Engineering Mesoscopic 3D Tumor Models with a Self‐Organizing Vascularized Matrix

Advanced Materials, vol. 36, pp. e2303196

Abstract

Advanced in vitro systems such as multicellular spheroids and lab-on-a-chip devices have been developed, but often fall short in reproducing the tissue scale and self-organization of human diseases. A bioprinted artificial tumor model is introduced with endothelial and stromal cells self-organizing into perfusable and functional vascular structures. This model uses 3D hydrogel matrices to embed multicellular tumor spheroids, allowing them to grow to mesoscopic scales and to interact with endothelial cells. It is shown that angiogenic multicellular tumor spheroids promote the growth of a vascular network, which in turn further enhances the growth of cocultivated tumor spheroids. The self-developed vascular structure infiltrates the tumor spheroids, forms functional connections with the bioprinted endothelium, and can be perfused by erythrocytes and polystyrene microspheres. Moreover, cancer cells migrate spontaneously from the tumor spheroid through the self-assembled vascular network into the fluid flow. Additionally, tumor type specific characteristics of desmoplasia, angiogenesis, and metastatic propensity are preserved between patient-derived samples and tumors derived from this same material growing in the bioreactors. Overall, this modular approach opens up new avenues for studying tumor pathophysiology and cellular interactions in vitro, providing a platform for advanced drug testing while reducing the need for in vivo experimentation.

Authors 18

1. Federica De Lorenzi Aachen Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

   Mildred Scheel School of Oncology (MSSO) Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO^ABCD) RWTH Aachen University Hospital 52074 Aachen Germany

   Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

   Mildred Scheel School of Oncology (MSSO) Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD) RWTH Aachen University Hospital 52074 Aachen Germany

2. Nadja Hansen Aachen Department of Dental Materials and Biomaterials Research

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Dental Materials and Biomaterials Research (ZWBF) RWTH Aachen University Hospital 52074 Aachen Germany

   Department of Dental Materials and Biomaterials Research (ZWBF) RWTH Aachen University Hospital 52074 Aachen Germany

3. Benjamin Theek Aachen Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

   Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

4. Rasika Daware Aachen Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

   Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

5. Alessandro Motta Aachen Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

   Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

6. Saskia Breuel Aachen Department of Gynecology and Obstetrics

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Gynecology and Obstetrics RWTH Aachen University Hospital 52074 Aachen Germany

   Department of Gynecology and Obstetrics RWTH Aachen University Hospital 52074 Aachen Germany

7. Ramin Nasehi Aachen Department of Dental Materials and Biomaterials Research

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Dental Materials and Biomaterials Research (ZWBF) RWTH Aachen University Hospital 52074 Aachen Germany

   Department of Dental Materials and Biomaterials Research (ZWBF) RWTH Aachen University Hospital 52074 Aachen Germany

8. Julian Baumeister Aachen Department of Hematology Oncology Hemostaseology and Stem Cell Transplantation

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Hematology Oncology Hemostaseology and Stem Cell Transplantation RWTH Aachen University Hospital 52074 Aachen Germany

   Mildred Scheel School of Oncology (MSSO) Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO^ABCD) RWTH Aachen University Hospital 52074 Aachen Germany

   Mildred Scheel School of Oncology (MSSO) Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD) RWTH Aachen University Hospital 52074 Aachen Germany

9. Jan Schöneberg Aachen Department of Dental Materials and Biomaterials Research

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Dental Materials and Biomaterials Research (ZWBF) RWTH Aachen University Hospital 52074 Aachen Germany

   Department of Dental Materials and Biomaterials Research (ZWBF) RWTH Aachen University Hospital 52074 Aachen Germany

10. Natalija M. Stojanovic Aachen Department of Dental Materials and Biomaterials Research

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Dental Materials and Biomaterials Research (ZWBF) RWTH Aachen University Hospital 52074 Aachen Germany

    Department of Dental Materials and Biomaterials Research (ZWBF) RWTH Aachen University Hospital 52074 Aachen Germany

11. Saskia Freifrau von Stillfried Aachen Institute of Pathology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute of Pathology RWTH Aachen University Hospital 52074 Aachen Germany

    Institute of Pathology RWTH Aachen University Hospital 52074 Aachen Germany

12. Michael Vogt Aachen Interdisciplinary Center for Clinical Research (IZKF)

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Interdisciplinary Center for Clinical Research (IZKF) RWTH Aachen University Hospital 52074 Aachen Germany

    Interdisciplinary Center for Clinical Research (IZKF) RWTH Aachen University Hospital 52074 Aachen Germany

13. Gerhard Müller‐Newen Aachen Institute of Biochemistry and Molecular Biology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute of Biochemistry and Molecular Biology RWTH Aachen University Hospital 52074 Aachen Germany

    Institute of Biochemistry and Molecular Biology RWTH Aachen University Hospital 52074 Aachen Germany

14. Jochen Maurer Aachen Department of Gynecology and Obstetrics

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Gynecology and Obstetrics RWTH Aachen University Hospital 52074 Aachen Germany

    Department of Gynecology and Obstetrics RWTH Aachen University Hospital 52074 Aachen Germany

15. Alexandros Marios Sofias Aachen Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging

    Norwegian University of Science and Technology · Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

    Mildred Scheel School of Oncology (MSSO) Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO^ABCD) RWTH Aachen University Hospital 52074 Aachen Germany

    Norwegian University of Science and Technology (NTNU) Department of Circulation and Medical Imaging Faculty of Medicine and Health Sciences Trondheim 7491 Norway

    Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

    Mildred Scheel School of Oncology (MSSO) Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD) RWTH Aachen University Hospital 52074 Aachen Germany

16. Twan Lammers corresponding Aachen Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

    Mildred Scheel School of Oncology (MSSO) Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO^ABCD) RWTH Aachen University Hospital 52074 Aachen Germany

    Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

    Mildred Scheel School of Oncology (MSSO) Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD) RWTH Aachen University Hospital 52074 Aachen Germany

17. Horst Fischer corresponding Aachen Department of Dental Materials and Biomaterials Research

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Dental Materials and Biomaterials Research (ZWBF) RWTH Aachen University Hospital 52074 Aachen Germany

    Department of Dental Materials and Biomaterials Research (ZWBF) RWTH Aachen University Hospital 52074 Aachen Germany

18. Fabian M. Kiessling corresponding Aachen Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · Fraunhofer Institute for Digital Medicine · RWTH Aachen University

    Affiliation as printed

    Fraunhofer Institute for Digital Medicine MEVIS 28359 Bremen Germany

    Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany

    Fraunhofer Institute for Digital Medicine MEVIS 28359 Bremen Germany

    Institute for Experimental Molecular Imaging (ExMI) RWTH Aachen University Hospital 52074 Aachen Germany