Innovative biofabrication: integrating microfluidics, nanotechnology, and multiphysics simulations in tissue engineering

The escalating cost of medicine production and ethical concerns surrounding animal testing have driven the need for alternative approaches in drug development. Tissue engineering, organ-on-a-chip technology, bioprinting, and advanced cell culture techniques have emerged as innovative strategies to i...

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Author: Rodríguez Ospino, Cristian Felipe
Format: master thesis
Status:Versión aceptada para publicación
Publication Date:2023
Country:Colombia
Institution:Universidad de los Andes
Repository:Séneca: repositorio Uniandes
Language:English
OAI Identifier:oai:repositorio.uniandes.edu.co:1992/69099
Online Access:http://hdl.handle.net/1992/69099
Access Level:Embargoed access
Keyword:Cell spheroids
Labs on a chip
Organ on a chip
Microfluidic
Comsol
Ingeniería
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oai_identifier_str oai:repositorio.uniandes.edu.co:1992/69099
network_acronym_str CO
network_name_str Colombia
repository_id_str
dc.title.none.fl_str_mv Innovative biofabrication: integrating microfluidics, nanotechnology, and multiphysics simulations in tissue engineering
title Innovative biofabrication: integrating microfluidics, nanotechnology, and multiphysics simulations in tissue engineering
spellingShingle Innovative biofabrication: integrating microfluidics, nanotechnology, and multiphysics simulations in tissue engineering
Rodríguez Ospino, Cristian Felipe
Cell spheroids
Labs on a chip
Organ on a chip
Microfluidic
Comsol
Ingeniería
title_short Innovative biofabrication: integrating microfluidics, nanotechnology, and multiphysics simulations in tissue engineering
title_full Innovative biofabrication: integrating microfluidics, nanotechnology, and multiphysics simulations in tissue engineering
title_fullStr Innovative biofabrication: integrating microfluidics, nanotechnology, and multiphysics simulations in tissue engineering
title_full_unstemmed Innovative biofabrication: integrating microfluidics, nanotechnology, and multiphysics simulations in tissue engineering
title_sort Innovative biofabrication: integrating microfluidics, nanotechnology, and multiphysics simulations in tissue engineering
dc.creator.none.fl_str_mv Rodríguez Ospino, Cristian Felipe
author Rodríguez Ospino, Cristian Felipe
author_facet Rodríguez Ospino, Cristian Felipe
author_role author
dc.contributor.none.fl_str_mv Cruz Jiménez, Juan Carlos
Muñoz Camargo, Carolina
Osma Cruz, Johann Faccelo
Briceño Triana, Juan Carlos
Reyes Barrios, Luis Humberto
dc.subject.none.fl_str_mv Cell spheroids
Labs on a chip
Organ on a chip
Microfluidic
Comsol
Ingeniería
topic Cell spheroids
Labs on a chip
Organ on a chip
Microfluidic
Comsol
Ingeniería
description The escalating cost of medicine production and ethical concerns surrounding animal testing have driven the need for alternative approaches in drug development. Tissue engineering, organ-on-a-chip technology, bioprinting, and advanced cell culture techniques have emerged as innovative strategies to improve the predictability and relevance of in vitro models while reducing reliance on traditional methods. One such approach is bioprinting with cell spheroids, which allows for precise placement of cells and biomaterials to fabricate intricate tissue constructs. However, challenges remain in accurately representing the fusion process of cell aggregates and expediting tissue fusion. To address these challenges, this study aims to achieve two objectives. Firstly, a multiphysical stochastic phase field model is proposed to accurately represent the fusion process of cellular spheroids. This model incorporates stochastic elements and phase field principles to capture the inherent variability and complexities of the fusion behavior. The model exhibits an average error of 6% when compared to experimental results, demonstrating its effectiveness in simulating and predicting the fusion behavior of spheroids. Secondly, the study explores the application of magnetic fields to accelerate the fusion process of cell aggregates. Magnetite nanoparticles are incorporated into the spheroids to magnetize them, enhancing the interaction and fusion of the cell aggregates. The rapid magnetization of the spheroids is facilitated by the translocating effect of the Buforin-II peptide, allowing for effective and quick penetration of nanoparticles throughout the entire spheroid. The application of a magnetic field significantly reduces the fusion time from 7 days to 2 days, leading to expedited maturation of bioprinted tissues. Increasing the number of magnetic spheroids further enhances the speed of the fusion process.The use of the proposed multiphysical stochastic phase field model and magnetite-assisted bioprinting technique holds great promise for tissue engineering and regenerative medicine. These advancements have the potential to revolutionize tissue engineering by improving the efficiency and reliability of the tissue development process, while also reducing the need for animal testing in drug development. Further investigations are recommended to ensure the safety and viability of cells under the stress exerted by the magnetic field.
publishDate 2023
dc.date.none.fl_str_mv 2023-05-29
dc.type.none.fl_str_mv Trabajo de grado - Maestría
info:eu-repo/semantics/masterThesis
info:eu-repo/semantics/acceptedVersion
http://purl.org/coar/resource_type/c_bdcc
http://purl.org/coar/version/c_ab4af688f83e57aa
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dc.identifier.none.fl_str_mv http://hdl.handle.net/1992/69099
instname:Universidad de los Andes
reponame:Repositorio Institucional Séneca
repourl:https://repositorio.uniandes.edu.co/
url http://hdl.handle.net/1992/69099
identifier_str_mv instname:Universidad de los Andes
reponame:Repositorio Institucional Séneca
repourl:https://repositorio.uniandes.edu.co/
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv World Health Organization. Noncommunicable Disease, & Mental Health Cluster. (2002). Innovative care for chronic conditions: building blocks for action: global report. World Health Organization.
Paul, S. M., Mytelka, D. S., Dunwiddie, C. T., Persinger, C. C., Munos, B. H., Lindborg, S. R., & Schacht, A. L. (2010). How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nature reviews Drug discovery, 9(3), 203-214.
Wang, H., Brown, P. C., Chow, E. C., Ewart, L., Ferguson, S. S., Fitzpatrick, S., ... & Huang, S. M. (2021). 3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration. Clinical and translational science, 14(5), 1659-1680.
Pan, S. Y., Zhou, S. F., Gao, S. H., Yu, Z. L., Zhang, S. F., Tang, M. K., ... & Ko, K. M. (2013). New perspectives on how to discover drugs from herbal medicines: CAM's outstanding contribution to modern therapeutics. Evidence-Based Complementary and Alternative Medicine, 2013.
Tolikas, M., Antoniou, A., & Ingber, D. E. (2017). The Wyss institute: A new model for medical technology innovation and translation across the academic-industrial interface. Bioengineering & translational medicine, 2(3), 247-257.
Mantilla-Orozco, A., Rodriguez, C. F., Quiroz, I., Bermudez, J. S., Forero, D. F., Monsalve, M. C., ... & Cruz, J. C. (2022, November). Modeling and Simulation of Magnetoliposome Formation by Encapsulation of Core-Shell, Magnetite-Chitosan Nanoparticles in Liposomes Enabled by a Low-Cost Microfluidic System. In Biology and Life Sciences Forum (Vol. 20, No. 1, p. 29). MDPI.
Dalton, P. D., Woodfield, T. B., Mironov, V., & Groll, J. (2020). Advances in hybrid fabrication toward hierarchical tissue constructs. Advanced Science, 7(11), 1902953.
Jung, J. P., Bhuiyan, D. B., & Ogle, B. M. (2016). Solid organ fabrication: comparison of decellularization to 3D bioprinting. Biomaterials research, 20, 1-11.
Ravanbakhsh, H., Karamzadeh, V., Bao, G., Mongeau, L., Juncker, D., & Zhang, Y. S. (2021). Emerging technologies in multi-material bioprinting. Advanced Materials, 33(49), 2104730.
Mironov, V., Visconti, R. P., Kasyanov, V., Forgacs, G., Drake, C. J., & Markwald, R. R. (2009). Organ printing: tissue spheroids as building blocks. Biomaterials, 30(12), 2164-2174.
Bhattacharyya, A., Janarthanan, G., & Noh, I. (2021). Nano-biomaterials for designing functional bioinks towards complex tissue and organ regeneration in 3D bioprinting. Additive Manufacturing, 37, 101639.
Ashammakhi, N., Ahadian, S., Xu, C., Montazerian, H., Ko, H., Nasiri, R., ... & Khademhosseini, A. (2019). Bioinks and bioprinting technologies to make heterogeneous and biomimetic tissue constructs. Materials Today Bio, 1, 100008.
O'Brien, C. M., Holmes, B., Faucett, S., & Zhang, L. G. (2015). Three-dimensional printing of nanomaterial scaffolds for complex tissue regeneration. Tissue Engineering Part B: Reviews, 21(1), 103-114.
Arjoca, S., Robu, A., Neagu, M., & Neagu, A. (2023). Mathematical and computational models in spheroid-based biofabrication. Acta Biomaterialia, 165, 125-139.
Rodríguez, C. F., Castilla-Bolanos, M. A., Ortiz, L., Rodriguez, K. A. G., Osma, J. F., Camargo, C. M., & Cruz, J. C. (2022, November). Study of Spheroids Fusion via Multiphysics Simulations: Feasibility of Applying Permanent Magnetic Field Gradients. In Biology and Life Sciences Forum (Vol. 20, No. 1, p. 30). MDPI.
Rodriguez, C. F., Ortiz, L., Muñoz, C., & Cruz, J. C. (2021, October). In silico study of spheroids fusion through magnetic field gradients. In 2021 IEEE 2nd International Congress of Biomedical Engineering and Bioengineering (CI-IB&BI) (pp. 1-9). IEEE.
C. Multiphysics, "CFD Module User's Guide," COMSOL Multiphysics, p. 598, 2016, [Online]. Available: https://doc.comsol.com/5.3/doc/com.comsol.help.cfd/CFDModuleUsersGuide.pdf.
C. Multiphysics, "ACD Module User's Guide," COMSOL Multiphysics, 2016.
D. J. Bustamante et al., "Biofabrication of spheroids fusion-based tumor models: computational simulation of glucose effects," Biofabrication, vol. 13, no. 3, p. 35010, Apr. 2021, : 10.1088/1758-5090/abe025.
A. C. Daly, M. D. Davidson, and J. A. Burdick, "3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels," Nat. Commun., no. 2021, pp. 1-13, : 10.1038/s41467-021-21029-2.
P. A. Fleming, W. S. Argraves, C. Gentile, A. Neagu, G. Forgacs, and C. J. Drake, "Fusion of uniluminal vascular spheroids: a model for assembly of blood vessels.," Dev. Dyn. an Off. Publ. Am. Assoc. Anat., vol. 239, no. 2, pp. 398-406, Feb. 2010, : 10.1002/dvdy.22161.
M. A. Gionet-Gonzales and J. K. Leach, "Engineering principles for guiding spheroid function in the regeneration of bone, cartilage, and skin.," Biomed. Mater., vol. 13, no. 3, p. 34109, Mar. 2018, : 10.1088/1748-605X/aab0b3.
A. Tocchio et al., "Magnetically Guided Self-Assembly and Coding of 3D Living Architectures.," Adv. Mater., vol. 30, no. 4, Jan. 2018, : 10.1002/adma.201705034.
Leung, C. M., De Haan, P., Ronaldson-Bouchard, K., Kim, G. A., Ko, J., Rho, H. S., ... & Toh, Y. C. (2022). A guide to the organ-on-a-chip. Nature Reviews Methods Primers, 2(1), 33.
Antoni, D., Burckel, H., Josset, E., & Noel, G. (2015). Three-dimensional cell culture: a breakthrough in vivo. International journal of molecular sciences, 16(3), 5517-5527.
Nath, S., & Devi, G. R. (2016). Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacology & therapeutics, 163, 94-108.
Di Caprio, N., & Burdick, J. A. (2022). Engineered biomaterials to guide spheroid formation, function, and fabrication into 3D tissue constructs. Acta Biomaterialia.
Kim, W., Gwon, Y., Park, S., Kim, H., & Kim, J. (2023). Therapeutic strategies of three-dimensional stem cell spheroids and organoids for tissue repair and regeneration. Bioactive Materials, 19, 50-74.
Rizzo, G., Bertotti, A., Leto, S. M., & Vetrano, S. (2021). Patient-derived tumor models: a more suitable tool for pre-clinical studies in colorectal cancer. Journal of Experimental & Clinical Cancer Research, 40(1), 178.
Malaney, P., Nicosia, S. V., & Davé, V. (2014). One mouse, one patient paradigm: New avatars of personalized cancer therapy. Cancer letters, 344(1), 1-12.
Tevlek, A., Kecili, S., Ozcelik, O. S., Kulah, H., & Tekin, H. C. (2023). Spheroid engineering in microfluidic devices. Acs Omega, 8(4), 3630-3649.
Fridman, I. B., Ugolini, G. S., VanDelinder, V., Cohen, S., & Konry, T. (2021). High throughput microfluidic system with multiple oxygen levels for the study of hypoxia in tumor spheroids. Biofabrication, 13(3), 035037.
Vadivelu, R. K., Kamble, H., Shiddiky, M. J., & Nguyen, N. T. (2017). Microfluidic technology for the generation of cell spheroids and their applications. Micromachines, 8(4), 94.
Damiati, S., Kompella, U. B., Damiati, S. A., & Kodzius, R. (2018). Microfluidic devices for drug delivery systems and drug screening. Genes, 9(2), 103.
Bahrami, S., Baheiraei, N., Najafi-Ashtiani, M., Nour, S., & Razavi, M. (2021). Microfluidic devices in tissue engineering. In Biomedical Applications of Microfluidic Devices (pp. 209-233). Academic Press.
Bolanos-Barbosa, A. D., Rodríguez, C. F., Acuña, O. L., Cruz, J. C., & Reyes, L. H. (2023). The Impact of Yeast Encapsulation in Wort Fermentation and Beer Flavor Profile. Polymers, 15(7), 1742.
Rodríguez, C. F., & Cruz, J. C. (2023). Critique-Simulation Apps. Education for Chemical Engineers, 42, 88-89
Jaramillo Mejía, V., Rodríguez Ospino, C. F., Cuestas Valenzuela, L. C., Rivas Bedoya, L. D., & Ramírez, L. (2021). VlacPort: monopuerto de bajo costo para la cirugía laparoscópica de única incisión.
Fuentes Melo, L. F. (2022). Microheater for microfluidic systems.
Rodríguez, C. F., Andrade-Pérez, V., Vargas, M. C., Mantilla-Orozco, A., Osma, J. F., Reyes, L. H., & Cruz, J. C. (2023). Breaking the clean room barrier: exploring low-cost alternatives for microfluidic devices. Frontiers in Bioengineering and Biotechnology, 11, 1176557.
Ortegón, S., Peñaranda, P. A., Rodríguez, C. F., Noguera, M. J., Florez, S. L., Cruz, J. C., ... & Osma, J. F. (2022). Magnetic torus microreactor as a novel device for sample treatment via solid-phase microextraction coupled to graphite furnace atomic absorption spectroscopy: A route for arsenic pre-concentration. Molecules, 27(19), 6198.
dc.rights.none.fl_str_mv Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/embargoedAccess
http://purl.org/coar/access_right/c_f1cf
rights_invalid_str_mv Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
http://purl.org/coar/access_right/c_f1cf
eu_rights_str_mv embargoedAccess
dc.format.none.fl_str_mv 50 páginas
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universidad de los Andes
Maestría en Ingeniería Biomédica
Facultad de Ingeniería
Departamento de Ingeniería Biomédica
publisher.none.fl_str_mv Universidad de los Andes
Maestría en Ingeniería Biomédica
Facultad de Ingeniería
Departamento de Ingeniería Biomédica
dc.source.none.fl_str_mv reponame:Séneca: repositorio Uniandes
instname:Universidad de los Andes
instacron:Universidad de los Andes
instname_str Universidad de los Andes
instacron_str Universidad de los Andes
institution Universidad de los Andes
reponame_str Séneca: repositorio Uniandes
collection Séneca: repositorio Uniandes
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spelling Innovative biofabrication: integrating microfluidics, nanotechnology, and multiphysics simulations in tissue engineeringRodríguez Ospino, Cristian FelipeCell spheroidsLabs on a chipOrgan on a chipMicrofluidicComsolIngenieríaThe escalating cost of medicine production and ethical concerns surrounding animal testing have driven the need for alternative approaches in drug development. Tissue engineering, organ-on-a-chip technology, bioprinting, and advanced cell culture techniques have emerged as innovative strategies to improve the predictability and relevance of in vitro models while reducing reliance on traditional methods. One such approach is bioprinting with cell spheroids, which allows for precise placement of cells and biomaterials to fabricate intricate tissue constructs. However, challenges remain in accurately representing the fusion process of cell aggregates and expediting tissue fusion. To address these challenges, this study aims to achieve two objectives. Firstly, a multiphysical stochastic phase field model is proposed to accurately represent the fusion process of cellular spheroids. This model incorporates stochastic elements and phase field principles to capture the inherent variability and complexities of the fusion behavior. The model exhibits an average error of 6% when compared to experimental results, demonstrating its effectiveness in simulating and predicting the fusion behavior of spheroids. Secondly, the study explores the application of magnetic fields to accelerate the fusion process of cell aggregates. Magnetite nanoparticles are incorporated into the spheroids to magnetize them, enhancing the interaction and fusion of the cell aggregates. The rapid magnetization of the spheroids is facilitated by the translocating effect of the Buforin-II peptide, allowing for effective and quick penetration of nanoparticles throughout the entire spheroid. The application of a magnetic field significantly reduces the fusion time from 7 days to 2 days, leading to expedited maturation of bioprinted tissues. Increasing the number of magnetic spheroids further enhances the speed of the fusion process.The use of the proposed multiphysical stochastic phase field model and magnetite-assisted bioprinting technique holds great promise for tissue engineering and regenerative medicine. These advancements have the potential to revolutionize tissue engineering by improving the efficiency and reliability of the tissue development process, while also reducing the need for animal testing in drug development. Further investigations are recommended to ensure the safety and viability of cells under the stress exerted by the magnetic field.Magíster en Ingeniería BiomédicaMaestríaUniversidad de los AndesMaestría en Ingeniería BiomédicaFacultad de IngenieríaDepartamento de Ingeniería BiomédicaCruz Jiménez, Juan CarlosMuñoz Camargo, CarolinaOsma Cruz, Johann FacceloBriceño Triana, Juan CarlosReyes Barrios, Luis Humberto2023-05-29Trabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionhttp://purl.org/coar/resource_type/c_bdcchttp://purl.org/coar/version/c_ab4af688f83e57aaTexthttps://purl.org/redcol/resource_type/TM50 páginasapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/1992/69099instname:Universidad de los Andesreponame:Repositorio Institucional Sénecarepourl:https://repositorio.uniandes.edu.co/engWorld Health Organization. Noncommunicable Disease, & Mental Health Cluster. (2002). Innovative care for chronic conditions: building blocks for action: global report. World Health Organization.Paul, S. M., Mytelka, D. S., Dunwiddie, C. T., Persinger, C. C., Munos, B. H., Lindborg, S. R., & Schacht, A. L. (2010). How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nature reviews Drug discovery, 9(3), 203-214.Wang, H., Brown, P. C., Chow, E. C., Ewart, L., Ferguson, S. S., Fitzpatrick, S., ... & Huang, S. M. (2021). 3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration. Clinical and translational science, 14(5), 1659-1680.Pan, S. Y., Zhou, S. F., Gao, S. H., Yu, Z. L., Zhang, S. F., Tang, M. K., ... & Ko, K. M. (2013). New perspectives on how to discover drugs from herbal medicines: CAM's outstanding contribution to modern therapeutics. Evidence-Based Complementary and Alternative Medicine, 2013.Tolikas, M., Antoniou, A., & Ingber, D. E. (2017). The Wyss institute: A new model for medical technology innovation and translation across the academic-industrial interface. Bioengineering & translational medicine, 2(3), 247-257.Mantilla-Orozco, A., Rodriguez, C. F., Quiroz, I., Bermudez, J. S., Forero, D. F., Monsalve, M. C., ... & Cruz, J. C. (2022, November). Modeling and Simulation of Magnetoliposome Formation by Encapsulation of Core-Shell, Magnetite-Chitosan Nanoparticles in Liposomes Enabled by a Low-Cost Microfluidic System. In Biology and Life Sciences Forum (Vol. 20, No. 1, p. 29). MDPI.Dalton, P. D., Woodfield, T. B., Mironov, V., & Groll, J. (2020). Advances in hybrid fabrication toward hierarchical tissue constructs. Advanced Science, 7(11), 1902953.Jung, J. P., Bhuiyan, D. B., & Ogle, B. M. (2016). Solid organ fabrication: comparison of decellularization to 3D bioprinting. Biomaterials research, 20, 1-11.Ravanbakhsh, H., Karamzadeh, V., Bao, G., Mongeau, L., Juncker, D., & Zhang, Y. S. (2021). Emerging technologies in multi-material bioprinting. Advanced Materials, 33(49), 2104730.Mironov, V., Visconti, R. P., Kasyanov, V., Forgacs, G., Drake, C. J., & Markwald, R. R. (2009). Organ printing: tissue spheroids as building blocks. Biomaterials, 30(12), 2164-2174.Bhattacharyya, A., Janarthanan, G., & Noh, I. (2021). Nano-biomaterials for designing functional bioinks towards complex tissue and organ regeneration in 3D bioprinting. Additive Manufacturing, 37, 101639.Ashammakhi, N., Ahadian, S., Xu, C., Montazerian, H., Ko, H., Nasiri, R., ... & Khademhosseini, A. (2019). Bioinks and bioprinting technologies to make heterogeneous and biomimetic tissue constructs. Materials Today Bio, 1, 100008.O'Brien, C. M., Holmes, B., Faucett, S., & Zhang, L. G. (2015). Three-dimensional printing of nanomaterial scaffolds for complex tissue regeneration. Tissue Engineering Part B: Reviews, 21(1), 103-114.Arjoca, S., Robu, A., Neagu, M., & Neagu, A. (2023). Mathematical and computational models in spheroid-based biofabrication. Acta Biomaterialia, 165, 125-139.Rodríguez, C. F., Castilla-Bolanos, M. A., Ortiz, L., Rodriguez, K. A. G., Osma, J. F., Camargo, C. M., & Cruz, J. C. (2022, November). Study of Spheroids Fusion via Multiphysics Simulations: Feasibility of Applying Permanent Magnetic Field Gradients. In Biology and Life Sciences Forum (Vol. 20, No. 1, p. 30). MDPI.Rodriguez, C. F., Ortiz, L., Muñoz, C., & Cruz, J. C. (2021, October). In silico study of spheroids fusion through magnetic field gradients. In 2021 IEEE 2nd International Congress of Biomedical Engineering and Bioengineering (CI-IB&BI) (pp. 1-9). IEEE.C. Multiphysics, "CFD Module User's Guide," COMSOL Multiphysics, p. 598, 2016, [Online]. Available: https://doc.comsol.com/5.3/doc/com.comsol.help.cfd/CFDModuleUsersGuide.pdf.C. Multiphysics, "ACD Module User's Guide," COMSOL Multiphysics, 2016.D. J. Bustamante et al., "Biofabrication of spheroids fusion-based tumor models: computational simulation of glucose effects," Biofabrication, vol. 13, no. 3, p. 35010, Apr. 2021, : 10.1088/1758-5090/abe025.A. C. Daly, M. D. Davidson, and J. A. Burdick, "3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels," Nat. Commun., no. 2021, pp. 1-13, : 10.1038/s41467-021-21029-2.P. A. Fleming, W. S. Argraves, C. Gentile, A. Neagu, G. Forgacs, and C. J. Drake, "Fusion of uniluminal vascular spheroids: a model for assembly of blood vessels.," Dev. Dyn. an Off. Publ. Am. Assoc. Anat., vol. 239, no. 2, pp. 398-406, Feb. 2010, : 10.1002/dvdy.22161.M. A. Gionet-Gonzales and J. K. Leach, "Engineering principles for guiding spheroid function in the regeneration of bone, cartilage, and skin.," Biomed. Mater., vol. 13, no. 3, p. 34109, Mar. 2018, : 10.1088/1748-605X/aab0b3.A. Tocchio et al., "Magnetically Guided Self-Assembly and Coding of 3D Living Architectures.," Adv. Mater., vol. 30, no. 4, Jan. 2018, : 10.1002/adma.201705034.Leung, C. M., De Haan, P., Ronaldson-Bouchard, K., Kim, G. A., Ko, J., Rho, H. S., ... & Toh, Y. C. (2022). A guide to the organ-on-a-chip. Nature Reviews Methods Primers, 2(1), 33.Antoni, D., Burckel, H., Josset, E., & Noel, G. (2015). Three-dimensional cell culture: a breakthrough in vivo. International journal of molecular sciences, 16(3), 5517-5527.Nath, S., & Devi, G. R. (2016). Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacology & therapeutics, 163, 94-108.Di Caprio, N., & Burdick, J. A. (2022). Engineered biomaterials to guide spheroid formation, function, and fabrication into 3D tissue constructs. Acta Biomaterialia.Kim, W., Gwon, Y., Park, S., Kim, H., & Kim, J. (2023). Therapeutic strategies of three-dimensional stem cell spheroids and organoids for tissue repair and regeneration. Bioactive Materials, 19, 50-74.Rizzo, G., Bertotti, A., Leto, S. M., & Vetrano, S. (2021). Patient-derived tumor models: a more suitable tool for pre-clinical studies in colorectal cancer. Journal of Experimental & Clinical Cancer Research, 40(1), 178.Malaney, P., Nicosia, S. V., & Davé, V. (2014). One mouse, one patient paradigm: New avatars of personalized cancer therapy. Cancer letters, 344(1), 1-12.Tevlek, A., Kecili, S., Ozcelik, O. S., Kulah, H., & Tekin, H. C. (2023). Spheroid engineering in microfluidic devices. Acs Omega, 8(4), 3630-3649.Fridman, I. B., Ugolini, G. S., VanDelinder, V., Cohen, S., & Konry, T. (2021). High throughput microfluidic system with multiple oxygen levels for the study of hypoxia in tumor spheroids. Biofabrication, 13(3), 035037.Vadivelu, R. K., Kamble, H., Shiddiky, M. J., & Nguyen, N. T. (2017). Microfluidic technology for the generation of cell spheroids and their applications. Micromachines, 8(4), 94.Damiati, S., Kompella, U. B., Damiati, S. A., & Kodzius, R. (2018). Microfluidic devices for drug delivery systems and drug screening. Genes, 9(2), 103.Bahrami, S., Baheiraei, N., Najafi-Ashtiani, M., Nour, S., & Razavi, M. (2021). Microfluidic devices in tissue engineering. In Biomedical Applications of Microfluidic Devices (pp. 209-233). Academic Press.Bolanos-Barbosa, A. D., Rodríguez, C. F., Acuña, O. L., Cruz, J. C., & Reyes, L. H. (2023). The Impact of Yeast Encapsulation in Wort Fermentation and Beer Flavor Profile. Polymers, 15(7), 1742.Rodríguez, C. F., & Cruz, J. C. (2023). Critique-Simulation Apps. Education for Chemical Engineers, 42, 88-89Jaramillo Mejía, V., Rodríguez Ospino, C. F., Cuestas Valenzuela, L. C., Rivas Bedoya, L. D., & Ramírez, L. (2021). VlacPort: monopuerto de bajo costo para la cirugía laparoscópica de única incisión.Fuentes Melo, L. F. (2022). 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