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However, most traditional 2D in vitro models yield HLCs with unpaired hepatic functions, hampering HLCs\u2019 adoption in the non\u2010clinical drug development process. Here, we design a novel hepatic perfused microphysiological system (HLC\u2010chip) that upon the optimization of the cell chamber architecture, cell inoculation strategy, and surface coating shows to improve the maturity of human HLCs derived from mesenchymal stem cell (MSC). The HLC\u2010chip is microfabricated by photolithography and soft lithography techniques, based on polydimethylsiloxane (PDMS) molding. In particular, the optimized square\u2010shaped HLC\u2010chip design with seven inlets sealed against a collagen\u2010coated polystyrene surface enables the homogeneous distribution of HLCs displaying the typical hepatic morphology. Additionally, HLCs can be maintained in the HLC\u2010chip up to 10\u00a0days under perfusion, being positive for the hepatic markers HNF\u20104a, CK\u201018, OATP\u2010C, and MRP2, while presenting increased ammonia detoxification ability. Likewise, upon GC\u2010MS analysis, the 11.96\u2010 and 6.85\u2010fold augment of diclofenac glucuronidation products in the HLC\u2010chip and 2D cultures, respectively, demonstrate the enhanced biotransformation competence of cells. This study supports the generation of high\u2010quality data from complex in vitro HLC systems and its usefulness for drug metabolism and toxicology studies.<\/jats:p>","DOI":"10.1002\/biot.70037","type":"journal-article","created":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T14:38:44Z","timestamp":1750603124000},"source":"Crossref","is-referenced-by-count":0,"title":["Enhancing the Maturity and Diclofenac Metabolism Ability of Mesenchymal Stem Cell\u2010Derived Human Hepatocytes In Vitro Using Microfluidics Technology"],"prefix":"10.1002","volume":"20","author":[{"given":"Joana Saraiva","family":"Rodrigues","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (imed) Faculty of Pharmacy Universidade de Lisboa  Lisbon Portugal"}]},{"given":"Sofia","family":"Relvas","sequence":"additional","affiliation":[{"name":"Instituto de Engenharia de Sistemas e Computadores \u2013 Microsistemas e Nanotecnologias (INESC MN)  Lisbon Portugal"}]},{"given":"Pedro Monteiro","family":"Condelipes","sequence":"additional","affiliation":[{"name":"Instituto de Engenharia de Sistemas e Computadores \u2013 Microsistemas e Nanotecnologias (INESC MN)  Lisbon Portugal"}]},{"given":"B\u00e1rbara","family":"Silva","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB \u2013 Institute for Health and Bioeconomy Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"},{"name":"UCIBIO Laborat\u00f3rio de Toxicologia Departamento de Ci\u00eancias Biol\u00f3gicas Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"}]},{"given":"Raquel","family":"Bozzo","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (imed) Faculty of Pharmacy Universidade de Lisboa  Lisbon Portugal"}]},{"given":"Paula Guedes","family":"de Pinho","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB \u2013 Institute for Health and Bioeconomy Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"},{"name":"UCIBIO Laborat\u00f3rio de Toxicologia Departamento de Ci\u00eancias Biol\u00f3gicas Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"}]},{"given":"Virginia","family":"Chu","sequence":"additional","affiliation":[{"name":"Instituto de Engenharia de Sistemas e Computadores \u2013 Microsistemas e Nanotecnologias (INESC MN)  Lisbon Portugal"}]},{"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB \u2013 Institute for Health and Bioeconomy Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"},{"name":"UCIBIO Laborat\u00f3rio de Toxicologia Departamento de Ci\u00eancias Biol\u00f3gicas Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"}]},{"given":"Jo\u00e3o Pedro","family":"Conde","sequence":"additional","affiliation":[{"name":"Instituto de Engenharia de Sistemas e Computadores \u2013 Microsistemas e Nanotecnologias (INESC MN)  Lisbon Portugal"},{"name":"Department of Bioengineering Instituto Superior T\u00e9cnico Universidade de Lisboa  Lisbon Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7804-4068","authenticated-orcid":false,"given":"Joana Paiva","family":"Miranda","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (imed) Faculty of Pharmacy Universidade de Lisboa  Lisbon Portugal"}]}],"member":"311","published-online":{"date-parts":[[2025,6,22]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.626805"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-016-1901-x"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-016-1838-0"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21113998"},{"key":"e_1_2_11_6_1","first-page":"1","article-title":"Improving Human Mesenchymal Stem Cell\u2010Derived Hepatic Cell Energy Metabolism by Manipulating Glucose Homeostasis and Glucocorticoid Signaling","volume":"13","author":"Rodrigues J. 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