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Towards 3D-Bioprinting of an Endocrine Pancreas: A Building-Block Concept for Bioartificial Insulin-Secreting Tissue

View ORCID ProfileGabriel Alexander Salg, View ORCID ProfileEric Poisel, View ORCID ProfileMatthias Neulinger Munoz, Daniel Cebulla, Vitor Vieira, Catrin Bludszuweit-Philipp, View ORCID ProfileFelix Nickel, Ingrid Herr, Nathalia A. Giese, View ORCID ProfileThilo Hackert, View ORCID ProfileHannes Goetz Kenngott
doi: https://doi.org/10.1101/2021.02.27.433164
Gabriel Alexander Salg
1University Hospital Heidelberg, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
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  • ORCID record for Gabriel Alexander Salg
Eric Poisel
1University Hospital Heidelberg, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
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Matthias Neulinger Munoz
1University Hospital Heidelberg, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
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Daniel Cebulla
2ASD Advanced Simulation and Design GmbH, Erich-Schlesinger-Strasse 50, 18059 Rostock, Germany
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Vitor Vieira
3INOVA DE GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany
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Catrin Bludszuweit-Philipp
2ASD Advanced Simulation and Design GmbH, Erich-Schlesinger-Strasse 50, 18059 Rostock, Germany
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Felix Nickel
1University Hospital Heidelberg, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
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Ingrid Herr
1University Hospital Heidelberg, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
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Nathalia A. Giese
1University Hospital Heidelberg, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
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Thilo Hackert
1University Hospital Heidelberg, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
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Hannes Goetz Kenngott
1University Hospital Heidelberg, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
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  • For correspondence: gabriel.salg@med.uni-heidelberg.de hannes.kenngott@med.uni-heidelberg.de
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Abstract

Background & Aims 3D-Bioprinting of an endocrine pancreas is a promising future curative treatment for selected patients with insulin secretion deficiency. In this study we present an end-to-end integrative, scalable concept extending from the molecular to the macroscopic level.

Methods A hybrid scaffold device was manufactured by 3D-(bio)printing. INS-1 cells with/without endothelial cells were bioprinted in gelatin methacrylate blend hydrogel. Polycaprolactone was 3D-printed and heparin-functionalized as structural scaffold component. In vitro evaluation was performed by viability and growth assays, total mRNA sequencing, and glucose-stimulated insulin secretion. In vivo, xenotransplantation to fertilized chicken eggs was used to investigate vascularization and function, and finite element analysis modeling served to detect boundary conditions and applicability for human islets of Langerhans.

Results Insulin-secreting pseudoislets were formed and resulted in a viable and proliferative experimental model. Transcriptomics revealed upregulation of proliferative and β-cell-specific signaling cascades, downregulation of apoptotic pathways, and overexpression of extracellular matrix proteins and VEGF induced by pseudoislet formation and 3D culture. Co-culture with human endothelial cells created a natural cellular niche resulting in enhanced insulin response after glucose stimulation. Survival and function of the pseudoislets after explantation and extensive scaffold vascularization of both the hydrogel and heparinized polycaprolactone components were demonstrated in ovo. Computer simulations of oxygen, glucose, and insulin flows were used to evaluate scaffold architectures and Langerhans islets at a future transplantation site along neurovascular structures.

Conclusion A defined end-to-end process for multidisciplinary bioconvergence research on a bioartificial endocrine pancreas was developed. A modular, patient-specific device architecture is proposed for future research studies.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166285

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 01, 2021.
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Towards 3D-Bioprinting of an Endocrine Pancreas: A Building-Block Concept for Bioartificial Insulin-Secreting Tissue
Gabriel Alexander Salg, Eric Poisel, Matthias Neulinger Munoz, Daniel Cebulla, Vitor Vieira, Catrin Bludszuweit-Philipp, Felix Nickel, Ingrid Herr, Nathalia A. Giese, Thilo Hackert, Hannes Goetz Kenngott
bioRxiv 2021.02.27.433164; doi: https://doi.org/10.1101/2021.02.27.433164
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Towards 3D-Bioprinting of an Endocrine Pancreas: A Building-Block Concept for Bioartificial Insulin-Secreting Tissue
Gabriel Alexander Salg, Eric Poisel, Matthias Neulinger Munoz, Daniel Cebulla, Vitor Vieira, Catrin Bludszuweit-Philipp, Felix Nickel, Ingrid Herr, Nathalia A. Giese, Thilo Hackert, Hannes Goetz Kenngott
bioRxiv 2021.02.27.433164; doi: https://doi.org/10.1101/2021.02.27.433164

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