Three-dimensional bioprinting of functional β-islet-like constructs

Abstract

256Diabetes is an autoimmune disease that ensues when the pancreas does not deliver adequate insulin or when the body cannot react to the existing insulin. Type 1 diabetes is an autoimmune disease defined by continuous high blood sugar levels and insulin deficiency due to β-cell destruction in the islets of Langerhans (pancreatic islets). Long-term complications, such as vascular degeneration, blindness, and renal failure, result from periodic glucose-level fluctuations following exogenous insulin therapy. Nevertheless, the shortage of organ donors and the lifelong dependency on immunosuppressive drugs limit the transplantation of the entire pancreas or pancreas islet, which is the therapy for this disease. Although encapsulating pancreatic islets using multiple hydrogels creates a semi-privileged environment to prevent immune rejection, hypoxia that occurs in the core of the capsules is the main hindrance that should be solved. Bioprinting technology is an innovative process in advanced tissue engineering that allows the arranging of a wide array of cell types, biomaterials, and bioactive factors as a bioink to simulate the native tissue environment for fabricating clinically applicable bioartificial pancreatic islet tissue. Multipotent stem cells have the potential to be a possible solution for donor scarcity and can be a reliable source for generating autograft and allograft functional β-cells or even pancreatic islet-like tissue. The use of supporting cells, such as endothelial cells, regulatory T cells, and mesenchymal stem cells, in the bioprinting of pancreatic islet-like construct could enhance vasculogenesis and regulate immune activity. Moreover, scaffolds bioprinted using biomaterials that can release oxygen postprinting or enhance angiogenesis could increase the function of β-cells and the survival of pancreatic islets, which could represent a promising avenue.

Keywords: Bioprinting; Hydrogels; Islets of Langerhans; Mesenchymal stem cells.

Figure 1

258Cell types and pancreas genesis. (A) Several cell types contribute to the morphology of pancreatic islets. (B) The endocrine pancreatic progenitor cells and main transcription factors associated with the principal phases of β-cell genesis. Abbreviations: Pdx1, pancreatic and duodenal homeobox1; Ptf1a, pancreas-specific transcription factor1a, SOX9, sex determine region Y (SRY)-box9; Ngn3, neurogenin3; Arx, Aristaless-related homeobox X-linked; Pax4, paired box 4; MafA, maturation factor A; GLP1, glucagon-like peptide1; PC1/3, proconvertase 1/3. (C) Schematic view of cell sources in bioartificial pancreatic islets. Abbreviations: ESCs, embryonic stem cells; BM-MSC, bone marrow mesenchymal stem cells; AD-MSC, adipose-derived mesenchymal stem cells; CB-MSC, cord blood mesenchymal stem cell; iPSC, induced pluripotent stem cells; OKT4, octamer binding transcription factor 4; SOX2, SRY-related high mobility group box protein 2; KLF4, Kruppel-like factor 4; MYC, myelocytomatosis viral oncogene.

Figure 2

261Bioartificial pancreatic islets. (A) PEC-Encap device, created by ViaCyte, committed pancreatic endoderm cells derived from human embryonic stem cells encapsulated in an immunoprotective membrane that can diffuse oxygen and glucose to induce insulin and glucagon secretion into the blood circulation. (B) Schematic view of different bioprinting approaches to creating pancreatic constructs. (C) Schematic view of coaxial extrusion bioprinting method that provides the possibility of bioprinting of pancreatic islets or insulin-producing cells in the core and supportive cells in the shell of extruded strands.