Functional Human Vascular Network Generated in Photocrosslinkable Gelatin Methacrylate Hydrogels

Authors

  • Ying-Chieh Chen,

    1. Department of Medicine, Center for Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
    2. Wyss Institute for Biologically Inspired Engineering, Harvard Medical School, Boston, MA 02155, USA
    3. Department of Applied Science, National Hsinchu University of Education, Hsinchu 300, Taiwan
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  • Ruei-Zeng Lin,

    1. Department of Cardiac Surgery, Children's Hospital Boston, Boston, MA 02115, USA
    2. Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
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  • Hao Qi,

    1. Department of Medicine, Center for Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
    2. Wyss Institute for Biologically Inspired Engineering, Harvard Medical School, Boston, MA 02155, USA
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  • Yunzhi Yang,

    1. Department of Orthopedic Surgery, Stanford University, 300 Pasteur Drive, Edwards, R155, Stanford, CA 94305, USA
    2. Houston Biomaterials Research Center, Department of Restorative Dentistry and Biomaterials, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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  • Hojae Bae,

    1. Department of Medicine, Center for Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
    2. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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  • Juan M. Melero-Martin,

    Corresponding author
    1. Department of Cardiac Surgery, Children's Hospital Boston, Boston, MA 02115, USA
    2. Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
    • Department of Cardiac Surgery, Children's Hospital Boston, Boston, MA 02115, USA.
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  • Ali Khademhosseini

    Corresponding author
    1. Department of Medicine, Center for Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
    2. Wyss Institute for Biologically Inspired Engineering, Harvard Medical School, Boston, MA 02155, USA
    3. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    • Department of Medicine, Center for Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Abstract

The generation of functional, 3D vascular networks is a fundamental prerequisite for the development of many future tissue engineering-based therapies. Current approaches in vascular network bioengineering are largely carried out using natural hydrogels as embedding scaffolds. However, most natural hydrogels present a poor mechanical stability and a suboptimal durability, which are critical limitations that hamper their widespread applicability. The search for improved hydrogels has become a priority in tissue engineering research. Here, the suitability of a photopolymerizable gelatin methacrylate (GelMA) hydrogel to support human progenitor cell-based formation of vascular networks is demonstrated. Using GelMA as the embedding scaffold, it is shown that 3D constructs containing human blood-derived endothelial colony-forming cells (ECFCs) and bone marrow-derived mesenchymal stem cells (MSCs) generate extensive capillary-like networks in vitro. These vascular structures contain distinct lumens that are formed by the fusion of ECFC intracellular vacuoles in a process of vascular morphogenesis. The process of vascular network formation is dependent on the presence of MSCs, which differentiate into perivascular cells occupying abluminal positions within the network. Importantly, it is shown that implantation of cell-laden GelMA hydrogels into immunodeficient mice results in a rapid formation of functional anastomoses between the bioengineered human vascular network and the mouse vasculature. Furthermore, it is shown that the degree of methacrylation of the GelMA can be used to modulate the cellular behavior and the extent of vascular network formation both in vitro and in vivo. These data suggest that GelMA hydrogels can be used for biomedical applications that require the formation of microvascular networks, including the development of complex engineered tissues.

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