Application of microphysiological systems for nonclinical evaluation of cell therapies

Main Article Content

Pelin L. Candarlioglu, Louise Delsing , Lauren Gauthier, Lauren Lewis, George Papadopoulos, May Freag, Tom S. Chan, Kimberly A. Homan, Mick D. Fellows, Amy Pointon, Kyle Kojala
[show affiliations]

Abstract

Microphysiological systems (MPS) are gaining broader application in the pharmaceutical industry but have primarily been leveraged in early discovery toxicology and pharmacology studies with small molecules. The adoption of MPS offers a promising avenue to reduce animal use, improve in-vitro-to-in-vivo translation of pharmacokinetics/pharmacodynamics and toxicity correlation, and provide mechanistic understanding of model species suitability. While MPS have demonstrated utility in these areas with small molecules and biologics, MPS models in cell therapy development have not been fully explored, let alone validated. Distinguishing features of MPS, including long-term viability and physiologically relevant expression of functional enzymes, receptors, and pharmacological targets make them attractive tools for nonclinical characterization. However, there is currently limited published evidence of MPS being utilized to study the disposition, metabolism, pharmacology, and toxicity profiles of cell therapies. This review provides an industry perspective on the nonclinical application of MPS on cell therapies, first with a focus on oncology applications followed by examples in regenerative medicine.


Plain language summary
Microphysiological systems (MPS) are advanced cell models, applied in the pharmaceutical industry to characterize novel therapies. While their application in studies of small molecule ther­apies has been very successful, the use of these models to study cell therapies has been limited. Cell therapies consist of cells and are living drugs, often with complex biological mechanisms of action, which can be very challenging to study. However, MPS have several features that make them attractive for studying cell therapies, including possibilities for longer-term studies and the ability to mimic physiologically relevant biological functions. MPS can mimic complex biological systems and processes, as such, the adoption of MPS offers a promising avenue to reduce the use of animals in the characterization of novel therapies. This review provides an industry perspective on current chal­lenges and highlights opportunities for using MPS in the development of cell therapies.

Article Details

How to Cite
Candarlioglu, P. L. (2024) “Application of microphysiological systems for nonclinical evaluation of cell therapies”, ALTEX - Alternatives to animal experimentation, 41(3), pp. 469–484. doi: 10.14573/altex.2402201.
Section
Articles
References

Abadpour, S., Aizenshtadt, A., Olsen, P. A. et al. (2020). Pancreas-on-a-chip technology for transplantation applications. Curr Diab Rep 20, 72. doi:10.1007/s11892-020-01357-1

Ahmed, I., Johnston Jr, R. J. and Singh, M. S. (2021). Pluripotent stem cell therapy for retinal diseases. Ann Translat Med 9, 1279. doi:10.21037/atm-20-4747

Ajeti, V., Lara-Santiago, J., Alkmin, S. et al. (2017). Ovarian and breast cancer migration dynamics on laminin and fibronectin bi-directional gradient fibers fabricated via multiphoton excited photochemistry. Cell Mol Bioeng 10, 295-311. doi:10.1007/s12195-017-0492-9

Anaya, J. M., Shoenfeld, Y., Rojas-Villarraga, A. et al. (eds) (2013). Autoimmunity: From Bench to Bedside. Bogota, Colombia: El Rosario University Press. https://www.ncbi.nlm.nih.gov/books/NBK459447/

Ando, Y., Siegler, E. L., Ta, H. P. et al. (2019). Evaluating CAR-T cell therapy in a hypoxic 3D tumor model. Adv Healthc Mater 8, e1900001. doi:10.1002/adhm.201900001

Aung, A., Kumar, V., Theprungsirikul, J. et al. (2020). An engineered tumor-on-a-chip device with breast cancer-immune cell interactions for assessing T-cell recruitment. Cancer Res 80, 263-275. doi:10.1158/0008-5472.can-19-0342

Ayuso, J. M., Truttschel, R., Gong, M. M. et al. (2019). Evaluating natural killer cell cytotoxicity against solid tumors using a microfluidic model. Oncoimmunology 8, 1553477. doi:10.1080/2162402x.2018.1553477

Bai, J. and Wang, C. (2020). Organoids and microphysiological systems: New tools for ophthalmic drug discovery. Front Pharmacol 11, 407. doi:10.3389/fphar.2020.00407

Baran, S. W., Brown, P. C., Baudy, A. R. et al. (2022). Perspectives on the evaluation and adoption of complex in vitro models in drug development: Workshop with the FDA and the pharmaceutical industry (IQ MPS affiliate). ALTEX 39, 297-314. doi:10.14573/altex.2112203

Barrett, D. M., Grupp, S. A. and June, C. H. (2015). Chimeric antigen receptor- and TCR-modified T cells enter main street and wall street. J Immunol 195, 755-761. doi:10.4049/jimmunol.1500751

Baudy, A., Otieno, M., Hewitt, P. et al. (2019). Liver microphysiological systems development guidelines for safety risk assessment in the pharmaceutical industry. Lab Chip 20, 215-225. doi:10.1039/c9lc00768g

Benmebarek, M. R., Karches, C. H., Cadilha, B. L. et al. (2019). Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int J Mol Sci 20, 1283. doi:10.3390/ijms20061283

Bersini, S., Jeon, J. S., Dubini, G. et al. (2014). A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone. Biomaterials 35, 2454-2461. doi:10.1016/j.biomaterials.2013.11.050

Bhatia, S. N. and Ingber, D. E. (2014). Microfluidic organs-on-chips. Nat Biotechnol 32, 760-772. doi:10.1038/nbt.2989

Campisi, M., Shin, Y., Osaki, T. et al. (2018). 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials 180, 117-129. doi:10.1016/j.biomaterials.2018.07.014

Candarlioglu, P. L., Dal Negro, G., Hughes, D. et al. (2022). Organ-on-a-chip: Current gaps and future directions. Biochem Soc Trans 50, 665-673. doi:10.1042/bst20200661

Carter, E. P., Roozitalab, R., Gibson, S. V. et al. (2021). Tumour microenvironment 3D-modelling: Simplicity to complexity and back again. Trends Cancer 7, 1033-1046. doi:10.1016/j.trecan.2021.06.009

Chen, M. B., Hajal, C., Benjamin, D. C. et al. (2018). Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation. Proc Natl Acad Sci U S A 115, 7022-7027. doi:10.1073/pnas.1715932115

Chen, Y. J., Abila, B. and Mostafa Kamel, Y. (2023). CAR-T: What is next? Cancers (Basel) 15, 663. doi:10.3390/cancers15030663

Chopp, L., Redmond, C., O’Shea, J. J. et al. (2023). From thymus to tissues and tumors: A review of T-cell biology. J Allergy Clin Immunol 151, 81-97. doi:10.1016/j.jaci.2022.10.011

Chou, D. B., Frismantas, V., Milton, Y. et al. (2020). On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology. Nat Biomed Eng 4, 394-406. doi:10.1038/s41551-019-0495-z

Chung, M., Ahn, J., Son, K. et al. (2017). Biomimetic model of tumor microenvironment on microfluidic platform. Adv Healthc Mater 6. doi:10.1002/adhm.201700196

Coecke, S., Balls, M., Bowe, G. et al. (2005). Guidance on good cell culture practice. A report of the second ECVAM task force on good cell culture practice. Altern Lab Anim 33, 261-287. doi:10.1177/026119290503300313

Colombo, E. and Cattaneo, M. (2021). Multicellular 3D models to study tumour-stroma interactions. Int J Mol Sci 22, 1633. doi:10.3390/ijms22041633

Crotty, S. (2019). T follicular helper cell biology: A decade of discovery and diseases. Immunity 50, 1132-1148. doi:10.1016/j.immuni.2019.04.011

Dasyam, N., George, P. and Weinkove, R. (2020). Chimeric antigen receptor T-cell therapies: Optimising the dose. Br J Clin Pharmacol 86, 1678-1689. doi:10.1111/bcp.14281

de Sousa e Melo, F., Kurtova, A. V., Harnoss, J. M. et al. (2017). A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature 543, 676-680. doi:10.1038/nature21713

Dey, M., Kim, M. H., Dogan, M. et al. (2022). Chemotherapeutics and CAR-T cell-based immunotherapeutics screening on a 3D bioprinted vascularized breast tumor model. Adv Funct Mater 32, 2203966. doi:10.1002/adfm.202203966

Di Modugno, F., Colosi, C., Trono, P. et al. (2019). 3D models in the new era of immune oncology: Focus on T cells, CAF and ECM. J Exp Clin Cancer Res 38, 117. doi:10.1186/s13046-019-1086-2

Doherty, E. L., Aw, W. Y., Hickey, A. J. et al. (2021). Microfluidic and organ-on-a-chip approaches to investigate cellular and microenvironmental contributions to cardiovascular function and pathology. Front Bioeng Biotechnol 9, 624435. doi:10.3389/fbioe.2021.624435

Duan, Z. and Luo, Y. (2021). Targeting macrophages in cancer immunotherapy. Signal Transduct Target Ther 6, 127. doi:10.1038/s41392-021-00506-6

Duncan, B. B., Dunbar, C. E. and Ishii, K. (2022). Applying a clinical lens to animal models of CAR-T cell therapies. Mol Ther Methods Clin Dev 27, 17-31. doi:10.1016/j.omtm.2022.08.008

Ekert, J. E., Deakyne, J., Pribul-Allen, P. et al. (2020). Recommended guidelines for developing, qualifying, and implementing complex in vitro models (CIVMs) for drug discovery. SLAS Discov 25, 1174-1190. doi:10.1177/2472555220923332

Ergir, E., Oliver-De La Cruz, J., Fernandes, S. et al. (2022). Generation and maturation of human iPSC-derived 3D organotypic cardiac microtissues in long-term culture. Sci Rep 12, 17409. doi:10.1038/s41598-022-22225-w

Fabre, K., Berridge, B., Proctor, W. R. et al. (2020). Introduction to a manuscript series on the characterization and use of microphysiological systems (MPS) in pharmaceutical safety and ADME applications. Lab Chip 20, 1049-1057. doi:10.1039/c9lc01168d

Frazier, T., Williams, C., Henderson, M. et al. (2021). Breast cancer reconstruction: Design criteria for a humanized microphysiological system. Tissue Eng Part A 27, 479-488. doi:10.1089/ten.tea.2020.0372

Fu, Z., Mowday, A. M., Smaill, J. B. et al. (2021). Tumour hypoxia-mediated immunosuppression: Mechanisms and therapeutic approaches to improve cancer immunotherapy. Cells 10, 1006. doi:10.3390/cells10051006

Ghareeb, A. E., Lako, M. and Steel, D. H. (2020). Coculture techniques for modeling retinal development and disease, and enabling regenerative medicine. Stem Cells Transl Med 9, 1531-1548. doi:10.1002/sctm.20-0201

Gibler, P., Gimble, J., Hamel, K. et al. (2021). Human adipose-derived stromal/stem cell culture and analysis methods for adipose tissue modeling in vitro: A systematic review. Cells 10, 1378. doi:10.3390/cells10061378

Goversen, B., van der Heyden, M. A. G., van Veen, T. A. B. et al. (2018). The immature electrophysiological phenotype of iPSC-CMs still hampers in vitro drug screening: Special focus on Ik1. Pharmacol Ther 183, 127-136. doi:10.1016/j.pharmthera.2017.10.001

Guerriero, J. L. (2019). Macrophages: Their untold story in T cell activation and function. Int Rev Cell Mol Biol 342, 73-93. doi:10.1016/bs.ircmb.2018.07.001

Haddad, R. and Saldanha-Araujo, F. (2014). Mechanisms of T-cell immunosuppression by mesenchymal stromal cells: What do we know so far? Biomed Res Int 2014, 2160806. doi:10.1155/2014/216806

Hassell, B. A., Goyal, G., Lee, E. et al. (2017). Human organ chip models recapitulate orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro. Cell Rep 21, 508-516. doi:10.1016/j.celrep.2017.09.043

Huang, J., Li, Y. B., Charlebois, C. et al. (2022). Application of blood brain barrier models in pre-clinical assessment of glioblastoma-targeting CAR-T based immunotherapies. Fluids Barriers CNS 19, 38. doi:10.1186/s12987-022-00342-y

Huh, D., Matthews, B. D., Mammoto, A. et al. (2010). Reconstituting organ-level lung functions on a chip. Science 328, 1662-1668. doi:10.1126/science.1188302

Jaini, R., Loya, M. G. and Eng, C. (2017). Immunotherapeutic target expression on breast tumors can be amplified by hormone receptor antagonism: A novel strategy for enhancing efficacy of targeted immunotherapy. Oncotarget 8, 32536-32549. doi:10.18632/oncotarget.15812

Jiang, L., Li, S., Zheng, J. et al. (2019). Recent progress in microfluidic models of the blood-brain barrier. Micromachines (Basel) 10, 375. doi:10.3390/mi10060375

Jogalekar, M. P., Rajendran, R. L., Khan, F. et al. (2022). CAR T-cell-based gene therapy for cancers: New perspectives, challenges, and clinical developments. Front Immunol 13, 925985. doi:10.3389/fimmu.2022.925985

Kankeu Fonkoua, L. A., Sirpilla, O., Sakemura, R. et al. (2022). CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities. Mol Ther Oncolytics 25, 69-77. doi:10.1016/j.omto.2022.03.009

Kapałczyńska, M., Kolenda, T., Przybyła, W. et al. (2018). 2D and 3D cell cultures – A comparison of different types of cancer cell cultures. Arch Med Sci 14, 910-919. doi:10.5114/aoms.2016.63743

Karmakar, S., Pal, P., Lal, G. (2021). Key activating and inhibitory ligands involved in the mobilization of natural killer cells for cancer immunotherapies. Immunotargets Ther 10, 387-407. doi:10.2147/itt.s306109

Kasendra, M, Luc, R., Yin, J. et al. (2020). Duodenum intestine-chip for preclinical drug assessment in a human relevant model. Elife 9, e50135. doi:10.7554/elife.50135

Kerns, S. J., Belgur, C., Petropolis, D. et al. (2021). Human immunocompetent organ-on-chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies. Elife 10, e67106. doi:10.7554/elife.67106

Khademhosseini, A., Langer, R., Borenstein, J. et al. (2006). Microscale technologies for tissue engineering and biology. Proc Natl Acad Sci U S A 103, 2480-2487. doi:10.1073/pnas.0507681102

Kim, B. S., Kwon, Y. W., Kong, J. S. et al. (2018). 3D cell printing of in vitro stabilized skin model and in vivo pre-vascularized skin patch using tissue-specific extracellular matrix bioink: A step towards advanced skin tissue engineering. Biomaterials 168, 38-53. doi:10.1016/j.biomaterials.2018.03.040

Kim, B. S., Das, S., Jang, J. et al. (2020). Decellularized extracellular matrix-based bioinks for engineering tissue- and organ-specific microenvironments. Chem Rev 120, 10608-10661. doi:10.1021/acs.chemrev.9b00808

Kirouac, D. C., Zmurchok, C., Deyati, A. et al. (2023). Deconvolution of clinical variance in CAR-T cell pharmacology and response. Nat Biotechnol 41, 1606-1617. doi:10.1038/s41587-023-01687-x

Kotha, S. S., Hayes, B. J., Phong, K. T. et al. (2018). Engineering a multicellular vascular niche to model hematopoietic cell trafficking. Stem Cell Res Ther 9, 77. doi:10.1186/s13287-018-0808-2

Kurosawa, T., Sako, D., Tega, Y. et al. (2022). Construction and functional evaluation of a three-dimensional blood-brain barrier model equipped with human induced pluripotent stem cell-derived brain microvascular endothelial cells. Pharm Res 39, 1535-1547. doi:10.1007/s11095-022-03249-3

Kusakawa, S., Yasuda, S., Kuroda, T. et al. (2015). Ultra-sensitive detection of tumorigenic cellular impurities in human cell-processed therapeutic products by digital analysis of soft agar colony formation. Sci Rep 5, 17892. doi:10.1038/srep17892

Kutluk, H., Bastounis, E. E. and Constantinou, I. (2023). Integration of extracellular matrices into organ-on-chip systems. Adv Healthc Mater 12, e2203256. doi:10.1002/adhm.202203256

Lam, M. S. Y., Reales-Calderon, J. A., Ow, J. R. et al. (2023). G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma. Nat Commun 14, 563. doi:10.1038/s41467-023-36160-5

Lauranzano, E., Campo, E., Rasile, M. et al. (2019). A microfluidic human model of blood-brain barrier employing primary human astrocytes. Adv Biosyst 3, e1800335. doi:10.1002/adbi.201800335

Lee, J.-H., Kim, S.-K., Khawar, I. A. et al. (2018). Microfluidic co-culture of pancreatic tumor spheroids with stellate cells as a novel 3D model for investigation of stroma-mediated cell motility and drug resistance. J Exp Clin Cancer Res 37, 4. doi:10.1186/s13046-017-0654-6

Lemmens, M., Fischer, B., Zogg, M. et al. (2021). Evaluation of two in vitro assays for tumorigenicity assessment of CRISPR-Cas9 genome-edited cells. Mol Ther Methods Clin Dev 23, 241-253. doi:10.1016/j.omtm.2021.09.004

Liu, C., Ayyar, V. S., Zheng, X. et al. (2021). Model-based cellular kinetic analysis of chimeric antigen receptor-T cells in humans. Clin Pharmacol Ther 109, 716-727. doi:10.1002/cpt.2040

Liu, Y.-W., Chen, B., Yang, X. et al. (2018). Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat Biotechnol 36, 597-605. doi:10.1038/nbt.4162

Low, L. A., Mummery, C., Berridge, B. R. et al. (2021). Organs-on-chips: Into the next decade. Nat Rev Drug Discov 20, 345-361. doi:10.1038/s41573-020-0079-3

Lyu, Z., Park, J., Kim, K.-M. et al. (2021). A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke. Nat Biomed Eng 5, 847-863. doi:10.1038/s41551-021-00744-7

Marx, U., Akabane, T., Andersson, T. B. et al. (2020). Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development. ALTEX 37, 365-394. doi:10.14573/altex.2001241

McCarthy, K. R. and Johnson, W. E. (2014). Plastic proteins and monkey blocks: How lentiviruses evolved to replicate in the presence of primate restriction factors. PLoS Pathog 10, e1004017. doi:10.1371/journal.ppat.1004017

McNamee, E. N., Korns Johnson, D., Homann, D. et al. (2013). Hypoxia and hypoxia-inducible factors as regulators of t T cell development, differentiation, and function. Immunol Res 55, 58-70. doi:10.1007/s12026-012-8349-8

Melton, D. (2021). The promise of stem cell-derived islet replacement therapy. Diabetologia 64, 1030-1036. doi:10.1007/s00125-020-05367-2

Morris, E. C., Neelapu, S. S., Giavridis, T. et al. (2022). Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol 22, 85-96. doi:0.1038/s41577-021-00547-6

Morton, C. L. and Houghton, P. J. (2007). Establishment of human tumor xenografts in immunodeficient mice. Nat Protoc 2, 247-250. doi:10.1038/nprot.2007.25

Mossu, A., Rosito, M., Khire, T. et al. (2019). A silicon nanomembrane platform for the visualization of immune cell trafficking across the human blood-brain barrier under flow. J Cereb Blood Flow Metab 39, 395-410. doi:10.1177/0271678x18820584

Nelson, M. R., Ghoshal, D., Mejías, J. C. et al. (2021). A multi-niche microvascularized human bone marrow (hBM) on-a-chip elucidates key roles of the endosteal niche in hBM physiology. Biomaterials 270, 120683. doi:10.1016/j.biomaterials.2021.120683

Nguyen, M., De Ninno, A., Mencattini, A. et al. (2018). Dissecting effects of anti-cancer drugs and cancer-associated fibroblasts by on-chip reconstitution of immunocompetent tumor microenvironments. Cell Rep 25, 3884-3893.e3883. doi:10.1016/j.celrep.2018.12.015

Nguyen, O. T. P., Misun, P. M., Lohasz, C. et al. (2021). An immunocompetent microphysiological system to simultaneously investigate effects of anti-tumor natural killer cells on tumor and cardiac microtissues. Front Immunol 12, 781337. doi:10.3389/fimmu.2021.781337

Nikolich-Zugich, J., Slifka, M. K. and Messaoudi, I. (2004). The many important facets of T-cell repertoire diversity. Nat Rev Immunol 4, 123-132. doi:10.1038/nri1292

OECD (2018). Guidance Document on Good In Vitro Method Practices (GIVIMP). OECD Series on Testing and Assessment, No. 286. OECD Publishing, Paris. doi:10.1787/9789264304796-en

Owens, K. and Bozic, I. (2021). Modeling CAR T-cell therapy with patient preconditioning. Bull Math Biol 83, 42. doi:10.1007/s11538-021-00869-5

Pamies, D., Leist, M., Coecke, S. et al. (2020). Good cell and tissue culture practice 2.0 (GCCP 2.0) – Draft for stakeholder discussion and call for action. ALTEX 37, 490-492. doi:10.14573/altex.2007091

Pamies, D., Leist, M., Coecke, S. et al. (2022). Guidance document on good cell and tissue culture practice 2.0 (GCCP 2.0). ALTEX 39, 30-70. doi:10.14573/altex.2111011

Pamies, D., Ekert, J., Zurich, M.-G. et al. (2024). Recommendations on fit-for-purpose criteria to establish quality management for microphysiological systems and for monitoring their reproducibility. Stem Cell Reports 19, 604-617. doi:10.1016/j.stemcr.2024.03.009

Park, D., Son, K., Hwang, Y. et al. (2019a). High-throughput microfluidic 3D cytotoxicity assay for cancer immunotherapy (CACI-IMPACT platform). Front Immunol 10, 1133. doi:10.3389/fimmu.2019.01133

Park, T.-E., Mustafaoglu, N., Herland, A. et al. (2019b). Hypoxia-enhanced blood-brain barrier chip recapitulates human barrier function and shuttling of drugs and antibodies. Nat Commun 10, 2621. doi:10.1038/s41467-019-10588-0

Parvatam, S., Pamies, D., Pistollato, F. et al. (2024). Taking the leap toward human-specific nonanimal methodologies: The need for harmonizing global policies for microphysiological systems. Stem Cell Reports 19, 37-40. doi:10.1016/j.stemcr.2023.11.008

Pasqualini, F. S., Emmert, M. Y., Parker, K. K. et al. (2017). Organ chips: Quality assurance systems in regenerative medicine. Clin Pharmacol Ther 101, 31-34. doi:10.1002/cpt.527

Pavesi, A., Tan, A. T., Koh, S. et al. (2017). A 3D microfluidic model for preclinical evaluation of TCR-engineered T cells against solid tumors. JCI Insight 2, e89762. doi:10.1172/jci.insight.89762

Pediaditakis, I., Kodella, K. R., Manatakis, D. V. et al. (2022). A microengineered brain-chip to model neuroinflammation in humans. iScience 25, 104813. doi:10.1016/j.isci.2022.104813

Peters, M., Choy, A., Pin, C. et al. (2020). Developing in vitro assays to transform gastrointestinal safety assessment: Potential for microphysiological systems. Lab Chip 20, 1177-1190. doi:10.1039/c9lc01107b

Peterson, N. C., Mahalingaiah, P. K., Fullerton, A. et al. (2020). Application of microphysiological systems in biopharmaceutical research and development. Lab Chip 20, 697-708. doi:10.1039/c9lc00962k

Piergiovanni, M., Cangar, O., Leite, S. B. et al. (2021a). Putting science into standards workshop on standards for organ-on-chip. Stem Cell Reports 16, 2076-2077. doi:10.1016/j.stemcr.2021.07.010

Piergiovanni, M., Leite, S. B., Corvi, R. et al. (2021b). Standardisation needs for organ on chip devices. Lab Chip 21, 2857-2868. doi:10.1039/d1lc00241d

Piergiovanni, M., Mennecozzi, M., Sampani, S. et al. (2024). Heads on! Designing a qualification framework for organ-on-chip. ALTEX 41, 320-323. doi:10.14573/altex.2401231

Pietrobon, V. and Marincola, F. M. (2021). Hypoxia and the phenomenon of immune exclusion. J Transl Med 19, 9. doi:10.1186/s12967-020-02667-4

Pietrobon, V., Todd, L. A., Goswami, A. et al. (2021). Improving CAR T-cell persistence. Int J Mol Sci 22, 10828. doi:10.3390/ijms221910828

Prabhakarpandian, B., Shen, M. C., Nichols, J. B. et al. (2015). Synthetic tumor networks for screening drug delivery systems. J Control Release 201, 49-55. doi:10.1016/j.jconrel.2015.01.018

Ragelle, H., Goncalves, A., Kustermann, S. et al. (2020). Organ-on-a-chip technologies for advanced blood-retinal barrier models. J Ocul Pharmacol Ther 36, 30-41. doi:10.1089/jop.2019.0017

Ramadan, Q. and Ting, F. C. W. (2016). In vitro micro-physiological immune-competent model of the human skin. Lab Chip 16, 1899-1908. doi:10.1039/c6lc00229c

Ravi, R., Noonan, K. A., Pham, V. et al. (2018). Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun 9, 741. doi:10.1038/s41467-017-02696-6

Reyes, D. R., Esch, M. B., Ewart, L. et al. (2024). From animal testing to in vitro systems: Advancing standardization in microphysiological systems. Lab Chip 24, 1076-1087. doi:10.1039/d3lc00994g

Rodrigues, J., Heinrich, M. A., Teixeira, L. M. et al. (2021). 3D in vitro model (r)evolution: Unveiling tumor-stroma interactions. Trends Cancer 7, 249-264. doi:10.1016/j.trecan.2020.10.009

Rogal, J., Zbinden, A., Schenke-Layland, K. et al. (2019). Stem-cell based organ-on-a-chip models for diabetes research. Adv Drug Deliv Rev 140, 101-128. doi:10.1016/j.addr.2018.10.010

Saez-Ibañez, A. R., Upadhaya, S., Partridge, T. et al. (2022). Landscape of cancer cell therapies: Trends and real-world data. Nat Rev Drug Discov 21, 631-632. doi:10.1038/d41573-022-00095-1

Santos Rosalem, G., Gonzáles Torres, L. A., de Las Casas E. B. et al. (2020). Microfluidics and organ-on-a-chip technologies: A systematic review of the methods used to mimic bone marrow. PLoS One 15, e0243840. doi:10.1371/journal.pone.0243840

Silbernagel, N., Körner, A., Balitzki, J. et al. (2020). Shaping the heart: Structural and functional maturation of iPSC-cardiomyocytes in 3D-micro-scaffolds. Biomaterials 227, 119551. doi:10.1016/j.biomaterials.2019.119551

Singh, A. P., Chen, W., Zheng, X. et al. (2021). Bench-to-bedside translation of chimeric antigen receptor (CAR) T cells using a multiscale systems pharmacokinetic-pharmacodynamic model: A case study with anti-BCMA CAR-T. CPT Pharmacometrics Syst Pharmacol 10, 362-376. doi:10.1002/psp4.12598

Sobrino, A., Phan, D. T. T., Datta, R. et al. (2016). 3D microtumors in vitro supported by perfused vascular networks. Sci Rep 6, 31589. doi:10.1038/srep31589

Tahbaz, M. and Yoshihara, E. (2021). Immune protection of stem cell-derived islet cell therapy for treating diabetes. Front Endocrinol 12, 16625. doi:10.3389/fendo.2021.716625

Taraseviciute, A., Kean, L. and Jensen, M. C. (2016). Creation of the first non-human primate model that faithfully recapitulates chimeric antigen receptor (CAR) T cell-mediated cytokine release syndrome (CRS) and neurologic toxicity following B cell-directed CAR-T cell therapy. Blood 128, 651-651. doi:10.1182/blood.V128.22.651.651

Thomas, E., Storb, R., Clift, R. A. et al. (1975). Bone-marrow transplantation (first of two parts). N Engl J Med 292, 832-843. doi:10.1056/nejm197504172921605

Tomlinson, L., Ramsden, D., Leite, S. B. et al. (2023). Considerations from an international regulatory and pharmaceutical industry (IQ MPS affiliate) workshop on the standardization of complex in vitro models in drug development. Adv Biol, e2300131. doi:10.1002/adbi.202300131

Vis, M. A. M., Ito, K. and Hofmann, S. (2020). Impact of culture medium on cellular interactions in in vitro co-culture systems. Front Bioeng Biotechnol 8, 911. doi:10.3389/fbioe.2020.00911

Waldman, A. D., Fritz, J. M. and Lenardo, M. J. (2020). A guide to cancer immunotherapy: From T cell basic science to clinical practice. Nat Rev Immunol 20, 651-668. doi:10.1038/s41577-020-0306-5

Wan, Z., Floryan, M. A., Coughlin, M. F. et al. (2023). New strategy for promoting vascularization in tumor spheroids in a microfluidic assay. Adv Healthc Mater 12, 2201784. doi:10.1002/adhm.202201784

Weber, E. W., Maus, M. V. and Mackall, C. L. (2020). The emerging landscape of immune cell therapies. Cell 181, 46-62. doi:10.1016/j.cell.2020.03.001

Wikswo, J. P. (2014). The relevance and potential roles of microphysiological systems in biology and medicine. Exp Biol Med 239, 1061-1072. doi:10.1177/1535370214542068

Wisdom, K. M., Suijker, J., Van den Broek, L. et al. (2023). Lung tumor microphysiological system with 3D endothelium to evaluate modulators of t-cell migration. ALTEX 40, 649-664. doi:10.14573/altex.2208121

Wolff, A., Antfolk, M., Brodin, B. et al. (2015). In vitro blood-brain barrier models-an overview of established models and new microfluidic approaches. J Pharm Sci 104, 2727-2746. doi:10.1002/jps.24329

Wright, C. B., Becker, S. M., Low, L. A. et al. (2020). Improved ocular tissue models and eye-on-a-chip technologies will facilitate ophthalmic drug development. J Ocul Pharmacol Ther 36, 25-29. doi:10.1089/jop.2018.0139

Wu, Q., Liu, J., Wang, X. et al. (2020). Organ-on-a-chip: Recent breakthroughs and future prospects. Biomed Eng Online 19, 9. doi:10.1186/s12938-020-0752-0

Xu, Z., Gao, Y., Hao, Y. et al. (2013). Application of a microfluidic chip-based 3D co-culture to test drug sensitivity for individualized treatment of lung cancer. Biomaterials 34, 4109-4117. doi:10.1016/j.biomaterials.2013.02.045

Yagyu, S., Mochizuki, H., Yamashima, K. et al. (2021). A lymphodepleted non-human primate model for the assessment of acute on-target and off-tumor toxicity of human chimeric antigen receptor-T cells. Clin Transl Immunol 10, e1291. doi:10.1002/cti2.1291

Zervantonakis, I. K., Hughes-Alford, S. K., Charest, J. L. et al. (2012). Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. Proc Natl Acad Sci U S A 109, 13515-13520. doi:10.1073/pnas.1210182109

Zhao, Y., Zheng, X., Zheng, Y. et al. (2021). Extracellular matrix: Emerging roles and potential therapeutic targets for breast cancer. Front Oncol 11, 650453. doi:10.3389/fonc.2021.650453

Most read articles by the same author(s)