Bioabsorption of Subcutaneous Nanofibrous Scaffolds Influences the Engraftment and Function of Neonatal Porcine Islets

Abstract

The subcutaneous space is currently being pursued as an alternative transplant site for ß-cell replacement therapies due to its retrievability, minimally invasive procedure and potential for graft imaging. However, implantation of ß-cells into an unmodified subcutaneous niche fails to reverse diabetes due to a lack of adequate blood supply. Herein, poly (ε-caprolactone) (PCL) and poly (lactic-co-glycolic acid) (PLGA) polymers were used to make scaffolds and were functionalized with peptides (RGD (Arginine-glycine-aspartate), VEGF (Vascular endothelial growth factor), laminin) or gelatin to augment engraftment. PCL, PCL + RGD + VEGF (PCL + R + V), PCL + RGD + Laminin (PCL + R + L), PLGA and PLGA + Gelatin (PLGA + G) scaffolds were implanted into the subcutaneous space of immunodeficient Rag mice. After four weeks, neonatal porcine islets (NPIs) were transplanted within the lumen of the scaffolds or under the kidney capsule (KC). Graft function was evaluated by blood glucose, serum porcine insulin, glucose tolerance tests, graft cellular insulin content and histologically. PLGA and PLGA + G scaffold recipients achieved significantly superior euglycemia rates (86% and 100%, respectively) compared to PCL scaffold recipients (0% euglycemic) (* p < 0.05, ** p < 0.01, respectively). PLGA scaffolds exhibited superior glucose tolerance (* p < 0.05) and serum porcine insulin secretion (* p < 0.05) compared to PCL scaffolds. Functionalized PLGA + G scaffold recipients exhibited higher total cellular insulin contents compared to PLGA-only recipients (* p < 0.05). This study demonstrates that the bioabsorption of PLGA-based fibrous scaffolds is a key factor that facilitates the function of NPIs transplanted subcutaneously in diabetic mice.

A porcine islet-encapsulation device that enables long-term discordant xenotransplantation in immunocompetent diabetic mice

“… 58 , 59 , 60 In general, the number of islets required to improve blood glucose levels in mouse diabetes models is species dependent. In the case of subrenal capsule transplantation into immunocompromised mice, which is often used in experiments due to its relatively high viability, it has been reported that 100–200 islets are required for mouse islets 61 , 62 , 63 and 500–2,000 islets for human islets, 63 , 64 , 65 , 66 while porcine islets require significantly more islets, about 2,000–12,600 IEQ) 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 …”

Bioengineering the Vascularized Endocrine Pancreas: A Fine-Tuned Interplay Between Vascularization, Extracellular-Matrix-Based Scaffold Architecture, and Insulin-Producing Cells

“…Kuppan et al used a poly lactic-co-glycolic acid (PLGA)-based fibrous scaffold modified with gelatin polymer, which was implanted in the abdominal subcutaneous space for 4 weeks to induce site vascularization. Implantation of xenogeneic islets has reversed the hyperglycemia within 20-25 days, similarly to mice with islets implanted at the kidney capsule site (95). Fibrin has been widely used as the Food and Drug Administration (FDA) approves its clinical use (25).…”

Construction of engineered 3D islet micro-tissue using porcine decellularized ECM for the treatment of diabetes

“…The development of biological materials that provide a similar native-like micromilieu for islet encapsulation and incorporate islet-resident nonhormonal cells to promote islet function has aroused researchers' interest. [11][12][13] Natural biological polymers, including collagen, alginate, heparin and fibronectin have been used to construct biomimetic engineered environments, which have been proven to maintain insulin release levels and beta cells specific gene expression. However, there are differences from batch to batch, pathogen/endotoxin pollution, a lack of adjustability and immunogenicity, and other shortcomings.…”