RT Journal Article
SR Electronic
T1 Towards 3D-Bioprinting of an Endocrine Pancreas: A Building-Block Concept for Bioartificial Insulin-Secreting Tissue
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.27.433164
DO 10.1101/2021.02.27.433164
A1 Gabriel Alexander Salg
A1 Eric Poisel
A1 Matthias Neulinger Munoz
A1 Daniel Cebulla
A1 Vitor Vieira
A1 Catrin Bludszuweit-Philipp
A1 Felix Nickel
A1 Ingrid Herr
A1 Nathalia A. Giese
A1 Thilo Hackert
A1 Hannes Goetz Kenngott
YR 2021
UL http://biorxiv.org/content/early/2021/03/01/2021.02.27.433164.abstract
AB 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 StatementThe authors have declared no competing interest.