Cerebral Organoids with Integrated Endothelial Networks Emulate the Neurovascular Unit and Mitigate Core Necrosis

Abstract: Cerebral organoids (COs) are multicellular, self-organized, in vitro, 3D brain-like tissues used for developmental biology, disease modelling and drug screening. However, their lack of vascularity renders them less physiologically accurate. Vascularization of COs remains challenging due to the different requirements between COs and vascular cells, limited vascular network penetration within the organoid, and the absence of luminal perfusion. Here, we devised an encapsulation approach in which human brain microvascular endothelial cells (HBMVECs) were delivered to developing COs from progressively degrading extracellular matrix (ECM)-based hydrogel droplets. By tuning this hydrogel concentration and media composition, we observed enhanced vascular-like network formation that expanded within the organoid tissue. Using pathway inhibitors, we showed that a subset of the endothelial cells (ECs) originated from the CO itself, promoting network integration. Endothelial networks displayed blood-brain barrier (BBB) features, including astrocytic end-footlike interactions, pericyte wrapping, and collagen-laminin basal lamina. Vascularized COs exhibited greater media internalization and up to three-fold lower apoptosis than non-vascularized COs. This comprehensive 3D neurovascular model is a promising platform for cerebrovascular research and drug testing applications.

Key Publications

Fumadó Navarro J., Crilly S., Chan W. K., Browne S., Mason J. O., Giraldo C. V., Pandit A., Lomora M.

Advanced Science, 2025 DOI: 10.1002/advs.202507256

BioRxiv DOI: 10.1101/2025.04.23.650161 )

Using atorvastatin-induced vascular weakness to model brain haemorrhage in vascularised cerebral organoids

Abstract: Intracerebral haemorrhage is the most severe subtype of stroke; however, pre-clinical investigation often fails to translate to the clinic. Cerebral organoids offer an adaptable, in vitro model of human brain tissue for pre-clinical investigation of disease. We recently demonstrated that the tissue can be successfully vascularised to mimic the cerebrovasculature.

Cerebrovascular weakness was induced with atorvastatin to mimic damage observed in intracerebral haemorrhage and to replicate the disease’s pathological features. We used atorvastatin to disrupt functional morphology in human brain microvascular endothelial cells in 2D and 3D model systems. Whole human blood was added to initiate damage to cerebral tissues.

Vascularised cerebral organoids exhibited loss of vascular integrity when treated with atorvastatin. Tissue was vulnerable to injury from human whole blood, and an innate immune response was initiated, resulting in increased cell death.

Here we show that vascularised cerebral organoids demonstrate a novel model platform for investigating pathology associated with human whole blood insult in intracerebral haemorrhage.

Siobhan Crilly, Sugunapriyadharshini Sundararaman, Michael J. Haley, Elisa Segantin, Nicola Campbell, Eulalie J. Lafarge, Antonn Cheeseman, Josep Fumadó Navarro, Declan McKernan, Kevin N. Couper, Mihai Lomora

Under review with Scientific Reports

BioRxiv preprint, 2026 DOI: https://doi.org/10.64898/2026.04.20.719465

Human in Vitro Models of Neurovasculature and the Application to Pre-Clinical Intracerebral Haemorrhage Research

Abstract: Haemorrhagic stroke continues to be a leading cause of death and disability globally, with limited treatment options. Pre-clinical models must adapt to offer translationally relevant and physiologically accurate alternatives to animals. The development of complex co-culture blood-brain barrier models and the incorporation of hydrogels and biomaterials has resulted in microphysical 3D platforms for interrogating drug transport and immune cell transcytosis, however with limited application to haemorrhagic stroke research. Cerebral organoids have revolutionised neuroscience, and novel strategies of vascularising and perfusing them offer a wholly human model system of the cerebrovasculature for the first time. With some adaptation, intracerebral haemorrhage research can benefit from these models for elucidating pathology and recovery mechanisms that can be exploited therapeutically.

Crilly S., Lomora M. 

KeAi: Bioactive Materials, 2026 DOI: https://doi.org/10.1016/j.bioactmat.2025.10.018

The Barley Malting Microbiome: Influence on Malt Quality, Control and Characterization Methods

Publications from group members

Steven Kasozi Galiwango, Elif Göksu Kızılyar, Gert De Rouck, Ilse Van de Voorde, Florian Weiland

Brewing Science, 2024. DOI: 10.23763/BrSc24-06galiwango

Fumadó Navarro J., Crilly S., Chan W. K., Browne S., Mason J. O., Giraldo C. V., Pandit A., Lomora M.

Advanced Science, 2025 DOI: 10.1002/advs.202507256

BioRxiv DOI: 10.1101/2025.04.23.650161 )

Mechanoresponsive Drug Delivery Systems for Vascular Diseases

An Engineered Coccolith-based Hybrid that Transforms Light into Swarming Motion

Lomora M., Larrañaga A., Rodriguez-Emmenegger C., Rodriguez B. J., Dinu I.A., Sarasua J.-R., Pandit A.

Cell Reports Physical Science, 2021. DOI: 10.1016/j.xcrp.2021.100373

AQP1 is Up-regulated by Hypoxia and Leads to Increased Cell Water Permeability, Motility, and Migration in Neuroblastoma

Huo Z., Lomora M, Kym U., Palivan C., Holland-Cunz S. G., Gros S. J.

Frontiers in Cell and Developmental Biology, 2021. DOI: 10.3389/fcell.2021.605272

Biomaterial Based Strategies to Reconstruct the Nigrostriatal Pathway in Organotypic Slice Co-cultures

Ucar B., Kajtez J., Foidl B. M., Eigel D., Werner C., Long K.R., Emnéus J., Bizeau J., Lomora M., Pandit A., Newland B., Humpel C.

Acta Biomaterialia, 2021. DOI: 10.1016/j.actbio.2020.11.035

Therapeutic Applications of Phytoplankton, with an Emphasis on Diatoms and Coccolithophores

Lomora M., Shumate D., Rahman A. A., Pandit A.

Advanced Therapeutics, 2019. DOI: 10.1002/adtp.201800099

Engineering Smart Polymeric Materials With Complex Architectures for Biomedical Applications

Dinu I. A., Dinu M. V., Lomora M., Palivan C. G., Meier W.

in Smart Materials: Integrated Design, Engineering Approaches, and Potential Applications 2018. Apple Academic Press, Eds: Anca Filimon DOI: 10.1201/9781351167963

Antioxidant Functionalized Polymer Capsules to Prevent Oxidative Stress

Larrañaga A., Isa I. L. M., Patil V., Thamboo S., Lomora M., Fernández-Yague M. Y., Sarasua J-R., Palivan C. G., Pandit A.

Acta Biomaterialia, 2018. DOI: 10.1016/j.actbio.2017.12.014

Polymer Capsules as Micro-/nanoreactors for Therapeutic Applications: Current Strategies to Control Membrane Permeability

Larrañaga A., Lomora M., Sarasua J.R., Palivan C.G., Pandit A.

Progress in Materials Science, 2017. DOI: 10.1016/j.pmatsci.2017.08.002

Bio-catalytic Nanocompartments for In Situ Production of Glucose-6-phosphate

Lomora M., Gunkel-Grabole G., Mantri S., Palivan C.G.

Chemical Communications, 2017. DOI: 10.1039/C7CC04739H

Artificial Organelles: Reactions Inside Protein–Polymer Supramolecular Assemblies

Garni M., Einfalt T., Lomora M., Car A., Meier W., Palivan C. G.

Chimia, 2016. DOI: 10.2533/chimia.2016.424

Active Surfaces Engineered by Immobilizing Protein-polymer Nanoreactors for Selectively Detecting Sugar Alcohols

Zhang X., Lomora M., Einfalt T., Meier W., Klein N., Schneider D., Palivan C. G.

Biomaterials, 2016. DOI: 10.1016/j.biomaterials.2016.02.042

Bionanoreactors: From Confined Reaction Spaces to Artificial Organelles

Postupalenko V., Einfalt T., Lomora M., Dinu I. A., Palivan C. G.

in Organic Nanoreactors: From Molecular to Supramolecular Organic Compounds, 2016. Academic Press, Eds: Samahe Sadjadi. DOI: 10.1016/B978-0-12-801713-5.00011-2

Does Membrane Thickness Affect the Transport of Selective Ions Mediated by Ionophores in Synthetic Membranes?

Lomora M., Dinu I.A., Itel F., Rigo S., Spulber M., Palivan C.G.

Macromolecular Rapid Communications, 2015. DOI: 10.1002/marc.201500289

Selective Ion-permeable Membranes by Insertion of Biopores into Polymersomes

Lomora M., Itel F., Dinu I.A., Palivan C.G.

Physical Chemistry Chemical Physics, 2015. DOI: 10.1039/C4CP05879H

Polymeric 3D Nano-architectures for Transport and Delivery of Therapeutically Relevant Biomacromolecules

Gunkel-Grabole G., Sigg S., Lomora M., Lörcher S., Palivan C. G., Meier W. P.

Biomaterials Science, 2015. DOI: 10.1039/C4BM00230J

Polymersomes with Engineered Ion Selective Permeability as Stimuli-responsive Nanocompartments with Preserved Architecture

Lomora M., Itel F., Dinu I.A., Palivan C.G.

Biomaterials, 2015. DOI: 10.1016/j.biomaterials.2015.02.080

Hematoma Interleukin‐1 Receptor Antagonist Concentrations Predict Long‐Term Outcome in Acute Human Intracerebral Hemorrhage

Parry‐Jones, Adrian R., Blessing Nyakutsikwa, Michael H. Askenase, Matthew Gittins, Mary Newland, Siobhan Crilly, Paul R. Kasher et al.

Annals of Neurology, 2026. DOI: https://doi.org/10.1002/ana.78237

Victor S Tapia, Sarah E Withers, Ran Zhou, Abigail Bennington, Christopher Hoyle, Frances Hedley, Adam El Khouja, Nadim Luka, Marco Massimo, Siobhan Crilly, Katherine R Long, Catherine B Lawrence, Paul R Kasher

Disease Models & Mechanisms, 2025. DOI: https://doi.org/10.1242/dmm.052145

The role of 25-hydroxycholesterol in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation

Loss of col4a1 in zebrafish recapitulates the cerebrovascular phenotypes associated with monogenic cerebral small vessel disease

Flatman, Daisy, Richard W. Naylor, Siobhan Crilly, Isabel Carter, Aleksandr Mironov, Emmanuel Pinteaux, Stuart M. Allan, Rachel Lennon, and Paul R. Kasher.

Matrix Biology, 2025. DOI: 10.1016/j.matbio.2025.08.005

Siobhan Crilly, Marietta Zille, Paul R Kasher, Michel Modo

Frontiers in Neurology, 2023. DOI: https://doi.org/10.3389/fneur.2023.1266075

Innovative models of stroke pathology

Investigating recovery after a spontaneous intracerebral haemorrhage in zebrafish larvae

Siobhan Crilly, Isabel Shand, Abigail Bennington, Emily McMahon, Daisy Flatman, Victor S Tapia, Paul R Kasher

Brain Communications, 2024. DOI: https://doi.org/10.1093/braincomms/fcae310

OS Qureshi, TF Rowley, F Junker, SJ Peters, S Crilly, J Compson, A Eddleston, H Björkelund, K Greenslade, M Parkinson, NL Davies, R Griffin, TL Pither, K Cain, L Christodoulou, L Staelens, E Ward, J Tibbitts, A Kiessling, B Smith, FR Brennan, M Malmqvist, F Fallah-Arani, DP Humphreys

Scientific Reports, 2017. DOI: https://doi.org/10.1038/s41598-017-17255-8

Multivalent Fcγ-receptor engagement by a hexameric Fc-fusion protein triggers Fcγ-receptor internalisation and modulation of Fcγ-receptor functions

Identifying applications of virtual reality to benefit the stroke translational pipeline

Matan Bone, Maham Malik, Siobhan Crilly

Brain and Neuroscience Advances, 2023. DOI: https://doi.org/10.1177/23982128231182506

Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndrome

Sarah E Withers, Charlie F Rowlands, Victor S Tapia, Frances Hedley, Ioana-Emilia Mosneag, Siobhan Crilly, Gillian I Rice, Andrew P Badrock, Andrew Hayes, Stuart M Allan, Tracy A Briggs, Paul R Kasher

Frontiers in immunology, 2023. DOI: https://doi.org/10.3389/fimmu.2023.1100967

Zebrafish for modeling stroke and their applicability for drug discovery and development

Siobhan Crilly, Emily McMahon, Paul R Kasher

Expert Opinion on Drug Discovery, 2022. DOI: 10.1080/17460441.2022.2072828

Zebrafish drug screening identifies candidate therapies for neuroprotection after spontaneous intracerebral haemorrhage

Siobhan Crilly, Adrian Parry-Jones, Xia Wang, Julian N Selley, James Cook, Victor S Tapia, Craig S Anderson, Stuart M Allan, Paul R Kasher

Disease Models and Mechanisms, 2022. DOI: https://doi.org/10.1242/dmm.049227

RNA-Seq Dataset From Isolated Leukocytes Following Spontaneous Intracerebral Hemorrhage in Zebrafish Larvae

Siobhan Crilly, James Cooper, Lauren Bradford, Ian E Prise, Siddharth Krishnan, Paul R Kasher

Frontiers in cellular neuroscience, 2021. DOI: https://doi.org/10.3389/fncel.2021.660732

Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine

Víctor Faundes, Martin D Jennings, Siobhan Crilly, Sarah Legraie, Sarah E Withers, Sara Cuvertino, Sally J Davies, Andrew GL Douglas, Andrew E Fry, Victoria Harrison, Jeanne Amiel, Daphné Lehalle, William G Newman, Patricia Newkirk, Judith Ranells, Miranda Splitt, Laura A Cross, Carol J Saunders, Bonnie R Sullivan, Jorge L Granadillo, Christopher T Gordon, Paul R Kasher, Graham D Pavitt, Siddharth Banka

Nature communications, 2021. DOI: https://doi.org/10.1038/s41467-021-21053-2

Revisiting promising preclinical intracerebral hemorrhage studies to highlight repurposable drugs for translation

Siobhan Crilly, Sarah E Withers, Stuart M Allan, Adrian R Parry-Jones, Paul R Kasher

International Journal of Stroke, 2021. DOI: https://doi.org/10.1177/1747493020972240

Analysis of U8 snoRNA variants in zebrafish reveals how bi-allelic variants cause leukoencephalopathy with calcifications and cysts

Andrew P Badrock, Carolina Uggenti, Ludivine Wacheul, Siobhan Crilly, Emma M Jenkinson, Gillian I Rice, Paul R Kasher, Denis LJ Lafontaine, Yanick J Crow, Raymond T O’Keefe

The American Journal of Human Genetics, 2020. DOI: 10.1016/j.ajhg.2020.04.003

Using zebrafish larvae to study the pathological consequences of hemorrhagic stroke

Siobhan Crilly, Alexandra Njegic, Adrian R Parry-Jones, Stuart M Allan, Paul R Kasher

Journal of Visualised Experiments (JoVE), 2019. DOI: 10.3791/59716

Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage

Siobhan Crilly, Alexandra Njegic, Sarah E Laurie, Elisavet Fotiou, Georgina Hudson, Jack Barrington, Kirsty Webb, Helen L Young, Andrew P Badrock, Adam Hurlstone, Jack Rivers-Auty, Adrian R Parry-Jones, Stuart M Allan, Paul R Kasher

F1000 Research, 2018. DOI: 10.12688/f1000research.16473.2

Natural Killer Cell-mimic Nanoparticles Can Actively Target and Kill Acute Myeloid Leukemia Cells

Zeinabad A.H.A, Yeoh W.J., Arif M., Lomora M., Banz Y., Riether C., Krebs P., Szegezdi E.

Biomaterials, 2023. DOI: 10.1016/j.biomaterials.2023.122126

Developing an in vitro model of haematoma for study of intracerebral haemorrhage

Siobhan Crilly, Victor Sebastian Tapia, Carlo Bawn, Annalisa Tirella

Biomaterials Science, 2024. DOI: https://doi.org/10.1039/d4bm00039k

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