University of Florida
Localized release of low-Dose dexamethasone from macroporous scaffolds improves islet engraftment in murine model
Kaiyuan Jiang1, Jessica Weaver2, Peter Buchwald3, Cherie Stabler1.
1Biomedical Engineering, University of Florida, Gainesville, FL, United States; 2Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, United States; 3Diabetes Research Institute, University of Miami, Miami, FL, United States
Introduction: Mitigating the activation of inflammatory processes following the implantation of tissue engineered grafts is of critical importance to protect graft cell viability and improve implant efficacy, particularly for islet transplantation. The local delivery of corticosteroids can serve to dampen activation of these pathways at the transplant site, while also minimizing the detrimental effects of systemic administration. Herein, we utilized a highly porous polydimethylsiloxane (PDMS) scaffold, which is used to house pancreatic islets, for the local release of dexamethasone (Dexa). We explored the impact of drug loading on both the efficacy and engraftment efficiency of an islet transplant in a murine model. Further, the impact of dexamethasone release on innate host responses at the local graft site was also characterized.
Materials and Methods: Dexa (0.1 – 1% w/v) was loaded within PDMS, and 85% macroporous scaffolds (10 mm diameter; 1 mm height) were fabricated. For efficacy studies, streptozotocin-induced diabetic B6 mice received Dexa-PDMS or PDMS-only scaffolds (600 IEQ) within the EFP site in a syngeneic mouse model. Graft efficacy was classified as stable BG < 200 mg/dL. Mechanistic studies explanted scaffolds up to day 30 post-implant and the stromal vascular fraction was isolated and characterized via flow cytometry (CD11b, F4/80, CD274, and CD86). Biocompatibility of explanted grafts was assessed via H/E, trichrome, and IHC.
Results and Discussion: To evaluate the impact of local dexamethasone release on modulation of inflammation, Dexa was loaded within macroporous scaffolds at five different doses (0%, 0.1%, 0.25%, 0.5%, and 1% (w/v). At the highest Dexa concentrations of 0.5% and 1%, overall graft efficacy and engraftment efficiency of functioning grafts were significantly delayed (P = 0.035), when compared to drug-free control scaffolds; however, a significant improvement in the engraftment rate was observed for mice receiving 0.1% or 0.25% Dexa scaffolds (P = 0.027 and 0.031, respectively), when compared to control scaffolds. Following establishment of normoglycemia, all grafts remained stable for the duration of the transplant. Upon elective graft retrieval 90 days post-transplantation, histological assessment found robust islets and healthy tissue remodeling. Macrophages phenotype studies sought to characterize the local impact of Dexa release on innate immunology responses. A significant decrease in expression of pro-inflammatory (M1) markers (CD274+/CD86+) was observed from 0.1% and 0.25% Dexa-PDMS scaffold implants in comparison to control scaffolds at 5 and 7 days post-implantation (P < 0.05 and < 0.001 for 0.1 and 0.25%), respectively.
Conclusions: Drug release from biomaterials provides a controlled means to locally deliver tailored dosages of anti-inflammatory agents. This data illustrates the importance of drug dosage, as pancreatic islets were sensitive to local Dexa levels > 0.5%, but exhibited significant benefits at Dexa levels < 0.25%. At the correct dosage, Dexa release from macroporous scaffolds was highly effective in suppressing deleterious inflammatory processes, as demonstrated by a significant increase in the time to efficacy for islet transplants and the observation of suppression of migration of pro-inflammatory macrophages to the graft site. As such, PDMS scaffolds provide a suitable platform for housing islets and locally delivering agents capable of generating a supportive environment.
Juvenile Diabetes Research Foundation. Diabetes Research Institute Foundation.
 Pedraza et al. Macro-porous PDMS Scaffolds for Extrahepatic Islet Transplantation. Cell Transplant.
15:30 - 17:00
|Modifying Islet Immunity - Adaptive, Innate, and Xenoimmunity||Localized release of low-Dose dexamethasone from macroporous scaffolds improves islet engraftment in murine model||Plenary Room 1|