Micro-fabricated scaffolds lead to efficient remission of diabetes in mice

Abstract

Despite the clinical success of intrahepatic islet transplantation in treating type 1 diabetes, factors specific to this transplantation site hinder long-term insulin independence. The adoption of alternative, extravascular sites likely improve islet survival and function, but few locations are able to sufficiently confine islets in order to facilitate engraftment. This work describes a porous microwell scaffold with a well-defined pore size and spacing designed to guarantee islet retention at an extrahepatic transplantation site and facilitate islet revascularization. Three techniques to introduce pores were characterized: particulate leaching; solvent casting on pillared wafers; and laser drilling. Our criteria of a maximum pore diameter of 40 μm were best achieved via laser drilling. Transplantation studies in the epididymal fat of diabetic mice elucidated the potential of this porous scaffold platform to restore blood glucose levels and facilitate islet engraftment. Six out of eight mice reverted to stable normoglycemia with a mean time to remission of 6.2 ± 3.2 days, which was comparable to that of the gold standard of renal subcapsular islet grafts. In contrast, when islets were transplanted in the epididymal fat pad without a microwell scaffold, only two out of seven mice reverted to stable normoglycemia. Detailed histological evaluation four weeks after transplantation found a comparable vascular density in scaffold-seeded islets, renal subcapsular islets and native pancreatic islets. However, the vascularization pattern in scaffold-seeded islets was more inhomogeneous compared to native pancreatic islets with a higher vascular density in the outer shell of the islets compared to the inner core. We also observed a corresponding decrease in the beta-cell density in the islet core. Despite this, our data indicated that islets transplanted in the microwell scaffold platform were able to maintain a viable beta-cell population and restore glycemic control. Furthermore, we demonstrated that the microwell scaffold platform facilitated detailed analysis at a subcellular level to correlate design parameters with functional physiological observations.

A collagen based cryogel bioscaffold coated with nanostructured polydopamine as a platform for mesenchymal stem cell therapy

“…The small pores will help promote blood vessel ingrowth into the bioscaffold, as supported by recent reports which have shown that pore sizes between 30–40 mm facilitates vascularization of implantable bioscaf-folds. 50,51 Our bioscaffold also has a high degree of porosity (75% ± 3%) with a corresponding high swelling ratio. 48 The high porosity and interconnected macropores of our bioscaf-fold creates a physical space to facilitate cell movement and distribution throughout the bioscaffold.…”

Tissue‐engineering approaches in pancreatic islet transplantation

“…Chen et al, 2007). Islets transplanted into the epididymal fat produced similar results to islets transplanted intraportally, although encapsulation or tissueengineered strategies are required (Buitinga et al, 2017;Manzoli et al, 2017;D. Mao et al, 2017;Rios, Zhang, Luo, & Shea, 2016; K. Wang, Wang, Han, Chen, & Luo, 2017;X.…”

“…Like the omentum , it is easily accessible and well vascularized, although it does not have portal drainage (X. Chen et al, ). Islets transplanted into the epididymal fat produced similar results to islets transplanted intraportally, although encapsulation or tissue‐engineered strategies are required (Buitinga et al, ; Manzoli et al, ; D. Mao et al, ; Rios, Zhang, Luo, & Shea, ; K. Wang, Wang, Han, Chen, & Luo, ; X. Wang, Wang, Zhang, Qiang, & Luo, ; Weaver et al, ). The renal subcapsular space has been considered one of the best sites for islet transplantation for more than 3 decades (Mellgren, Schnell Landström, Petersson, & Andersson, ) and is used as a positive control in most studies instead of the liver (Ar’Rajab, Ahrén, Alumets, Lögdberg, & Bengmark, ; Halberstadt et al, ; Medarova et al, ; Pepper et al, ). Compared to intraportally transplanted islets, renal subcapsular islet grafts show a faster vascular engraftment that increases success rates (Olsson, Olerud, Pettersson, & Carlsson, ; Stokes et al, ).…”

“…Like the omentum , it is easily accessible and well vascularized, although it does not have portal drainage (X. Chen et al, ). Islets transplanted into the epididymal fat produced similar results to islets transplanted intraportally, although encapsulation or tissue‐engineered strategies are required (Buitinga et al, ; Manzoli et al, ; D. Mao et al, ; Rios, Zhang, Luo, & Shea, ; K. Wang, Wang, Han, Chen, & Luo, ; X. Wang, Wang, Zhang, Qiang, & Luo, ; Weaver et al, ).…”

A Collagen Based Cryogel Bioscaffold that Generates Oxygen for Islet Transplantation

“…Although majority of biotechnology research related to islet transplantation has focused on encapsulation strategies,1–3 there has been a growing interest in creating new biocompatible 3D structures, known as bioscaffolds 4–8. Bioscaffolds provide an interesting solution for islet transplantation given that they contain spaces that can accommodate islets while concurrently offering a unique interface which can be modulated to address critical shortcomings faced by islets in the immediate post‐transplantation period (i.e., hypoxia) 9.…”