3D Bioprinting of Multi-Scale Encapsulation System for Islet Transplantation

Abstract

Islet transplantation is a promising treatment for Type 1 diabetes (T1D). However, there are clinical limitations such as cell dispersion, hypoxia, and infl ammatory response, which lead to loss of cell functions. Islet encapsulation has been studied to overcome these limitations. Macroencapsulation refers to encapsulating a large volume of islets in one system so that it is retrievable. However, this system has a low surface-to-volume ratio, which interferes with the diffusion of oxygen and nutrients. Here, we suggest a 3D bioprinting strategy for a one-step fabrication of a multi-scale encapsulation system. The developed 3D bioprinted system has both features of macroencapsulation and microencapsulation systems. The polycaprolactone (PCL) construct acts as a macroencapsulation system by protecting internal engineered pancreatic tissue and allow it retrievable. In addition, engineered pancreatic tissue that is printed directly into the PCL encapsulation system using a pancreatic tissuederived decellularized extracellular matrix (pdECM) bioink serves as a microencapsulation system. The engineered pancreatic tissue contains cells fabricated into the aggregates to mimic the native islet morphology, and these aggregates are placed at the demanding position to prevent clumping of cell aggregates and to a have high surface-to-volume ratio. It was confirmed that the pore characteristics of the PCL staggered membrane retained the viability and function of the encapsulated cells while presenting a reduced pore size. Moreover, the mitigation of infl ammatory response was investigated in vitro by measuring infl ammatory cytokine secretion of macrophages, and in vivo by subcutaneous implantation into Sprague Dawley rats. Together with this, beta cell aggregates were designed to contain 500 pancreatic β cells with 250 μm diameter. These aggregates showed reduced hypoxia-induced apoptosis compared to the non-printed group having the same cell concentration with a large volume. Also, the aggregates showed earlier expression of E-cadherin, cell-cell adhesion molecule related to the maintenance of β -cell viability, and promoting insulin secretion, than non-printed groups. The results of this study suggest the possibility of 3D printing for manufacturing islet encapsulation system, and it could also be applied for cell or tissue delivery (e.g., adrenal cell, Leydig cell, parathyroid, and thyroid gland) for treatment of other endocrine diseases. Further research would be undertaken to investigate the applicability of induced pluripotent stem cell-derived insulin-producing cells to this system and its ability to regulate blood sugar levels.