Vascularised cardiac spheroids-on-a-chip for testing the toxicity of therapeutics
Abstract Microfabricated organ-on-a-chips are rapidly becoming the gold standard for the testing of safety and efficacy of therapeutics. A broad range of designs has emerged, but recreating microvascularised tissue models remains difficult in many cases. This is particularly relevant to mimic the sy...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-53678-w |
| _version_ | 1797275110007111680 |
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| author | Stefania Di Cio Emilie Marhuenda Malcolm Haddrick Julien E. Gautrot |
| author_facet | Stefania Di Cio Emilie Marhuenda Malcolm Haddrick Julien E. Gautrot |
| author_sort | Stefania Di Cio |
| collection | DOAJ |
| description | Abstract Microfabricated organ-on-a-chips are rapidly becoming the gold standard for the testing of safety and efficacy of therapeutics. A broad range of designs has emerged, but recreating microvascularised tissue models remains difficult in many cases. This is particularly relevant to mimic the systemic delivery of therapeutics, to capture the complex multi-step processes associated with trans-endothelial transport or diffusion, uptake by targeted tissues and associated metabolic response. In this report, we describe the formation of microvascularised cardiac spheroids embedded in microfluidic chips. Different protocols used for embedding spheroids within vascularised multi-compartment microfluidic chips were investigated first to identify the importance of the spheroid processing, and co-culture with pericytes on the integration of the spheroid within the microvascular networks formed. The architecture of the resulting models, the expression of cardiac and endothelial markers and the perfusion of the system was then investigated. This confirmed the excellent stability of the vascular networks formed, as well as the persistent expression of cardiomyocyte markers such as cTNT and the assembly of striated F-actin, myosin and α-actinin cytoskeletal networks typically associated with contractility and beating. The ability to retain beating over prolonged periods of time was quantified, over 25 days, demonstrating not only perfusability but also functional performance of the tissue model. Finally, as a proof-of-concept of therapeutic testing, the toxicity of one therapeutic associated with cardiac disfunction was evaluated, identifying differences between direct in vitro testing on suspended spheroids and vascularised models. |
| first_indexed | 2024-03-07T15:09:37Z |
| format | Article |
| id | doaj.art-e389f9a68ca5476bb645cfadc3c071bb |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:09:37Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-e389f9a68ca5476bb645cfadc3c071bb2024-03-05T18:46:25ZengNature PortfolioScientific Reports2045-23222024-02-0114111310.1038/s41598-024-53678-wVascularised cardiac spheroids-on-a-chip for testing the toxicity of therapeuticsStefania Di Cio0Emilie Marhuenda1Malcolm Haddrick2Julien E. Gautrot3Institute of Bioengineering, Queen Mary, University of LondonInstitute of Bioengineering, Queen Mary, University of LondonMedicines Discovery CatapultInstitute of Bioengineering, Queen Mary, University of LondonAbstract Microfabricated organ-on-a-chips are rapidly becoming the gold standard for the testing of safety and efficacy of therapeutics. A broad range of designs has emerged, but recreating microvascularised tissue models remains difficult in many cases. This is particularly relevant to mimic the systemic delivery of therapeutics, to capture the complex multi-step processes associated with trans-endothelial transport or diffusion, uptake by targeted tissues and associated metabolic response. In this report, we describe the formation of microvascularised cardiac spheroids embedded in microfluidic chips. Different protocols used for embedding spheroids within vascularised multi-compartment microfluidic chips were investigated first to identify the importance of the spheroid processing, and co-culture with pericytes on the integration of the spheroid within the microvascular networks formed. The architecture of the resulting models, the expression of cardiac and endothelial markers and the perfusion of the system was then investigated. This confirmed the excellent stability of the vascular networks formed, as well as the persistent expression of cardiomyocyte markers such as cTNT and the assembly of striated F-actin, myosin and α-actinin cytoskeletal networks typically associated with contractility and beating. The ability to retain beating over prolonged periods of time was quantified, over 25 days, demonstrating not only perfusability but also functional performance of the tissue model. Finally, as a proof-of-concept of therapeutic testing, the toxicity of one therapeutic associated with cardiac disfunction was evaluated, identifying differences between direct in vitro testing on suspended spheroids and vascularised models.https://doi.org/10.1038/s41598-024-53678-w |
| spellingShingle | Stefania Di Cio Emilie Marhuenda Malcolm Haddrick Julien E. Gautrot Vascularised cardiac spheroids-on-a-chip for testing the toxicity of therapeutics Scientific Reports |
| title | Vascularised cardiac spheroids-on-a-chip for testing the toxicity of therapeutics |
| title_full | Vascularised cardiac spheroids-on-a-chip for testing the toxicity of therapeutics |
| title_fullStr | Vascularised cardiac spheroids-on-a-chip for testing the toxicity of therapeutics |
| title_full_unstemmed | Vascularised cardiac spheroids-on-a-chip for testing the toxicity of therapeutics |
| title_short | Vascularised cardiac spheroids-on-a-chip for testing the toxicity of therapeutics |
| title_sort | vascularised cardiac spheroids on a chip for testing the toxicity of therapeutics |
| url | https://doi.org/10.1038/s41598-024-53678-w |
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