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.
Highlights
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
Islet transplantation re-establishes glucose homeostasis, eliminates hypoglycemic unawareness, improves glycosylated hemoglobin (HbA1c) levels and stabilizes secondary complications associated with type 1 diabetes (T1D) [1–5]
There is strong rationale to pursue the use of porcine donors for clinical islet xenotransplantation, including (a) the reproducibility and quality of preparing porcine islets by eluding co-morbidities, brain death insults and ischemic damage associated with human islet procurement [7–9]; (b) the ubiquitous availability of porcine islets; thereby increasing access and reducing transplant wait times [8]; (c) allowance of genetic modification and cloning of pigs to reduce immunogenicity [9–11]; and (d) porcine islets are a potential therapy for highly allosensitized patients [12]
Summary
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. 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. There is strong rationale to pursue the use of porcine donors for clinical islet xenotransplantation, including (a) the reproducibility and quality of preparing porcine islets by eluding co-morbidities, brain death insults and ischemic damage associated with human islet procurement [7–9]; (b) the ubiquitous availability of porcine islets; thereby increasing access and reducing transplant wait times [8]; (c) allowance of genetic modification and cloning of pigs to reduce immunogenicity [9–11]; and (d) porcine islets are a potential therapy for highly allosensitized patients [12]. We have previously demonstrated that these NPIs, isolated from 1- to 3-day-old pancreata, can reverse hyperglycemia in mice [13], allogeneic pigs [14] and non-human primates [15,16]
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