SCIENTIFIC AND ETHICAL DIMENSIONS OF MODELLING, SOURCING, AND PROTECTION IN ORGAN-ON-CHIP TECHNOLOGY FOR NEURODEGENERATIVE DISEASE RESEARCH
Volume 3Issue IV Year 2024
IWIN JOJO
III Year BSc (H) Chemistry, St. Stephen’s College, University of Delhi
iwinvj@gmail.com
Table of Contents
IWIN JOJO
III Year BSc (H) Chemistry, St. Stephen’s College, University of Delhi
iwinvj@gmail.com
Organ-on-chip- neurodegenerative diseases- disease modelling- ethical standards- cell sourcing regulations.
1. Dan Xiao, Role of neuroinflammation in neurodegeneration development, Signal Transduction and Targeted Therapy (Oct. 29, 2021)
2. Jialin C Zheng, Translational Neurodegeneration in the era of fast-growing international brain research, Full Text (Jan 2, 2022)
3. Donald E Ingber, Microfluidic organs-on-chips, Nature Biotechnology (May 12, 2022)
4. Donald E Ingber, Microfluidic organs-on-chips, Nature Biotechnology (May 12, 2022)
5. The 3Rs and Humane Experimental Technique:Implementing Change, The 3Rs and Humane Experimental Technique: https://doi.org/10.3390/ani9100754.
6. Systematic Reviews of Animal Experiments Demonstrate Poor Contributions Toward Human Healthcare, Bentham Science https://doi.org/10.2174/157488708784223844.
7. Annamaria A Bottini, Food for thought on the economics of animal testing | ALTEX, Alternatives to animal experimentation (Feb. 1, 2009)
8. Ran-Sook Woo, Neuropathogenesis-on-chips for neurodegenerative diseases, Nature Communications (Aug. 1, 2022)
9. Ma, C., Seong, H., Li, X., Yu, X., Xu, S., & Li, Y. (2022). Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening. Stem cells international, 2022, 2150680. https://doi.org/10.1155/2022/2150680
10. Robert Mannix1, Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies, Nature Communications (Jan. 7, 2022)
11. Park, J., Lee, B. K., Jeong, G. S., Hyun, J. K., Lee, C. J., & Lee, S. H. (2015). Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimers disease. Lab on a Chip, 15(1), 141-150. https://doi.org/10.1039/c4lc00962b
12. Pratibha Parihar1, Frontiers | Revolutionizing drug development: harnessing the potential of organ-on-chip technology for disease modeling and drug discovery, Revolutionizing drug development: harnessing the p https://doi.org/10.3389/fphar.2023.1139229.
13. Dongeun Huh, Microfabrication of human organs-on-chips, Nature Protocols (May 12, 2022)
14. Erika Ferrari, Photo and Soft Lithography for Organ-on-Chip Applications, SpringerLink (Sept. 15, 2021)
15. Donald E Ingber, Microfluidic organs-on-chips, Nature Biotechnology (May 12, 2022)
16. Pratibha Parihar, Frontiers | Revolutionizing drug development: harnessing the potential of organ-on-chip technology for disease modeling and drug discovery, Revolutionizing drug development: harnessing the p https://doi.org/10.3389/fphar.2023.1139229.
17. Noah Goshi, A primary neural cell culture model to study neuron, astrocyte, and microglia interactions in neuroinflammation, Full Text (May 11, 2020)
18. Ran-Sook Woo, Neuropathogenesis-on-chips for neurodegenerative diseases, Nature Communications (Aug. 1, 2022)
19. Amirifar, Leyla, et al. Brain-on-a-chip: Recent advances in design and techniques for microfluidic models of the brain in health and disease, Biomaterials, vol. 285, June 2022, p. 121531. https://doi.org/10.1016/j.biomaterials.2022.121531
20. Electrophysiology Read-Out Tools for Brain-on-Chip Biotechnology, Electrophysiology Read-Out Tools for Brain-on-Chip https://doi.org/10.3390/mi12020124.
21. Robert Mannix1, Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies, Nature Communications (Jan. 7, 2022)
22. From 2D to 3D Co-Culture Systems: A Review of Co-Culture Models to Study the Neural Cells Interaction
23. Rezaei, Nima Tabatabaei, et al., Recent Advances in Organ-on-Chips Integrated With Bioprinting Technologies for Drug Screening, Advanced Healthcare Materials, vol. 12, no. 20, May 2023
24. Frontiers | Guiding organs-on-chips towards applications: a balancing act between integration of advanced technologies and standardization, Guiding organs-on-chips towards applications: a ba https://doi.org/10.3389/frlct.2024.1376964.
25. Sung-Hyun Jo5, Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids, Nature Communications (Feb. 14, 2023)
26. Xu, Longqian, et al. Trends and Recent Development of the Microelectrode Arrays (MEAs), Biosensors and Bioelectronics, vol. 175, Mar. 2021, p. 112854. https://doi.org/10.1016/j.bios.2020.112854.
27. Electrophysiology Read-Out Tools for Brain-on-Chip Biotechnology
28. Yanhong Shi, Induced pluripotent stem cell technology: a decade of progress, Nature Reviews Drug Discovery (Apr. 26, 2024)
29. Takahashi, Kazutoshi, et al. Induction of Pluripotent Stem Cells From Adult Human Fibroblasts by Defined Factors, Cell, vol. 131, no. 5, Nov. 2007, pp. 861-72. https://doi.org/10.1016/j.cell.2007.11.019.
30. Gabriel Luna, Functional neuronal circuitry and oscillatory dynamics in human brain organoids, Nature Communications (Aug. 23, 2021)
31. Fanizza F, Campanile M, Forloni G, Giordano C, Albani D. Induced pluripotent stem cell-based organ-on-a-chip as personalized drug screening tools: A focus on neurodegenerative disorders, Journal of Tissue Engineering. 2022;13. doi:10.1177/20417314221095339
32. Wang, Z., Zhang, Y., Li, Z., Wang, H., Li, N., & Deng, Y. (2023). Microfluidic Brain-on-a-Chip: From Key Technology to System Integration and Application, Small (Weinheim an der Bergstrasse, Germany),19(52), e2304427. https://doi.org/10.1002/smll.202304427
33. Chopra, H., Chakraborty, S., Akash, S., Chakraborty, C., & Dhama, K. (2023). Organ-on-chip: a new paradigm for clinical trials - correspondence. International journal of surgery (London, England), 109(10), 3240-3241. https://doi.org/10.1097/JS9.0000000000000578
34. Huh, D., Kim, H., Fraser, J. et al. Microfabrication of human organs-on-chips. Nat Protoc 8, 2135-2157 (2013). https://doi.org/10.1038/nprot.2013.137
35. Candarlioglu, P. L., Dal Negro, G., Hughes, D., Balkwill, F., Harris, K., Screen, H., Morgan, H., David, R., Beken, S., Guenat, O., Rowan, W., & Amour, A. (2022). Organ-on-a-chip: current gaps and future directions. Biochemical Society transactions, 50(2), 665-673. https://doi.org/10.1042/BST20200661
36. Organ-on-chip technology: Opportunities and challenges https://doi.org/10.1016/j.biotno.2024.01.001
37. Vlahou, A., Hallinan, D., Apweiler, R., Argiles, A., Beige, J., Benigni, A., Bischoff, R., Black, P. C., Boehm, F., Ceraline, J., Chrousos, G. P., Delles, C., Evenepoel, P., Fridolin, I., Glorieux, G., van Gool, A. J., Heidegger, I., Ioannidis, J. P. A., Jankowski, J., Jankowski, V., Vanholder, R. (2021). Data Sharing Under the General Data Protection Regulation: Time to Harmonize Law and Research Ethics? Hypertension (Dallas, Tex. : 1979), 77(4), 1029-1035. https://doi.org/10.1161/HYPERTENSIONAHA.120.16340
38. Summary of the HIPAA Privacy Rule, HHS.gov (May 7, 2008)
39. Pirnay, J. P., Vanderkelen, A., Zizi, M., De Vos, D., Rose, T., Laire, G., Ectors, N., & Verbeken, G. (2010). Human cells and tissues: the need for a global ethical framework. Bulletin of the World Health Organization, 88(11), 870-872. https://doi.org/10.2471/BLT.09.074542
40. Dankar, F. K., Gergely, M., & Dankar, S. K. (2019). Informed Consent in Biomedical Research. Computational and structural biotechnology journal, 17, 463-474. https://doi.org/10.1016/j.csbj.2019.03.010
41. Rothschild J. (2020). Ethical considerations of gene editing and genetic selection. Journal of general and family medicine, 21(3), 37-47. https://doi.org/10.1002/jgf2.321
42. Wang, S., Bonomi, L., Dai, W., Chen, F., Cheung, C., Bloss, C. S., Cheng, S., & Jiang, X. (2020). Big Data Privacy in Biomedical Research. IEEE transactions on big data, 6(2), 296-308. https://doi.org/10.1109/TBDATA.2016.2608848
43. Horch, R. E., Pepescu, L. M., Vacanti, C., & Maio, G. (2008). Ethical issues in cellular and molecular medicine and tissue engineering. Journal of cellular and molecular medicine, 12(5B), 1785-1793. https://doi.org/10.1111/j.1582-4934.2008.00460.x
44. Arellano, A. M., Dai, W., Wang, S., Jiang, X., & Ohno-Machado, L. (2018). Privacy Policy and Technology in Biomedical Data Science. Annual review of biomedical data science, 1, 115-129. https://doi.org/10.1146/annurev-biodatasci-080917-013416
45. Rizk, Samia Hassan, Ethical and Regulatory Challenges of Emerging Health Technologies, Advances in human and social aspects of technology book series, 2021, pp. 84-100, https://doi.org/10.4018/978-1-7998-8467-5.ch007
46. (Sept. 25, 2018)
47. (Jan. 15, 2021)
48. OECD (1998), OECD Principles on Good Laboratory Practice, OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring, No. 1, OECD Publishing, Paris, https://doi.org/10.1787/9789264078536-en.
49. Standardisation needs for organ on chip devices https://doi.org/10.1039/D1LC00241D.
50. Quality Systems Approach to Pharmaceutical Current Good Manufacturing, (Sept. 29, 2023)
51. Organ On A Chip Market Size, Share & Trends Report, 2030
52. Organ-on-Chip Market Size, Share & Trends [2029]
53. Human-on-a-Chip Data Enables Clinical Trial (NCT04658472) Highlighting Potential for In Vitro Approach in lieu of Animal Studies for Rare Neuromuscular Disorders, Hesperos Inc. (Apr. 19, 2022)
54.
55. Timms, Kevin, Exploring product liability: putting medical devices into a clinical context. Journal of Aesthetic Nursing, vol. 3, no. 9, Nov. 2014, pp. 450-52. https://doi.org/10.12968/joan.2014.3.9.450.
56. Directive
57. (Sept. 25, 2017)
58. Mascalzoni, D., Dove, E., Rubinstein, Y. et al. International Charter of principles for sharing bio-specimens and data. Eur J Hum Genet 23, 721-728 (2015). https://doi.org/10.1038/ejhg.2014.197
59. Minding Rights: Mapping Ethical and Legal Foundations of Neurorights | Cambridge Quarterly of Healthcare Ethics, Cambridge Core (May 15, 2023)
60. Damian Eke, The ethical and legal landscape of brain data governance, PLOS ONE (Dec. 29, 2022)
61. Neurorights: Do our brains need to be protected by legislation?, European Science-Media Hub (Nov. 8, 2023)
62. Mousume Roy, Organ-on-chip technology: The next wave in the healthcare market, HCLTech (July 1, 2024)
63. Market Forecast: Global Organ-On-Chip (OOC) Trends and Impact Analysis (2024 - 2031) By Application (Pharmaceutical & Biotechnology Companies,Academic, 2031) By Application (Pharmaceutical & Biotechnolo (July 28, 2024)
64. Wang, Z., Zhang, Y., Li, Z., Wang, H., Li, N., & Deng, Y. (2023). Microfluidic Brain-on-a-Chip: From Key Technology to System Integration and Application. Small (Weinheim an der Bergstrasse, Germany), 19(52), e2304427. https://doi.org/10.1002/smll.202304427
65. Mastrangeli, M., & van den Eijnden-van Raaij, J. (2021). Organs-on-chip: The way forward. Stem cell reports, 16(9), 2037-2043. https://doi.org/10.1016/j.stemcr.2021.06.015
References
1. Dan Xiao, Role of neuroinflammation in neurodegeneration development, Signal Transduction and Targeted Therapy (Oct. 29, 2021)
2. Jialin C Zheng, Translational Neurodegeneration in the era of fast-growing international brain research, Full Text (Jan 2, 2022)
3. Donald E Ingber, Microfluidic organs-on-chips, Nature Biotechnology (May 12, 2022)
4. Donald E Ingber, Microfluidic organs-on-chips, Nature Biotechnology (May 12, 2022)
5. The 3Rs and Humane Experimental Technique:Implementing Change, The 3Rs and Humane Experimental Technique: https://doi.org/10.3390/ani9100754.
6. Systematic Reviews of Animal Experiments Demonstrate Poor Contributions Toward Human Healthcare, Bentham Science https://doi.org/10.2174/157488708784223844.
7. Annamaria A Bottini, Food for thought on the economics of animal testing | ALTEX, Alternatives to animal experimentation (Feb. 1, 2009)
8. Ran-Sook Woo, Neuropathogenesis-on-chips for neurodegenerative diseases, Nature Communications (Aug. 1, 2022)
9. Ma, C., Seong, H., Li, X., Yu, X., Xu, S., & Li, Y. (2022). Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening. Stem cells international, 2022, 2150680. https://doi.org/10.1155/2022/2150680
10. Robert Mannix1, Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies, Nature Communications (Jan. 7, 2022)
11. Park, J., Lee, B. K., Jeong, G. S., Hyun, J. K., Lee, C. J., & Lee, S. H. (2015). Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimers disease. Lab on a Chip, 15(1), 141-150. https://doi.org/10.1039/c4lc00962b
12. Pratibha Parihar1, Frontiers | Revolutionizing drug development: harnessing the potential of organ-on-chip technology for disease modeling and drug discovery, Revolutionizing drug development: harnessing the p https://doi.org/10.3389/fphar.2023.1139229.
13. Dongeun Huh, Microfabrication of human organs-on-chips, Nature Protocols (May 12, 2022)
14. Erika Ferrari, Photo and Soft Lithography for Organ-on-Chip Applications, SpringerLink (Sept. 15, 2021)
15. Donald E Ingber, Microfluidic organs-on-chips, Nature Biotechnology (May 12, 2022)
16. Pratibha Parihar, Frontiers | Revolutionizing drug development: harnessing the potential of organ-on-chip technology for disease modeling and drug discovery, Revolutionizing drug development: harnessing the p https://doi.org/10.3389/fphar.2023.1139229.
17. Noah Goshi, A primary neural cell culture model to study neuron, astrocyte, and microglia interactions in neuroinflammation, Full Text (May 11, 2020)
18. Ran-Sook Woo, Neuropathogenesis-on-chips for neurodegenerative diseases, Nature Communications (Aug. 1, 2022)
19. Amirifar, Leyla, et al. Brain-on-a-chip: Recent advances in design and techniques for microfluidic models of the brain in health and disease, Biomaterials, vol. 285, June 2022, p. 121531. https://doi.org/10.1016/j.biomaterials.2022.121531
20. Electrophysiology Read-Out Tools for Brain-on-Chip Biotechnology, Electrophysiology Read-Out Tools for Brain-on-Chip https://doi.org/10.3390/mi12020124.
21. Robert Mannix1, Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies, Nature Communications (Jan. 7, 2022)
22. From 2D to 3D Co-Culture Systems: A Review of Co-Culture Models to Study the Neural Cells Interaction
23. Rezaei, Nima Tabatabaei, et al., Recent Advances in Organ-on-Chips Integrated With Bioprinting Technologies for Drug Screening, Advanced Healthcare Materials, vol. 12, no. 20, May 2023
24. Frontiers | Guiding organs-on-chips towards applications: a balancing act between integration of advanced technologies and standardization, Guiding organs-on-chips towards applications: a ba https://doi.org/10.3389/frlct.2024.1376964.
25. Sung-Hyun Jo5, Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids, Nature Communications (Feb. 14, 2023)
26. Xu, Longqian, et al. Trends and Recent Development of the Microelectrode Arrays (MEAs), Biosensors and Bioelectronics, vol. 175, Mar. 2021, p. 112854. https://doi.org/10.1016/j.bios.2020.112854.
27. Electrophysiology Read-Out Tools for Brain-on-Chip Biotechnology
28. Yanhong Shi, Induced pluripotent stem cell technology: a decade of progress, Nature Reviews Drug Discovery (Apr. 26, 2024)
29. Takahashi, Kazutoshi, et al. Induction of Pluripotent Stem Cells From Adult Human Fibroblasts by Defined Factors, Cell, vol. 131, no. 5, Nov. 2007, pp. 861-72. https://doi.org/10.1016/j.cell.2007.11.019.
30. Gabriel Luna, Functional neuronal circuitry and oscillatory dynamics in human brain organoids, Nature Communications (Aug. 23, 2021)
31. Fanizza F, Campanile M, Forloni G, Giordano C, Albani D. Induced pluripotent stem cell-based organ-on-a-chip as personalized drug screening tools: A focus on neurodegenerative disorders, Journal of Tissue Engineering. 2022;13. doi:10.1177/20417314221095339
32. Wang, Z., Zhang, Y., Li, Z., Wang, H., Li, N., & Deng, Y. (2023). Microfluidic Brain-on-a-Chip: From Key Technology to System Integration and Application, Small (Weinheim an der Bergstrasse, Germany),19(52), e2304427. https://doi.org/10.1002/smll.202304427
33. Chopra, H., Chakraborty, S., Akash, S., Chakraborty, C., & Dhama, K. (2023). Organ-on-chip: a new paradigm for clinical trials - correspondence. International journal of surgery (London, England), 109(10), 3240-3241. https://doi.org/10.1097/JS9.0000000000000578
34. Huh, D., Kim, H., Fraser, J. et al. Microfabrication of human organs-on-chips. Nat Protoc 8, 2135-2157 (2013). https://doi.org/10.1038/nprot.2013.137
35. Candarlioglu, P. L., Dal Negro, G., Hughes, D., Balkwill, F., Harris, K., Screen, H., Morgan, H., David, R., Beken, S., Guenat, O., Rowan, W., & Amour, A. (2022). Organ-on-a-chip: current gaps and future directions. Biochemical Society transactions, 50(2), 665-673. https://doi.org/10.1042/BST20200661
36. Organ-on-chip technology: Opportunities and challenges https://doi.org/10.1016/j.biotno.2024.01.001
37. Vlahou, A., Hallinan, D., Apweiler, R., Argiles, A., Beige, J., Benigni, A., Bischoff, R., Black, P. C., Boehm, F., Ceraline, J., Chrousos, G. P., Delles, C., Evenepoel, P., Fridolin, I., Glorieux, G., van Gool, A. J., Heidegger, I., Ioannidis, J. P. A., Jankowski, J., Jankowski, V., Vanholder, R. (2021). Data Sharing Under the General Data Protection Regulation: Time to Harmonize Law and Research Ethics? Hypertension (Dallas, Tex. : 1979), 77(4), 1029-1035. https://doi.org/10.1161/HYPERTENSIONAHA.120.16340
38. Summary of the HIPAA Privacy Rule, HHS.gov (May 7, 2008)
39. Pirnay, J. P., Vanderkelen, A., Zizi, M., De Vos, D., Rose, T., Laire, G., Ectors, N., & Verbeken, G. (2010). Human cells and tissues: the need for a global ethical framework. Bulletin of the World Health Organization, 88(11), 870-872. https://doi.org/10.2471/BLT.09.074542
40. Dankar, F. K., Gergely, M., & Dankar, S. K. (2019). Informed Consent in Biomedical Research. Computational and structural biotechnology journal, 17, 463-474. https://doi.org/10.1016/j.csbj.2019.03.010
41. Rothschild J. (2020). Ethical considerations of gene editing and genetic selection. Journal of general and family medicine, 21(3), 37-47. https://doi.org/10.1002/jgf2.321
42. Wang, S., Bonomi, L., Dai, W., Chen, F., Cheung, C., Bloss, C. S., Cheng, S., & Jiang, X. (2020). Big Data Privacy in Biomedical Research. IEEE transactions on big data, 6(2), 296-308. https://doi.org/10.1109/TBDATA.2016.2608848
43. Horch, R. E., Pepescu, L. M., Vacanti, C., & Maio, G. (2008). Ethical issues in cellular and molecular medicine and tissue engineering. Journal of cellular and molecular medicine, 12(5B), 1785-1793. https://doi.org/10.1111/j.1582-4934.2008.00460.x
44. Arellano, A. M., Dai, W., Wang, S., Jiang, X., & Ohno-Machado, L. (2018). Privacy Policy and Technology in Biomedical Data Science. Annual review of biomedical data science, 1, 115-129. https://doi.org/10.1146/annurev-biodatasci-080917-013416
45. Rizk, Samia Hassan, Ethical and Regulatory Challenges of Emerging Health Technologies, Advances in human and social aspects of technology book series, 2021, pp. 84-100, https://doi.org/10.4018/978-1-7998-8467-5.ch007
46. (Sept. 25, 2018)
47. (Jan. 15, 2021)
48. OECD (1998), OECD Principles on Good Laboratory Practice, OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring, No. 1, OECD Publishing, Paris, https://doi.org/10.1787/9789264078536-en.
49. Standardisation needs for organ on chip devices https://doi.org/10.1039/D1LC00241D.
50. Quality Systems Approach to Pharmaceutical Current Good Manufacturing, (Sept. 29, 2023)
51. Organ On A Chip Market Size, Share & Trends Report, 2030
52. Organ-on-Chip Market Size, Share & Trends [2029]
53. Human-on-a-Chip Data Enables Clinical Trial (NCT04658472) Highlighting Potential for In Vitro Approach in lieu of Animal Studies for Rare Neuromuscular Disorders, Hesperos Inc. (Apr. 19, 2022)
54.
55. Timms, Kevin, Exploring product liability: putting medical devices into a clinical context. Journal of Aesthetic Nursing, vol. 3, no. 9, Nov. 2014, pp. 450-52. https://doi.org/10.12968/joan.2014.3.9.450.
56. Directive
57. (Sept. 25, 2017)
58. Mascalzoni, D., Dove, E., Rubinstein, Y. et al. International Charter of principles for sharing bio-specimens and data. Eur J Hum Genet 23, 721-728 (2015). https://doi.org/10.1038/ejhg.2014.197
59. Minding Rights: Mapping Ethical and Legal Foundations of Neurorights | Cambridge Quarterly of Healthcare Ethics, Cambridge Core (May 15, 2023)
60. Damian Eke, The ethical and legal landscape of brain data governance, PLOS ONE (Dec. 29, 2022)
61. Neurorights: Do our brains need to be protected by legislation?, European Science-Media Hub (Nov. 8, 2023)
62. Mousume Roy, Organ-on-chip technology: The next wave in the healthcare market, HCLTech (July 1, 2024)
63. Market Forecast: Global Organ-On-Chip (OOC) Trends and Impact Analysis (2024 - 2031) By Application (Pharmaceutical & Biotechnology Companies,Academic, 2031) By Application (Pharmaceutical & Biotechnolo (July 28, 2024)
64. Wang, Z., Zhang, Y., Li, Z., Wang, H., Li, N., & Deng, Y. (2023). Microfluidic Brain-on-a-Chip: From Key Technology to System Integration and Application. Small (Weinheim an der Bergstrasse, Germany), 19(52), e2304427. https://doi.org/10.1002/smll.202304427
65. Mastrangeli, M., & van den Eijnden-van Raaij, J. (2021). Organs-on-chip: The way forward. Stem cell reports, 16(9), 2037-2043. https://doi.org/10.1016/j.stemcr.2021.06.015