{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T11:20:32Z","timestamp":1777029632457,"version":"3.51.4"},"reference-count":22,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,18]],"date-time":"2020-04-18T00:00:00Z","timestamp":1587168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Polymers"],"abstract":"<jats:p>The use of digital twins in tissue engineering (TE) applications is of paramount importance to reduce the number of in vitro and in vivo tests. To pursue this aim, a novel multimodal bioreactor is developed, combining 3D design with numerical stimulation. This approach will facilitate the reproducibility between studies and the platforms optimisation (physical and digital) to enhance TE. The new bioreactor was specifically designed to be additive manufactured, which could not be reproduced with conventional techniques. Specifically, the design suggested allows the application of dual stimulation (electrical and mechanical) of a scaffold cell culture. For the selection of the most appropriate material for bioreactor manufacturing several materials were assessed for their cytotoxicity. Numerical modelling methods were then applied to the new bioreactor using one of the most appropriate material (Polyethylene Terephthalate Glycol-modified (PETG)) to find the optimal stimulation input parameters for bone TE based on two reported in vitro studies.<\/jats:p>","DOI":"10.3390\/polym12040940","type":"journal-article","created":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T05:48:52Z","timestamp":1587448132000},"page":"940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["A Multimodal Stimulation Cell Culture Bioreactor for Tissue Engineering: A Numerical Modelling Approach"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6920-7152","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Meneses","sequence":"first","affiliation":[{"name":"Centre for Rapid and Sustainable Product Development (CDRSP-IPLeiria), 2430-028 Marinha Grande, Portugal"},{"name":"Instituto de Biof\u00edsica e Engenharia Biom\u00e9dica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4773-6771","authenticated-orcid":false,"given":"Jo\u00e3o","family":"C. Silva","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0576-8364","authenticated-orcid":false,"given":"Sofia","family":"R. Fernandes","sequence":"additional","affiliation":[{"name":"Centre for Rapid and Sustainable Product Development (CDRSP-IPLeiria), 2430-028 Marinha Grande, Portugal"},{"name":"Instituto de Biof\u00edsica e Engenharia Biom\u00e9dica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]},{"given":"Abhishek","family":"Datta","sequence":"additional","affiliation":[{"name":"Soterix Medical, Inc., New York, NY 10001, USA"},{"name":"Department of Biomedical Engineering, City College of New York, New York, NY 10031, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5177-6237","authenticated-orcid":false,"given":"Frederico","family":"Castelo Ferreira","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2610-1005","authenticated-orcid":false,"given":"Carla","family":"Moura","sequence":"additional","affiliation":[{"name":"Centre for Rapid and Sustainable Product Development (CDRSP-IPLeiria), 2430-028 Marinha Grande, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8356-4810","authenticated-orcid":false,"given":"Sandra","family":"Amado","sequence":"additional","affiliation":[{"name":"Centre for Rapid and Sustainable Product Development (CDRSP-IPLeiria), 2430-028 Marinha Grande, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5016-0868","authenticated-orcid":false,"given":"Nuno","family":"Alves","sequence":"additional","affiliation":[{"name":"Centre for Rapid and Sustainable Product Development (CDRSP-IPLeiria), 2430-028 Marinha Grande, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1474-9496","authenticated-orcid":false,"given":"Paula","family":"Pascoal-Faria","sequence":"additional","affiliation":[{"name":"Centre for Rapid and Sustainable Product Development (CDRSP-IPLeiria), 2430-028 Marinha Grande, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/apj.1800","article-title":"Mass transfer aspects of 3D cell cultures in tissue engineering","volume":"9","author":"Mekala","year":"2014","journal-title":"Asia-Pac. J. Chem. Eng."},{"key":"ref_2","first-page":"185","article-title":"Design and Assessment of a Dynamic Perfusion Bioreactor for Large Bone Tissue Engineering Scaffolds","volume":"2","author":"Bhaskar","year":"2018","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.biomaterials.2017.10.003","article-title":"Unraveling the mechanistic effects of electric field stimulation towards directing stem cell fate and function: A tissue engineering perspective","volume":"150","author":"Thrivikraman","year":"2018","journal-title":"Biomaterials"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.jcot.2019.12.002","article-title":"3D printing applications in bone tissue engineering","volume":"11","author":"Haleem","year":"2020","journal-title":"J. Clin. Orthop. Trauma"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Dhinakaran, V., Kumar, K.P.M., Ram, P.M.B., Ravichandran, M., and Vinayagamoorthy, M. (2020). A review on recent advancements in fused deposition modeling. Mater. Today Proc., in press.","DOI":"10.1016\/j.matpr.2019.12.036"},{"key":"ref_6","first-page":"243","article-title":"Integration of Technologies for Bone Tissue Engineering","volume":"1","author":"Golebiowska","year":"2019","journal-title":"Encycl. Tissue Eng. Regen. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Selden, C., and Fuller, B. (2018). Role of Bioreactor Technology in Tissue Engineering for Clinical Use and Therapeutic Target Design. Bioengineering, 5.","DOI":"10.3390\/bioengineering5020032"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1080\/0951192X.2013.812244","article-title":"Computer modelling and simulation of a bioreactor for tissue engineering","volume":"27","author":"Pereira","year":"2014","journal-title":"Int. J. Comput. Integr. Manuf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jbiomech.2018.08.004","article-title":"Flow rates in perfusion bioreactors to maximise mineralisation in bone tissue engineering in vitro","volume":"79","author":"Zhao","year":"2018","journal-title":"J. Biomech."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2144\/000114382","article-title":"Direct current electrical stimulation chamber for treating cells in vitro","volume":"60","author":"Mobini","year":"2016","journal-title":"BioTechniques"},{"key":"ref_11","unstructured":"Meneses, J., Alves, N., Moura, C., Datta, A., Ferreira, F., Amado, S., and Pascoal-Faria, P. (2019, January 23\u201328). Electrical Stimulation of Bioscaolds for Tissue Engineering: A Numerical Analysis. Proceedings of the ICNAAM 2019\u201417th International Conference of Numerical Analysis and Applied Mathematics, Rhodes, Greece."},{"key":"ref_12","unstructured":"International Organization for Standardization (2009). Biological Evaluation of Medical Devices\u2014Part:5 Tests for Citotoxicity (ISO EN 10993-5) and Part 12: SamplePreparation and Reference Materials (ISO EN 10993-12), International Organization for Standardization."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16944","DOI":"10.1038\/s41598-018-35019-w","article-title":"Enhancing all-in-one bioreactors by combining interstitial perfusion, electrical stimulation, on-line monitoring and testing within a single chamber for cardiac constructs","volume":"8","author":"Visone","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_14","unstructured":"(2020, April 04). Online Database of Engineering Materials Information Resource. Available online: http:www.matweb.com."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.eng.2018.09.013","article-title":"Laminar-to-Turbulence Transition Revealed Through a Reynolds Number Equivalence","volume":"5","author":"Chen","year":"2019","journal-title":"Engineering"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/BF02476917","article-title":"Considerations of Quasi-Stationarity in Electrophysiological Systems","volume":"29","author":"Plonsey","year":"1967","journal-title":"Bull. Math. Biophys."},{"key":"ref_17","unstructured":"Lorrain, P., Corson, D.R., and Lorrain, F. (2000). Fundamentals of Electromagnetic Phenomena, W.H. Freeman and Company."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14867","DOI":"10.1016\/j.ijhydene.2018.06.080","article-title":"Low voltage water electrolysis: Decoupling hydrogen production using bioelectrochemical system","volume":"43","author":"Belleville","year":"2018","journal-title":"Int. J. Hydrogen Energy"},{"key":"ref_19","first-page":"255","article-title":"In Vitro Bone-Cell Response to a Capacitively Coupled Electrical Field","volume":"III","author":"Brighton","year":"1991","journal-title":"Basic Sci. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Titushkin, I.A., and Cho, M.R. (2009, January 3\u20136). Controlling Cellular Biomechanics of Human Mesenchymal Stem Cells. Proceedings of the 2009 Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Minneapolis, MN, USA.","DOI":"10.1109\/IEMBS.2009.5333949"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1089\/ten.tea.2008.0554","article-title":"Novel Effect of Biphasic Electric Current on In Vitro Osteogenesis and Cytokine Production in Human Mesenchymal Stromal Cells","volume":"15","author":"Kim","year":"2009","journal-title":"Tissue Eng. Part A"},{"key":"ref_22","first-page":"e59127","article-title":"Construction and Use of an Electrical Stimulation Chamber for Enhancing Osteogenic Differentiation in Mesenchymal Stem\/Stromal Cells In Vitro","volume":"143","author":"Leppik","year":"2019","journal-title":"JoVE"}],"container-title":["Polymers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4360\/12\/4\/940\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:09:00Z","timestamp":1760364540000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4360\/12\/4\/940"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,18]]},"references-count":22,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["polym12040940"],"URL":"https:\/\/doi.org\/10.3390\/polym12040940","relation":{},"ISSN":["2073-4360"],"issn-type":[{"value":"2073-4360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,18]]}}}