Half‐Pipe Melt Electrowritten Scaffolds Support Engineering of an Immunocompetent Hydrogel‐Embedded Intestine‐on‐a‐Chip

Robine Janssen; Henrike S. Schulze; Claire M. L. Nelissen; Marta G. Valverde; Andrei Hrynevich; Govardus A. H. de Jong; Anne Metje van Genderen; Jos Malda; Shanna Bastiaan‐Net; Linette E. M. Willemsen; Rosalinde Masereeuw

doi:10.1002/advs.202507132

Half‐Pipe Melt Electrowritten Scaffolds Support Engineering of an Immunocompetent Hydrogel‐Embedded Intestine‐on‐a‐Chip

Robine Janssen
, Henrike S. Schulze
, Claire M. L. Nelissen
, Marta G. Valverde
, Andrei Hrynevich
, Govardus A. H. de Jong
, Anne Metje van Genderen
, Jos Malda
, Shanna Bastiaan‐Net
, Linette E. M. Willemsen
, Rosalinde Masereeuw^*

^*Corresponding author for this work

Utrecht University
Wageningen Food & Biobased Research Wageningen University & Research Wageningen 6708 WG The Netherlands

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

In vitro models that mimic intestinal mucosal tissue inflammation and assess the sensitizing capacity of food proteins are essential for understanding food allergy mechanisms and improving safety assessments. Current 2D models lack spatial epithelial-immune cell interactions, including dendritic cell (DC) migration and DC–T cell crosstalk. Intestine-on-a-chip (IoC) models are used for infections and inflammatory bowel disease (IBD) but are not yet widely used in food allergy research. Here, a 3D immunocompetent IoC model is presented using extrusion-based bioprinting and melt electrowriting (MEW). The system integrates human intestinal epithelial cells (Caco-2) seeded on half-pipe-shaped MEW scaffolds and co-cultured with hydrogel-embedded monocyte-derived DCs (moDCs) inside the printed device. Subsequent moDC–T cell interactions are studied separately in a hydrogel-embedded system. IoCs exhibited leak-tight epithelial barriers comparable to transwell-like systems, while demonstrating higher metabolic and brush border enzyme activity, and lower LDH leakage. After food allergens (peanut, milk, and egg), non-allergen (Rubisco) or pro-inflammatory stimuli (toxin A and LPS) exposure, distinguishable effects on epithelial barrier integrity and moDC driven Th1/Th2 immune responses are observed. The IoC model presents a significant step toward 3D in vitro systems that mimic the intestinal mucosa's compartments to study food allergen sensitization and inflammatory diseases.

Original language	English
Article number	e07132
Pages (from-to)	e07132
Number of pages	16
Journal	Advanced Science
Volume	12
Issue number	37
Early online date	10 Jul 2025
DOIs	https://doi.org/10.1002/advs.202507132
Publication status	Published - 6 Oct 2025

Bibliographical note

Publisher Copyright:
© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

Funding

The authors would like to thank the knowledge partners in the PREFER consortium (Wageningen UR dep. Wageningen Food & Biobased Research, Erasmus MC dep. Allergology and clinical immunology, and Utrecht University dep. Experimental Pharmacology) for their substantive scientific contribution and for having made this project possible. The authors also acknowledge the Dutch funding program: This project receives financial support from the Top Sector Agri & Food. Within the Top Sector, the business community, knowledge institutions, and the government work together on innovations for safe and healthy food for 9 billion people in a resilient world. The authors would like to thank K. Westphal (Department of Pharmaceutical Sciences, Pharmacology (UIPS), The Netherlands) for the confocal training, C.T.W.M. Schneijdenberg (Utrecht Electron Microscopy Center, The Netherlands) for the training provided for scanning electron microscopy imaging and Y. Li (Department of Orthopaedics, University Medical Center Utrecht, Utrecht University, The Netherlands) for the support in IoC device printing. The authors would also like to thank J. Visser (Department of Pharmaceutical Sciences, Pharmacology (UIPS), The Netherlands) for his contribution to supplementary experimental work, M.M.M. Tomassen (Wageningen UR dep. Wageningen Food & Biobased Research, The Netherlands) for her contribution to LPS measurements, and H. Wichers (Wageningen UR dep. Wageningen Food & Biobased Research, The Netherlands) and J. Garssen (Department of Pharmaceutical Sciences, Pharmacology, Utrecht University, The Netherlands) for their contribution in securing funding. This work was funded by the Dutch Ministry of Economic Affairs program TKI-AF under grant agreement LWV200123: PRedictive model For thE sensitising capacity of novel nutritional pRoteins (PREFER study), and industrial partners Nutricia Research B.V., Cargill R&D Centre Europe, Arla Foods Ingredients Group P/S, Societe des Produits Nestle S.A., Phycom BV, The Seaweed Company B.V., and Mycorena AB, the Dutch Research Council (NWO) Gravitation Program (Materials Driven Regeneration (024.003.013)), and by Utrecht Institute for Pharmaceutical Sciences. The views expressed in this manuscript are those of the authors and do not necessarily reflect the position or policy of the collaborators.

Funders	Funder number
Dutch Ministry of Economic Affairs program TKI-AF under grant agreement
Wageningen Food & Biobased Research, Erasmus MC
Allergology and clinical immunology, and Utrecht University
Top Sector Agri Food
Wageningen Food & Biobased Research	LWV200123
Wageningen Food & Biobased Research, The Netherlands) - Dutch Ministry of Economic Affairs program TKI-AF
Nutricia Research B.V., Cargill R&D Centre Europe, Arla Foods Ingredients Group P/S
Seaweed Company B.V.
Mycorena AB	024.003.013
Dutch Research Council (NWO) Gravitation Program (Materials Driven Regeneration)
Utrecht Institute for Pharmaceutical Sciences

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

3D printing
biofabrication
food allergies
immunocompetent intestine-on-a-chip
in vitro models

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Advanced Science - 2025 - Janssen - Half‐Pipe Melt Electrowritten Scaffolds Support Engineering of an ImmunocompetentFinal published version, 7.94 MBLicence: CC BY

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Janssen, R., Schulze, H. S., Nelissen, C. M. L., Valverde, M. G., Hrynevich, A., de Jong, G. A. H., van Genderen, A. M., Malda, J., Bastiaan‐Net, S., Willemsen, L. E. M., & Masereeuw, R. (2025). Half‐Pipe Melt Electrowritten Scaffolds Support Engineering of an Immunocompetent Hydrogel‐Embedded Intestine‐on‐a‐Chip. Advanced Science, 12(37), e07132. Article e07132. https://doi.org/10.1002/advs.202507132

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abstract = "In vitro models that mimic intestinal mucosal tissue inflammation and assess the sensitizing capacity of food proteins are essential for understanding food allergy mechanisms and improving safety assessments. Current 2D models lack spatial epithelial-immune cell interactions, including dendritic cell (DC) migration and DC{\textendash}T cell crosstalk. Intestine-on-a-chip (IoC) models are used for infections and inflammatory bowel disease (IBD) but are not yet widely used in food allergy research. Here, a 3D immunocompetent IoC model is presented using extrusion-based bioprinting and melt electrowriting (MEW). The system integrates human intestinal epithelial cells (Caco-2) seeded on half-pipe-shaped MEW scaffolds and co-cultured with hydrogel-embedded monocyte-derived DCs (moDCs) inside the printed device. Subsequent moDC{\textendash}T cell interactions are studied separately in a hydrogel-embedded system. IoCs exhibited leak-tight epithelial barriers comparable to transwell-like systems, while demonstrating higher metabolic and brush border enzyme activity, and lower LDH leakage. After food allergens (peanut, milk, and egg), non-allergen (Rubisco) or pro-inflammatory stimuli (toxin A and LPS) exposure, distinguishable effects on epithelial barrier integrity and moDC driven Th1/Th2 immune responses are observed. The IoC model presents a significant step toward 3D in vitro systems that mimic the intestinal mucosa's compartments to study food allergen sensitization and inflammatory diseases.",

keywords = "3D printing, biofabrication, food allergies, immunocompetent intestine-on-a-chip, in vitro models",

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Janssen, R, Schulze, HS, Nelissen, CML, Valverde, MG, Hrynevich, A, de Jong, GAH, van Genderen, AM , Malda, J, Bastiaan‐Net, S, Willemsen, LEM & Masereeuw, R 2025, 'Half‐Pipe Melt Electrowritten Scaffolds Support Engineering of an Immunocompetent Hydrogel‐Embedded Intestine‐on‐a‐Chip', Advanced Science, vol. 12, no. 37, e07132, pp. e07132. https://doi.org/10.1002/advs.202507132

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AU - Janssen, Robine

AU - Schulze, Henrike S.

AU - Nelissen, Claire M. L.

AU - Valverde, Marta G.

AU - Hrynevich, Andrei

AU - de Jong, Govardus A. H.

AU - van Genderen, Anne Metje

AU - Malda, Jos

AU - Bastiaan‐Net, Shanna

AU - Willemsen, Linette E. M.

AU - Masereeuw, Rosalinde

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N2 - In vitro models that mimic intestinal mucosal tissue inflammation and assess the sensitizing capacity of food proteins are essential for understanding food allergy mechanisms and improving safety assessments. Current 2D models lack spatial epithelial-immune cell interactions, including dendritic cell (DC) migration and DC–T cell crosstalk. Intestine-on-a-chip (IoC) models are used for infections and inflammatory bowel disease (IBD) but are not yet widely used in food allergy research. Here, a 3D immunocompetent IoC model is presented using extrusion-based bioprinting and melt electrowriting (MEW). The system integrates human intestinal epithelial cells (Caco-2) seeded on half-pipe-shaped MEW scaffolds and co-cultured with hydrogel-embedded monocyte-derived DCs (moDCs) inside the printed device. Subsequent moDC–T cell interactions are studied separately in a hydrogel-embedded system. IoCs exhibited leak-tight epithelial barriers comparable to transwell-like systems, while demonstrating higher metabolic and brush border enzyme activity, and lower LDH leakage. After food allergens (peanut, milk, and egg), non-allergen (Rubisco) or pro-inflammatory stimuli (toxin A and LPS) exposure, distinguishable effects on epithelial barrier integrity and moDC driven Th1/Th2 immune responses are observed. The IoC model presents a significant step toward 3D in vitro systems that mimic the intestinal mucosa's compartments to study food allergen sensitization and inflammatory diseases.

AB - In vitro models that mimic intestinal mucosal tissue inflammation and assess the sensitizing capacity of food proteins are essential for understanding food allergy mechanisms and improving safety assessments. Current 2D models lack spatial epithelial-immune cell interactions, including dendritic cell (DC) migration and DC–T cell crosstalk. Intestine-on-a-chip (IoC) models are used for infections and inflammatory bowel disease (IBD) but are not yet widely used in food allergy research. Here, a 3D immunocompetent IoC model is presented using extrusion-based bioprinting and melt electrowriting (MEW). The system integrates human intestinal epithelial cells (Caco-2) seeded on half-pipe-shaped MEW scaffolds and co-cultured with hydrogel-embedded monocyte-derived DCs (moDCs) inside the printed device. Subsequent moDC–T cell interactions are studied separately in a hydrogel-embedded system. IoCs exhibited leak-tight epithelial barriers comparable to transwell-like systems, while demonstrating higher metabolic and brush border enzyme activity, and lower LDH leakage. After food allergens (peanut, milk, and egg), non-allergen (Rubisco) or pro-inflammatory stimuli (toxin A and LPS) exposure, distinguishable effects on epithelial barrier integrity and moDC driven Th1/Th2 immune responses are observed. The IoC model presents a significant step toward 3D in vitro systems that mimic the intestinal mucosa's compartments to study food allergen sensitization and inflammatory diseases.

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KW - biofabrication

KW - food allergies

KW - immunocompetent intestine-on-a-chip

KW - in vitro models

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DO - 10.1002/advs.202507132

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JO - Advanced Science

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ER -

Half‐Pipe Melt Electrowritten Scaffolds Support Engineering of an Immunocompetent Hydrogel‐Embedded Intestine‐on‐a‐Chip

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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