Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC1816610.15690/vramn18166NEUROLOGY AND NEUROSURGERY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ НЕВРОЛОГИИ И НЕЙРОХИРУРГИИReview ArticleMicrophysiological systems for studying neuroplasticity and cerebral microcirculationМикрофизиологические системы для изучения нейропластичности и церебральной микроциркуляцииhttps://orcid.org/0000-0003-4012-63486504-7657SalminaAlla B.СалминаАлла Борисовна
Russian Federation

MD, PhD, Professor, Corresponding Member of the RAS

д.м.н., профессор, член-корреспондент РАН

allasalmina@mail.ruhttps://orcid.org/0000-0002-1284-67117276-8713AverchukAnton S.АверчукАнтон Сергеевич
Russian Federation

PhD in Biology, Assistant Professor

к.б.н., доцент

antonaverchuk@yandex.ruhttps://orcid.org/0000-0001-5742-83561585-8130KomlevaYulia K.КомлеваЮлия Константиновна
Russian Federation

MD, PhD

д.м.н.

yuliakomleva@mail.ru5815-0989KolotyevaNatalia A.КолотьеваНаталия Александровна
Russian Federation

MD, PhD, Assistant Professor

д.м.н., доцент

bortnikova.n@gmail.comhttps://orcid.org/0000-0001-9619-46797696-1738RozanovaNatalia A.РозановаНаталья Александровна
Russian Federation
nataliarozanovaa@gmail.comhttps://orcid.org/0000-0001-9743-87004229-9507PotapenkoIlya V.ПотапенкоИлья Викторович
Russian Federation

PhD

iluminator@snkip.ruhttps://orcid.org/0009-0006-9109-14632705-7186AlexandrovaOlga P.АлександроваОльга Петровна
Russian Federation

PhD in Biology

к.б.н.

molka-molka@yandex.ruhttps://orcid.org/0009-0001-6127-80445367-8372LifanovDmitry A.ЛифановДмитрий Алексеевич
Russian Federation
dmtlifnv@gmail.comhttps://orcid.org/0000-0001-6888-32237548-0933AbaimovDenis A.АбаимовДенис Александрович
Russian Federation

PhD in Biology

к.б.н.

abaimov@neurology.ruhttps://orcid.org/0000-0002-2319-48945400-0828DragunMaksim A.ДрагунМаксим Алексеевич
Russian Federation
drmaksim@icloud.comhttps://orcid.org/0009-0007-5034-62442083-6046KushnirIvan A.КушнирИван Андреевич
Russian Federation
ivankushnir.x@gmail.comhttps://orcid.org/0000-0001-9269-83006918-5588KorsakovаSofia A.КорсаковаСофья Андреевна
Russian Federation
sofia.korsakova@gmail.comhttps://orcid.org/0000-0001-6821-904X3313-1005YurchenkoStanislav O.ЮрченкоСтанислав Олегович
Russian Federation

PhD in Physical and Mathematical Sciences, Professor

д.ф.-м.н., профессор

st.yurchenko@mail.ruhttps://orcid.org/0000-0002-2704-62828646-9426IllarioshkinSergey N.ИллариошкинСергей Николаевич
Russian Federation

MD, PhD, Professor, Academician of the RAS

д.м.н., профессор, академик РАН

illarioshkin@neurology.ruRussian Сenter of Neurology and NeurosciencesРоссийский центр неврологии и нейронаукMoscow State Technical University named after N.E. BaumanМосковский государственный технический университет им. Н.Э. Баумана1605202681114222212202527032026Copyright ©; 2026, "Paediatrician" Publishers LLCCopyright ©; 2026, Издательство "Педиатръ"2026"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/18166

This review systematizes modern bioengineering strategies for modeling tissue barriers, neurovascular unit (NVU) and perivascular unit (PVU) for translational neuroscience. The aim is to provide a critical analysis of the current understandings of neuroplasticity, organization of NVU, PVU and blood-brain barrier as well as advantages and limitations of currently available in vitro microphysiological models. It is clear that, despite progress in replicating three-dimensional architecture, the next key challenge is to imitate the temporal dynamics of histogenesis (angiogenesis, barrierogenesis, neurogenesis). This defines the transition towards the development of a novel class of 4D models capable of spatiotemporal self-organization. The analysis reveals the necessity to adapt model complexity to the target function: highly complex systems are a priority for fundamental research into plasticity and pathogenesis of nervous system disorders, while standardized platforms are well-suited for high-throughput pharmacological screening. It is concluded that creating relevant, validated platforms remains a critical interdisciplinary task. This will help bridge the gap between preclinical and clinical research, enhancing the reliability of studying pathological mechanisms and the preclinical evaluation of therapeutic agents.

В обзоре систематизированы современные стратегии биоинженерного моделирования тканевых барьеров, нейроваскулярной единицы (НВЕ), периваскулярной единицы (ПВЕ) головного мозга для трансляционной неврологии. Целью является критический анализ текущего понимания нейропластичности, организации НВЕ, ПВЕ, гематоэнцефалического барьера и данных о преимуществах и недостатках существующих микрофизиологических in vitro моделей. Показано, что, несмотря на прогресс в воспроизведении трехмерной архитектуры, следующей ключевой задачей выступает имитация временной динамики гистогенеза (ангиогенез, барьерогенез, нейрогенез). Это определяет переход к разработке принципиально нового класса 4D-моделей, способных к пространственно-временной самоорганизации. Анализ выявляет необходимость адаптации сложности модели к целевой функции: сложные системы приоритетны для фундаментальных исследований пластичности и патогенеза заболеваний нервной системы, тогда как стандартизированные и упрощенные платформы — для массового фармакологического скрининга. Делается вывод, что создание релевантных, валидированных платформ остается критически важной междисциплинарной задачей. Это позволит сократить разрыв между доклиническими и клиническими исследованиями, повысив достоверность изучения механизмов патологии и доклинической оценки терапевтических средств.

neurovascular unitperivascular unitmicrophysiological systemsin vitro modelsнейроваскулярная единицапериваскулярная единицамикрофизиологические системыin vitro моделиМинистерство науки и высшего образования Российской ФедерацииMinistry of Science and Higher Education of the Russian Federation075-15-2024-638This work was supported by a grant from the Ministry of Science and Higher Education of the Russian Federation for the implementation of large-scale scientific projects in priority areas of science and technology development (project No. 075-15-2024-638).Работа выполнена при поддержке гранта Министерства науки и высшего образования Российской Федерации для реализации крупных научных проектов по приоритетным направлениям развития науки и техники (проект № 075-15-2024-638).Koch G, Spampinato D. Alzheimer disease and neuroplasticity. Handb Clin Neurol. 2022;184:473–479. doi: https://doi.org/10.1016/B978-0-12-819410-2.00027-8Paro MR, Chakraborty AR, Angelo S, et al. Molecular mediators of angiogenesis and neurogenesis after ischemic stroke. Rev Neurosci. 2022;34(4):425–442. doi: https://doi.org/10.1515/revneuro-2022-0049Salmina AB, Kharitonova EV, Gorina YV, et al. Blood-Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration. Int J Mol Sci. 2021;22(9):4661. doi: https://doi.org/10.3390/ijms22094661Loryan I, Hammarlund-Udenaes M, Syvänen S. Brain Distribution of Drugs: Pharmacokinetic Considerations. Handb Exp Pharmacol. 2022;273:121–150. doi: https://doi.org/10.1007/164_2020_405Tregub PP, Averchuk AS, Baranich TI, et al. Physiological and Pathological Remodeling of Cerebral Microvessels. Int J Mol Sci. 2022;23(20):12683. doi: https://doi.org/10.3390/ijms232012683Kumar NN, Pizzo ME, Nehra G, et al. Passive Immunotherapies for Central Nervous System Disorders: Current Delivery Challenges and New Approaches. Bioconjug Chem. 2018;29(12):3937–3966. doi: https://doi.org/10.1021/acs.bioconjchem.8b00548Gupta M, Feng J, Bhisetti G. Experimental and Computational Methods to Assess Central Nervous System Penetration of Small Molecules. Molecules. 2024;29(6):1264. doi: https://doi.org/10.3390/molecules29061264Miller K. Biomechanics of soft tissues. Med Sci Monit. 2000;6(1):158–167.Tanigami H, Okamoto T, Yasue Y, et al. Astroglial integrins in the development and regulation of neurovascular units. Pain Res Treat. 2012;2012:964652. doi: https://doi.org/10.1155/2012/964652Troili F, Cipollini V, Moci M, et al. Perivascular Unit: This Must Be the Place. The Anatomical Crossroad between the Immune, Vascular and Nervous System. Front Neuroanat. 2020;14:17. doi: https://doi.org/10.3389/fnana.2020.00017Lohela TJ, Lilius TO, Nedergaard M. The glymphatic system: implications for drugs for central nervous system diseases. Nat Rev Drug Discov. 2022;21(10):763–779. doi: https://doi.org/10.1038/s41573-022-00500-9Pozhilenkova EA, Lopatina OL, Komleva YK, et al. Blood-brain barrier-supported neurogenesis in healthy and diseased brain. Rev Neurosci. 2017;28(4):397–415. doi: https://doi.org/10.1515/revneuro-2016-0071Bressan C, Saghatelyan A. Intrinsic Mechanisms Regulating Neuronal Migration in the Postnatal Brain. Front Cell Neurosci. 2021;14:620379. doi: https://doi.org/10.3389/fncel.2020.620379James R, Kim Y, Hockberger PE, et al. Subventricular zone cell migration: lessons from quantitative two-photon microscopy. Front Neurosci. 2011;5:30. doi: https://doi.org/10.3389/fnins.2011.00030Lange C, Turrero Garcia M, Decimo I, et al. Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis. EMBO J. 2016;35(9):924–941. doi: https://doi.org/10.15252/embj.201592372Hatakeyama M, Ninomiya I, Kanazawa M. Angiogenesis and neuronal remodeling after ischemic stroke. Neural Regen Res. 2020;15(1):16–19. doi: https://doi.org/10.4103/1673-5374.264442Bonfanti L, La Rosa C, Ghibaudi M, et al. Adult neurogenesis and “immature” neurons in mammals: an evolutionary trade-off in plasticity? Brain Struct Funct. 2024;229(8):1775–1793. doi: https://doi.org/10.1007/s00429-023-02717-9Perosa V, Priester A, Ziegler G, et al. Hippocampal vascular reserve associated with cognitive performance and hippocampal volume. Brain. 2020;143(2):622–634. doi: https://doi.org/10.1093/brain/awz383Pulga A, Porte Y, Morel JL. Changes in C57BL6 Mouse Hippocampal Transcriptome Induced by Hypergravity Mimic Acute Corticosterone-Induced Stress. Front Mol Neurosci. 2016;9:153. doi: https://doi.org/10.3389/fnmol.2016.00153Abbott NJ, Friedman A. Overview and introduction: the blood-brain barrier in health and disease. Epilepsia. 2012;53(6):1–6. doi: https://doi.org/10.1111/j.1528-1167.2012.03696.xFigley CR, Stroman PW. The role(s) of astrocytes and astrocyte activity in neurometabolism, neurovascular coupling, and the production of functional neuroimaging signals. Eur J Neurosci. 2011;33(4):577–588. doi: https://doi.org/10.1111/j.1460-9568.2010.07584.xFilosa JA. Vascular tone and neurovascular coupling: considerations toward an improved in vitro model. Front Neuroenergetics. 2010;2:16. doi: https://doi.org/10.3389/fnene.2010.00016Tarasoff-Conway JM, Carare RO, Osorio RS, et al. Clearance systems in the brain — implications for Alzheimer disease. Nat Rev Neurol. 2015;11:457–470. doi: https://doi.org/10.1038/nrneurol.2015.119Kim KJ, Ramiro DJ, Iddings JA, et al. Vasculo-Neuronal Coupling: Retrograde Vascular Communication to Brain Neurons. J Neurosci. 2016;36:12624–12639. doi: https://doi.org/10.1523/JNEUROSCI.1300-16.2016Andreone BJ, Lacoste B, Gu C. Neuronal and vascular interactions. Annu Rev Neurosci. 2015;38:25–46. doi: https://doi.org/10.1146/annurev-neuro-071714-033835Zhao Z, Nelson AR, Betsholtz C, et al. Establishment and Dysfunction of the Blood-Brain Barrier. Cell. 2015;163(5):1064–1078. doi: https://doi.org/10.1016/j.cell.2015.10.067Castro DM, Mapunda JA, Vladymyrov M, et al. Structure and Junctional Complexes of Endothelial, Epithelial and Glial Brain Barriers. Int J Mol Sci. 2019;20(21):5372. doi: https://doi.org/10.3390/ijms20215372Osipova ED, Semyachkina-Glushkovskaya OV, Morgun AV, et al. Gliotransmitters and cytokines in the control of blood-brain barrier permeability. Rev Neurosci. 2018;29(5):567–591. doi: https://doi.org/10.1515/revneuro-2017-0092Khadka B, Lee JY, Park EK, et al. Impacts of Drug Interactions on Pharmacokinetics and the Brain Transporters: A Recent Review of Natural Compound-Drug Interactions in Brain Disorders. Int J Mol Sci. 2021;22(4):1809. doi: https://doi.org/10.3390/ijms22041809Hashimoto Y, Campbell M. Eyes on glutamate in angiogenesis and barrier formation. Neuron. 2024;112(12):1895–1897. doi: https://doi.org/10.1016/j.neuron.2024.05.020Zhdankina VI, Perepelitsa ES, Blagova AV, et al. The involvement of HIF-1α-dependent paracrine factors in Alzheimer’s disease. Rev Neurosci. 2025. doi: https://doi.org/10.1515/revneuro-2025-0102Salmina AB, Saridis MR, Ryzhkov VV, et al. Development of microvascular network in microfluidic brain-on-a-chip models in vitro: a multidisciplinary review. Biotechnol J. 2025;20(10):e70126. doi: https://doi.org/10.1002/biot.70126Biron KE, Dickstein DL, Gopaul R, et al. Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer’s disease. PLoS One. 2011;6(8):e23789. doi: https://doi.org/10.1371/journal.pone.0023789Alvarez-Vergara MI, Rosales-Nieves AE, March-Diaz R, et al. Non-productive angiogenesis disassembles Aß plaque-associated blood vessels. Nat Commun. 2021;12(1):3098. doi: https://doi.org/10.1038/s41467-021-23337-zAverchuk AS, Ryazanova MV, Baranich TI, et al. The Neurotoxic Effect of β-Amyloid Is Accompanied by Changes in the Mitochondrial Dynamics and Autophagy in Neurons and Brain Endothelial Cells in the Experimental Model of Alzheimer’s Disease. Bull Exp Biol Med. 2023;175(3):315–320. doi: https://doi.org/10.1007/s10517-023-05859-2Baranich TI, Averchuk AS, Kukla MV, et al. Subpopulation Alterations of Vascular Endothelial Cells in the Cerebral Cortex in Experimental Models of Alzheimer’s Disease. Bull Exp Biol Med. 2025;178(3):371–375. doi: https://doi.org/10.1007/s10517-025-06339-5Singh CSB, Choi KB, Munro L, et al. Reversing pathology in a preclinical model of Alzheimer’s disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics. EBioMedicine. 2021;71:103503. doi: https://doi.org/10.1016/j.ebiom.2021.103503Ogaki A, Ikegaya Y, Koyama R. Vascular Abnormalities and the Role of Vascular Endothelial Growth Factor in the Epileptic Brain. Front Pharmacol. 2020;11:20. doi: https://doi.org/10.3389/fphar.2020.00020Boitsova EB, Morgun AV, Osipova ED, et al. The inhibitory effect of LPS on the expression of GPR81 lactate receptor in blood-brain barrier model in vitro. J Neuroinflammation. 2018;15(1):196. doi: https://doi.org/10.1186/s12974-018-1233-2Salmina AB, Gorina YV, Komleva YK, et al. Early Life Stress and Metabolic Plasticity of Brain Cells: Impact on Neurogenesis and Angiogenesis. Biomedicines. 2021;9(9):1092. doi: https://doi.org/10.3390/biomedicines9091092Moya ELJ, Vandenhaute E, Rizzi E, et al. Miniaturization and Automation of a Human In Vitro Blood-Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery. Pharmaceutics. 2021;13(6):892. doi: https://doi.org/10.3390/pharmaceutics13060892Salmina AB, Alexandrova OP, Averchuk AS, et al. Current progress and challenges in the development of brain tissue models: How to grow up the changeable brain in vitro? J Tissue Eng. 2024;15:20417314241235527. doi: https://doi.org/10.1177/20417314241235527Brofiga M, Massobrio P. Brain-on-a-Chip: Dream or Reality? Front Neurosci. 2022;16:837623. doi: https://doi.org/10.3389/fnins.2022.837623Maoz BM. Brain-on-a-Chip: Characterizing the next generation of advanced in vitro platforms for modeling the central nervous system. APL Bioeng. 2021;5(3):030902. doi: https://doi.org/10.1063/5.0055812Bang S, Jeong S, Choi N, et al. Brain-on-a-chip: A history of development and future perspective. Biomicrofluidics. 2019;13(5):051301. doi: https://doi.org/10.1063/1.5120555Park TE, Mustafaoglu N, Herland A, et al. Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies. Nat Commun. 2019;10(1):2621. doi: https://doi.org/10.1038/s41467-019-10588-0Cho H, Seo JH, Wong KH, et al. Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology. Sci Rep. 2015;5:15222. doi: https://doi.org/10.1038/srep15222Hogberg HT, Smirnova L. The Future of 3D Brain Cultures in Developmental Neurotoxicity Testing. Front Toxicol. 2022;4:808620. doi: https://doi.org/10.3389/ftox.2022.808620Nikolakopoulou P, Rauti R, Voulgaris D, et al. Recent progress in translational engineered in vitro models of the central nervous system. Brain. 2020;143(11):3181–3213. doi: https://doi.org/10.1093/brain/awaa268Mäger I, Meyer AH, Li J, et al. Targeting blood-brain-barrier transcytosis — perspectives for drug delivery. Neuropharmacology. 2017;120:4–7. doi: https://doi.org/10.1016/j.neuropharm.2016.08.025Mitusova K, Peltek OO, Karpov TE, et al. Overcoming the blood-brain barrier for the therapy of malignant brain tumor: current status and prospects of drug delivery approaches. J Nanobiotechnology. 2022;20(1):412. doi: https://doi.org/10.1186/s12951-022-01610-7Adriani G, Ma D, Pavesi A, et al. A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood-brain barrier. Lab Chip. 2017;17(3):448–459. doi: https://doi.org/10.1039/c6lc00638hCecen B, Saygili E, Zare I, et al. Biosensor integrated brain-on-a-chip platforms: Progress and prospects in clinical translation. Biosens Bioelectron. 2023;225:115100. doi: https://doi.org/10.1016/j.bios.2023.115100Ahn SI, Sei YJ, Park HJ, et al. Microengineered human blood-brain barrier platform for understanding nanoparticle transport mechanisms. Nat Commun. 2020;11(1):175. doi: https://doi.org/10.1038/s41467-019-13896-7Wei W, Cardes F, Hierlemann A, et al. 3D In Vitro Blood-Brain-Barrier Model for Investigating Barrier Insults. Adv Sci (Weinh). 2023;10(11):e2205752. doi: https://doi.org/10.1002/advs.202205752