Relevance: Engineering Hydrogel Systems for Biological Maturity. Gels, 11.","DOI":"10.3390\/gels11080636"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kheiri, S., Shah, J., Venkatesh, S.A., Kamm, R.D., and Raman, R. (2025). 4D force patterning enables spatial control of angiogenesis. bioRxiv.","DOI":"10.1101\/2025.11.11.687921"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.stem.2025.02.010","article-title":"Vascular network-inspired diffusible scaffolds for engineering functional midbrain organoids","volume":"32","author":"Cai","year":"2025","journal-title":"Cell Stem Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3794","DOI":"10.1038\/s41598-025-33940-5","article-title":"Vascularized human brain organoids as a model of the brain\u2013peripheral axis in HIV-1 neuropathogenesis","volume":"16","author":"Selvam","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Huang, J., Zhu, Y., Tang, J., Liu, Y., Lu, M., Zhang, R., and Sun, A.X. (2025). Navigating Brain Organoid Maturation: From Benchmarking Frameworks to Multimodal Bioengineering Strategies. Biomolecules, 15.","DOI":"10.3390\/biom15081118"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Kugler, E.C., Greenwood, J., and MacDonald, R.B. (2021). The \u201cNeuro-Glial-Vascular\u201d Unit: The Role of Glia in Neurovascular Unit Formation and Dysfunction. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.732820"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.tice.2018.03.010","article-title":"Spatial and temporal recruitment of the neurovascular unit during development of the mouse blood-retinal barrier","volume":"52","author":"Vogels","year":"2018","journal-title":"Tissue Cell"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Karakatsani, A., Shah, B., and Ruiz de Almodovar, C. (2019). Blood Vessels as Regulators of Neural Stem Cell Properties. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00085"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1038\/ncomms2271","article-title":"Moving from static to dynamic complexity in hydrogel design","volume":"3","author":"Burdick","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1172\/JCI93825","article-title":"YAP\/TAZ regulates sprouting angiogenesis and vascular barrier maturation","volume":"127","author":"Kim","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1039\/D0LC01283A","article-title":"Mechanotransduction-on-chip: Vessel-chip model of endothelial YAP mechanobiology reveals matrix stiffness impedes shear response","volume":"21","author":"Walther","year":"2021","journal-title":"Lab A Chip"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e2021571118","DOI":"10.1073\/pnas.2021571118","article-title":"A spatial model of YAP\/TAZ signaling reveals how stiffness, dimensionality, and shape contribute to emergent outcomes","volume":"118","author":"Scott","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/s41540-024-00414-9","article-title":"Insights gained from computational modeling of YAP\/TAZ signaling for cellular mechanotransduction","volume":"10","author":"Jafarinia","year":"2024","journal-title":"npj Syst. Biol. Appl."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.1016\/j.cell.2025.03.037","article-title":"Fate and state transitions during human blood vessel organoid development","volume":"188","author":"Nikolova","year":"2025","journal-title":"Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e07256","DOI":"10.1002\/advs.202507256","article-title":"Cerebral Organoids with Integrated Endothelial Networks Emulate the Neurovascular Unit and Mitigate Core Necrosis","volume":"12","author":"Crilly","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e03768","DOI":"10.1002\/advs.202503768","article-title":"Multi-Region Brain Organoids Integrating Cerebral, Mid-Hindbrain, and Endothelial Systems","volume":"12","author":"Kshirsagar","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Xie, B., and Xie, H. (2024). Application of stimuli-responsive hydrogel in brain disease treatment. Front. Bioeng. Biotechnol., 12.","DOI":"10.3389\/fbioe.2024.1450267"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Li, X., Duan, L., Kong, M., Wen, X., Guan, F., and Ma, S. (2022). Applications and Mechanisms of Stimuli-Responsive Hydrogels in Traumatic Brain Injury. Gels, 8.","DOI":"10.3390\/gels8080482"},{"key":"ref_78","first-page":"378","article-title":"Emerging brain organoids: 3D models to decipher, identify and revolutionize brain","volume":"47","author":"Zhao","year":"2025","journal-title":"Bioact. Mater."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e70008","DOI":"10.1002\/btm2.70008","article-title":"Engineered microvascular basement membrane mimetic for real-time neutrophil tracking in the microvascular wall","volume":"10","author":"Morales","year":"2025","journal-title":"Bioeng. Transl. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"eady4738","DOI":"10.1126\/sciadv.ady4738","article-title":"Murine vascular organoids are responsive and adaptable 3D systems with cellular heterogeneity and dynamic plasticity","volume":"11","author":"Guelfi","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Wang, T., Bagnell, A., McDonald, V., Gastfriend, B.D., Steiner, J.P., Elkahloun, A.G., Johnson, K., Langston, R.G., Cookson, M.R., and Nath, A. (2025). 3D organoids containing endothelial and neural cells generation by serial inductions of differentiation on human iPSC-derived embryoid bodies. bioRxiv.","DOI":"10.1101\/2025.05.20.653559"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e2500301","DOI":"10.1002\/adhm.202500301","article-title":"Organoid Vascularization: Strategies and Applications","volume":"14","author":"Gao","year":"2025","journal-title":"Adv. Healthc. Mater."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e2404484","DOI":"10.1002\/adhm.202404484","article-title":"Actuated Hydrogel Platforms to Study Brain Cell Behavior","volume":"14","author":"Zhurenkov","year":"2025","journal-title":"Adv. Healthc. Mater."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/978-1-0716-3429-5_16","article-title":"Measurement of Transendothelial Electrical Resistance in Blood-Brain Barrier Endothelial Cells","volume":"2711","author":"Waithe","year":"2024","journal-title":"Methods Mol. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1177\/2211068214561025","article-title":"TEER measurement techniques for in vitro barrier model systems","volume":"20","author":"Srinivasan","year":"2015","journal-title":"J. Lab Autom."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Nogueira Pinto, H., Kok, N.R., Hauger, P.C., Karsten-van Diepen, M., de Kok, M., Paauw, N.J., van der Pol, S.M.A., Nugteren-Boogaard, J.P., Hordijk, P.L., and Beekhuis-Hoekstra, S.D. (2025). Pericytes and Wnt signaling induce functional blood-brain barrier phenotype in human iPSC-based model. bioRxiv.","DOI":"10.1101\/2025.09.26.678752"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/nyas.14798","article-title":"Tight junction proteins occludin and ZO-1 as regulators of epithelial proliferation and survival","volume":"1514","author":"Kuo","year":"2022","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Cioni, C., Turlizzi, E., Zanelli, U., Oliveri, G., and Annunziata, P. (2012). Expression of Tight Junction and Drug Efflux Transporter Proteins in an in vitro Model of Human Blood\u2013Brain Barrier. Front. Psychiatry, 3.","DOI":"10.3389\/fpsyt.2012.00047"},{"key":"ref_89","first-page":"e57038","article-title":"An In Vivo Blood-brain Barrier Permeability Assay in Mice Using Fluorescently Labeled Tracers","volume":"132","author":"Devraj","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3591","DOI":"10.2147\/DDDT.S218708","article-title":"In-vitro blood-brain barrier models for drug screening and permeation studies: An overview","volume":"13","author":"Bagchi","year":"2019","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1002\/jnr.22738","article-title":"GLUT-1 glucose transporters in the blood-brain barrier: Differential phosphorylation","volume":"89","author":"Devraj","year":"2011","journal-title":"J. Neurosci. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1602\/neurorx.2.1.86","article-title":"Blood-brain barrier active efflux transporters: ATP-binding cassette gene family","volume":"2","author":"Potschka","year":"2005","journal-title":"NeuroRx"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-0716-2289-6_1","article-title":"Cells of the Blood-Brain Barrier: An Overview of the Neurovascular Unit in Health and Disease","volume":"2492","author":"McConnell","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"eabq5031","DOI":"10.1126\/sciadv.abq5031","article-title":"Shell microelectrode arrays (MEAs) for brain organoids","volume":"8","author":"Huang","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Passaro, A.P., and Stice, S.L. (2020). Electrophysiological Analysis of Brain Organoids: Current Approaches and Advancements. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.622137"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Gu, L., Cai, H., Chen, L., Gu, M., Tchieu, J., and Guo, F. (2024). Functional Neural Networks in Human Brain Organoids. BME Front., 5.","DOI":"10.34133\/bmef.0065"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"6642","DOI":"10.1007\/s12035-024-03998-9","article-title":"Shaping the Neurovascular Unit Exploiting Human Brain Organoids","volume":"61","author":"Rizzuti","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"20240026","DOI":"10.1098\/rsfs.2024.0026","article-title":"Model-driven exploration of poro-viscoelasticity in human brain tissue: Be careful with the parameters!","volume":"14","author":"Greiner","year":"2024","journal-title":"Interface Focus"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1016\/j.tibtech.2024.11.021","article-title":"Vascularized human brain organoids: Current possibilities and prospects","volume":"43","author":"Kistemaker","year":"2025","journal-title":"Trends Biotechnol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"100779","DOI":"10.1016\/j.crmeth.2024.100779","article-title":"Bioengineering methods for vascularizing organoids","volume":"4","author":"Nwokoye","year":"2024","journal-title":"Cell Rep. Methods"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"015001","DOI":"10.1088\/1758-5090\/ad867e","article-title":"Dynamic culture of cerebral organoids using a pillar\/perfusion plate for the assessment of developmental neurotoxicity","volume":"17","author":"Acharya","year":"2024","journal-title":"Biofabrication"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"33140","DOI":"10.34172\/bi.33140","article-title":"Organoid-engineered neurovascular units for drug discovery and neurodegeneration research","volume":"15","author":"Nakhlband","year":"2025","journal-title":"Bioimpacts"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1557\/mrc.2019.159","article-title":"Response of neuroglia to hypoxia-induced oxidative stress using enzymatically crosslinked hydrogels","volume":"10","author":"Zambuto","year":"2020","journal-title":"MRS Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3721","DOI":"10.1039\/D4MH00289J","article-title":"ROS-responsive hydrogels: From design and additive manufacturing to biomedical applications","volume":"11","author":"Pu","year":"2024","journal-title":"Mater. Horiz."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e2300123","DOI":"10.1002\/adhm.202300123","article-title":"ROS-Scavenging Hydrogels Synergize with Neural Stem Cells to Enhance Spinal Cord Injury Repair via Regulating Microenvironment and Facilitating Nerve Regeneration","volume":"12","author":"Liu","year":"2023","journal-title":"Adv. Healthc. Mater."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"5755","DOI":"10.1039\/D5BM00403A","article-title":"Tuning the mechanical properties and printability of viscoelastic skin-derived hydrogels for 3D cell culture","volume":"13","author":"Palierse","year":"2025","journal-title":"Biomater. Sci."}],"container-title":["Gels"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2310-2861\/12\/4\/287\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T08:54:21Z","timestamp":1774860861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2310-2861\/12\/4\/287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,29]]},"references-count":106,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["gels12040287"],"URL":"https:\/\/doi.org\/10.3390\/gels12040287","relation":{},"ISSN":["2310-2861"],"issn-type":[{"value":"2310-2861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,29]]}}}