Vasculature-on-a-chip platform with innate immunity enables identification of angiopoietin-1 derived peptide as a therapeutic for SARS-CoV-2 induced inflammation
Open accessAbstract
Microfluidic polymeric blood vessel captures the adverse effects of SARS-CoV-2 on vasculature and enables identification of a therapeutic peptide that abolished virus induced cytokine storm orchestrated by the immune cells.
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Organoids and lung-on-a-chip models identified key COVID-19 mechanisms such as endothelial dysfunction, cytokine storm and variable infection susceptibility.
“central pathomechanisms, such as the contribution of endothelial dysfunction, the ‘cytokine storm’ and the intercellular variability of infection susceptibility, were identified in organoids and lung-on-a-chip models82–86.”
From Human disease models in drug development (2023) · cites this paper as [82]
The Results and Discussion report endothelial barrier dysfunction and increased inflammatory cytokines after SARS-CoV-2 exposure, with PBMCs amplifying the response. But this study used a vasculature-on-a-chip, not an organoid or lung-on-a-chip, and it did not establish intercellular variability in infection susceptibility in those models. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA vasculature-on-a-chip study found SARS-CoV-2 impairs endothelial barrier function by disrupting VE-cadherin junctions and raising pro-inflammatory cytokine release.
“A vasculature-on-a-chip setup revealed that SARS-CoV-2 exposure substantially reduces endothelial barrier function by perturbing vascular endothelial–cadherin junctions and increasing pro-inflammatory cytokine release.”
From Human disease models in drug development (2023) · cites this paper as [82]
Adding peripheral blood mononuclear cells worsens endothelial dysfunction and causes excessive inflammation.
“This endothelial dysfunction is exacerbated after the introduction of peripheral blood mononuclear cells, resulting in excessive inflammation82.”
From Human disease models in drug development (2023) · cites this paper as [82]
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Tan, J., Guo, Q., Tian, L., Pei, Z., Li, D., Wu, M., Zhang, J., & Gao, X. (2022) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2022.106329 · Cited by 39 · see citing works
“In addition, Lu R et al. developed a vasculature-on-a-chip to study SARS-CoV-2 infection, first simulating the interaction of the virus alone with the endothelialized vasculature on the chip and then studying endothelial cells exposed to the virus and peripheral blood mononuclear cells (PBMCs).”
BackgroundInfluentialIntegration of immune cells in organs-on-chips: a tutorial
van Os, L., Engelhardt, B., & Guenat, O. T. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1191104 · Cited by 39 · see citing works
Cardiovascular signatures of COVID-19 predict mortality and identify barrier stabilizing therapies
Gustafson, D., Ngai, M., Wu, R., Hou, H., Schöffel, A. C., Erice, C., Mandla, S., Billia, F., Wilson, M. D., Radisic, M., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103982 · Cited by 33 · see citing works
Self-citationSparks, H. D., Mandla, S., Vizely, K., Rosin, N. L., Radisic, M., & Biernaskie, J. A. (2022) · Scientific Reports · doi:10.1038/s41598-022-18204-w · Cited by 26 · see citing works
Self-citationElastomeric Polyesters in Cardiovascular Tissue Engineering and Organs-on-a-Chip
Okhovatian, S., Shakeri, A., Huyer, L. D., & Radisic, M. (2023) · Biomacromolecules · doi:10.1021/acs.biomac.3c00387 · Cited by 27 · see citing works
Self-citationBioengineering vascularization
Landau, S., Okhovatian, S., Zhao, Y., Liu, C., Shakeri, A., Wang, Y., Ramsay, K., Kieda, J., Jiang, R., & Radisic, M. (2024) · Development · doi:10.1242/dev.204455 · Cited by 23 · see citing works
Self-citationLim, J., Fang, H., Bupphathong, S., Sung, P.-C., Yeh, C.-E., Huang, W. R., & Lin, C.-H. (2024) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.3c01978 · Cited by 19 · see citing works
Organ-on-a-chip models for elucidating the cellular biology of infectious diseases
Yokoi, F., Deguchi, S., & Takayama, K. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2023.119504 · Cited by 15 · see citing works
Wagner, K. T., Lu, R. X. Z., Landau, S., Shawky, S. A., Zhao, Y., Bodenstein, D. F., Vargas, L. F. J., Jiang, R., Okhovatian, S., Wang, Y., et al. (2024) · Biofabrication · doi:10.1088/1758-5090/ad76d9 · Cited by 16 · see citing works
“…media collected from EC/DPSC and EC/DPSC/CM tissues on day 10 was analyzed by ELISA (Simple Plex Ella platform, ProteinSimple) to quantify concentrations of endothelin-1, IL-6, IL-8, TREM-1, E-selectin, ICAM-1, and VCAM-1 according to the manufacturer’s protocol and as previously described [63].”
MethodSelf-citationSIRT-associated attenuation of cellular senescence in vascular wall
Sazdova, I., Hadzi‐Petrushev, N., Keremidarska‐Markova, M., Stojchevski, R., Sopi, R., Shileiko, S. A., Mitrokhin, V. M., Gagov, H., Avtanski, D. B., Lubomirov, L. T., et al. (2024) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2024.111943 · Cited by 14 · see citing works
Wu, Q., Rafatian, N., Wagner, K. T., Blamer, J., Smith, J. B., Okhovatian, S., Aggarwal, P., Wang, E. Y., Banerjee, A., Zhao, Y., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2403581121 · Cited by 13 · see citing works
“We previously demonstrated the impact of immune cell inclusion in a blood vessel on a chip perfused with monocytes, resulting in ~ 100 - fold upregulation of IL - 6 and IL - 8 upon SARS - CoV - 2 exposure (59).”
Self-citationMicrofluidic strategies for biomimetic lung chip establishment and SARS-CoV2 study
Wang, H., Wen, T., Zhu, W., Li, K., Gong, X., & Li, Z. (2023) · Materials Today Bio · doi:10.1016/j.mtbio.2023.100905 · Cited by 13 · see citing works
“Of course, several groups have successfully explored the effects of SARS-CoV2 infection on the intestinal and vascular systems [120, 121].”
BackgroundFujimoto, K., Kameda, Y., Nagano, Y., Deguchi, S., Yamamoto, T., Krol, R. P., Gee, P., Matsumura, Y., Okamoto, T., Nagao, M., et al. (2024) · Lab on a Chip · doi:10.1039/d3lc00768e · Cited by 12 · see citing works
Gu, L., Liu, P., Zhao, W. Y., Fan, Y., Wang, Y., & Chen, P. (2025) · MedMat. · doi:10.1097/mm9.0000000000000016 · Cited by 11 · see citing works
Heart-on-a-chip and vasculature-on-a-chip platforms as models of cardiovascular disease
Khosravi, R., & Radisic, M. (2026) · Nature Reviews Cardiology · doi:10.1038/s41569-026-01255-1 · Cited by 12 · see citing works
“This system was first used to model the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the vasculature, specifically on endothelial cells, and demonstrated that the virus suppressed endothelial barrier function by disrupting VE-cadherin junctions and increased the levels of pro-in…”
Self-citationBreaking down the barriers to animal-free research
Hope, L., & Bailey, J. (2025) · Alternatives to Laboratory Animals · doi:10.1177/02611929251349465 · Cited by 12 · see citing works
Weener, H. J., van Haaps, T. F., van Helden, R. W. J., Albers, H. J., Haverkate, R., Middelkamp, H. H. T., Ridderikhof, M. L., van Mens, T. E., van den Berg, A., Mummery, C. L., et al. (2025) · Lab on a Chip · doi:10.1039/d4lc00848k · Cited by 10 · see citing works
Ahmed, S. H., AlMoslemany, M. A., Witwer, K. W., Tehamy, A. G., & El‐Badri, N. (2024) · Stem Cell Reviews and Reports · doi:10.1007/s12015-023-10675-2 · Cited by 9 · see citing works
“These findings were supported by a study by Lu et al., who reported that Ang-1-derived peptide inhibited apoptosis and improved endothelial cell survival, thus reducing inflammation induced by the SARS-CoV-2 virus [104].”
ResultMulti-organ microphysiological system: A new paradigm for COVID-19 research
Wang, P., Wang, Y., & Qin, J. (2023) · Organs-on-a-Chip · doi:10.1016/j.ooc.2023.100029 · Cited by 9 · see citing works
Vascular dysfunction in hemorrhagic viral fevers: opportunities for organotypic modeling
Zarate-Sanchez, E., George, S. C., Moya, M. L., & Robertson, C. (2024) · Biofabrication · doi:10.1088/1758-5090/ad4c0b · Cited by 8 · see citing works
“Two additional MPS in this category include studies by Lu et al [296] and Rajeeva Pandian et al [297] which evaluate the recruitment of peripheral blood mononuclear cells (PBMCs) and clotting, respectively, upon exposure of HUVECs to SARS-CoV-2.”
BackgroundDevice Processing Challenges for Miniaturized Sensing Systems Targeting Biological Fluids
Stoukatch, S., Dupont, F., & Redouté, J. (2022) · Biomedical Materials & Devices · doi:10.1007/s44174-022-00034-z · Cited by 8 · see citing works
“3b, [67]), the microfluidic system can be directly integrated on top of the biochip [72, 73].”
BackgroundLu, R. X. Z., Rafatian, N., Zhao, Y., Wagner, K. T., Beroncal, E. L., Li, B., Lee, C. M., Chen, J., Churcher, E., Vosoughi, D., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.09.552495 · Cited by 8 · see citing works
Self-citationLab-on-a-chip models of cardiac inflammation
Popovic, A. M., Lei, M. H. C., Shakeri, A., Khosravi, R., & Radisic, M. (2024) · Biomicrofluidics · doi:10.1063/5.0231735 · Cited by 7 · see citing works
Self-citationNtekoumes, D., & Gerecht, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137416 · Cited by 7 · see citing works
Organoids and microphysiological systems for pharmaceutical research of viral respiratory infections
Deguchi, S., Yokoi, F., & Takayama, K. (2024) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2024.101041 · Cited by 7 · see citing works
Vessel-on-a-Chip: A Powerful Tool for Investigating Endothelial COVID-19 Fingerprints
Shevchuk, O. O., Palii, S. M., Pak, A., Chantada, N., Seoane, N., Korda, M. M., Campos‐Toimil, M., & Álvarez, E. (2023) · Cells · doi:10.3390/cells12091297 · Cited by 7 · see citing works
“The results of the study support the idea of the need for an inflammatory attenuation treatment to protect vascular tissue integrity in the case of SARS-CoV-2 infection [167].”
ResultLong-term effect of sodium selenite on the integrity and permeability of on-chip microvasculature
Shaji, M., Kitada, A., Fujimoto, K., Karsten, S. L., & Yokokawa, R. (2022) · APL Bioengineering · doi:10.1063/5.0122804 · Cited by 5 · see citing works
A dermis-on-a-chip model for compound screening
Abdo, D., Zhao, Y., Okhovatian, S., Vargas, L. F. J., Wagner, K. T., Shakeri, A., Vosoughi, D., & Radisic, M. (2025) · Materials Today Bio · doi:10.1016/j.mtbio.2025.102111 · Cited by 4 · see citing works
“…400 μ M, consistent with previous studies showing anti-inflammatory effects of the peptide in vitro in the context of SARS-CoV-2 induced inflammation [45] and in the middle range (100 – 650 μ M) of previous in vitro studies exploring the effects of Q-peptide on human keratinocytes [24].”
Self-citationEffect of coronaviruses on blood vessel permeability: potential therapeutic targets
Machado, N. R., Dias, K. T., Cortes, B. F. S., & Rodrigues, S. F. (2023) · Therapeutic Advances in Respiratory Disease · doi:10.1177/17534666231162252 · Cited by 4 · see citing works
Guiding the spatial organization of engineered heart tissues
Beeghly, G. F., Shakeri, A., Mirzapourshafiyi, F., Dikyol, C., Offen, N., Alsaafin, A., Nuber, U. A., & Radisic, M. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115907 · Cited by 3 · see citing works
Self-citationLu, R. X. Z., Zhao, Y., & Radisic, M. (2023) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10581 · Cited by 3 · see citing works
“35,38 This enables virus access to several vital organs, including the heart.”
BackgroundSelf-citationMicrofluidic chips as drug screening platforms
Kim, I. G., Kwon, J., Rhyou, J., & Jeon, J. S. (2024) · JMST Advances · doi:10.1007/s42791-024-00078-w · Cited by 3 · see citing works
Toxicological and Regulatory Aspects of Natural Product Based Bio-Scaffold
Boruah, T., Chetia, T., Borgohain, R., Roy, H., Parveen, M., Bharali, R., & Paul, S. (2024) · Springer eBooks · doi:10.1007/978-981-97-3111-4_11 · Cited by 2 · see citing works
Microfluidic engineering of immune-competent organs-on-chips and their applications
Liang, X., Bu, X., Yuan, S., Wu, C., Liu, D., & Deng, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1743806 · Cited by 2 · see citing works
“For instance, Lu et al. demonstrated in a vasculature-on-a-chip infected with SARS-CoV-2 that introducing PBMCs exacerbated cytokine-induced endothelial dysfunction, revealing monocyte, endothelium crosstalk in hyperin fl ammation (42).”
Biofabrication of Vascularized Tissues
Schimelman, J. B., Sun, Y., Lyu, C., Lu, T.-Y., Yao, E. J., Huang, L., Altera, A. K., Xiang, Y., & Chen, S. (2026) · Chemical Reviews · doi:10.1021/acs.chemrev.5c00914 · Cited by 2 · see citing works
Engineering Organoid Platforms for Pathogenesis Research
Gao, X., Han, X., Bai, J., Tian, W., Zhou, J., Ding, L., & Gao, X. (2026) · Research · doi:10.34133/research.1346 · Cited by 2 · see citing works
“Recent studies have successfully utilized these platforms to model the recruitment of circulating immune cells, the specific adhesion of pathogens to endothelial barriers, and their subsequent transmigration into the tissue parenchyma [ 87 , 88 ].”
Dasgupta, S., & Barui, A. (2025) · Biomaterials Science · doi:10.1039/d4bm01544d · Cited by 2 · see citing works
The Effects of SARS-CoV-2 on the Angiopoietin/Tie Axis and the Vascular Endothelium
Janchivlamdan, D., Shivkumar, M., & Singh, H. (2024) · Encyclopedia · doi:10.3390/encyclopedia4010035 · Cited by 2 · see citing works
Kwon, J., Nam, H., Park, J., Kim, I. U., & Jeon, J. S. (2025) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c00469 · Cited by 1 · see citing works
Faley, S. L., Boghdeh, N. A., Schaffer, D. K., Spivey, E. C., Alem, F., Narayanan, A., Wikswo, J. P., & Brown, J. A. (2025) · Lab on a Chip · doi:10.1039/d5lc00510h · Cited by 1 · see citing works
Johansen, M. D., Ming, C. L. C., Hansbro, P. M., & Gentile, C. (2026) · Biofabrication · doi:10.1088/1758-5090/ae38d7 · Cited by 1 · see citing works
“…in CD4 + and CD8 + T cell populations, a high proportion of functionally exhausted T cells persisting after recovery from acute SARS-CoV-2 infection, increased hospitalisation rates, and higher all-cause mortality among COVID-19 patients (Lu et al 2022, Jamoussi et al 2023, Nikkhoo et al 2023).”
Advances in virus-host interaction research based on microfluidic platforms
Wang, C., Wang, J., Liu, D., & Zhang, Z. (2024) · Chinese Chemical Letters · doi:10.1016/j.cclet.2024.110302 · Cited by 1 · see citing works
The Effects of SARS-CoV-2 on Angiopoietin/Tie Axis and Vascular EndotheliumPreprint
Janchivlamdan, D., Shivkumar, M., & Singh, H. (2024) · Preprints.org · doi:10.20944/preprints202402.0212.v1 · Cited by 1 · see citing works
Severe acute respiratory syndrome coronavirus 2 may cause liver injury via Na+/H+ exchanger
Cüre, M. C., & Cüre, E. (2023) · World Journal of Virology · doi:10.5501/wjv.v12.i1.12
Peptide and protein in therapeutics
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Stem cell-based strategies for vascular aging: from mechanistic insights to clinical translation
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Ventosa-Capell, H., Martínez-Sánchez, J., Moner, B. D., Ramos, A., Torramadé‐Moix, S., Palomo, M., Moreno‐Castaño, A. B., Riera‐Escamilla, A., Fernández, S., Tellez, A., et al. (2026) · Thrombosis and Haemostasis · doi:10.1055/a-2786-9957
Insight to Neglected Biomarkers in COVID-19: A Comprehensive Narrative Review”
Jalilian, S., Bastani, M., & Afsharzadeh, F. (2026) · Biomarker Insights · doi:10.1177/11772719261452224
“23 Based on the findings presented, angiopoietin holds potential both as a biomarker and as a therapeutic intervention for COVID-19.”
Advancing immunity research with immune-integrated organ-on-a-chip technologies
Ozefe, F., Körükcü, K. İ., & Tekin, H. C. (2026) · Biosensors and Bioelectronics X · doi:10.1016/j.biosx.2026.100830
- Authors
- Lu, R. X. Z., Lai, B. F. L., Rafatian, N., Gustafson, D., Campbell, S. B., Banerjee, A., Kozak, R., Mossman, K., Mubareka, S., Howe, K. L., Fish, J. E., & Radisic, M.
- Affiliations
- University of Toronto (CA)
- University Health Network (CA)
- University of Saskatchewan (CA)
- McMaster University (CA)
- Sunnybrook Health Science Centre (CA)
- Corresponding author
- Radisic, Milica
- ORCID
- Venue
- Lab on a Chip
- Publisher
- Royal Society of Chemistry (RSC)
- Published
- 2022
- Volume
- 22
- Issue
- 6
- Pages
- 1171-1186
- ISSN
- 1473-0189 (ISSN-L)
- 1473-0197
- PMC
- PMC9207819
- OpenAlex
- W4210700717
- Cited by
- 58
- References
- 63
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 17 · 2023: 18 · 2022: 6
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Lab on a Chip (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research (FDN-167274)
- Natural Sciences and Engineering Research Council of Canada (RGPIN 326982-10, ALLRP 5550)
- National Institutes of Health (2R01 HL076485)
- Connaught Fund
- Killam Trusts
- Canada Research Chairs
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, COVID-19 pandemic, endothelial barrier dysfunction, innate immunity, peripheral blood mononuclear cells, inflammatory cytokines, angiopoietin-2, HCoV-NL63, endothelial dysfunction, hyperinflammation
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Endothelium, Vascular, Humans, Immunity, Innate, Inflammation, Leukocytes, Mononuclear, Angiopoietin-1, Endothelial Cells, Lab-On-A-Chip Devices
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