194

Localized drug delivery in a islet transplant site via engineered biomaterials

Jessica D. Weaver^1,2, Yun Song^1,3, Antonello Pileggi^1,2,4,5, Camillo Ricordi^1,2,4,5,6, Peter Buchwald^1,3, Cherie L. Stabler^1,2,4

¹Diabetes Research Institute; ²Department of Biomedical Engineering; ³Department of Molecular and Cellular Pharmacology; ⁴Department of Surgery; ⁵Department of Microbiology & Immunology; ⁶Department of Medicine, University of Miami, Miami, FL, United States

Inflammation during engraftment is a prominent issue in cellular implantation. For islet transplantation, it contributes to low graft survival rates and the necessity for high islet loadings. The local, sustained delivery of anti-inflammatory agents at the site of transplantation might alleviate this problem, while avoiding side-effects caused by systemic administration. As a model system, we evaluated the local delivery of dexamethasone (Dex) from polydimethylsiloxane (PDMS) implants.

Dex-PDMS materials were fabricated by incorporating dexamethasone into PDMS prior to curing. Geometries tested include: disks, rods, and cages. Drug release was characterized in-vitro. Suppression of activation of human monocytes and macrophages by Dex-PDMS was assessed via surface marker expression and IL-6 release, respectively. Drug release and effects on islet function of Dex-PDMS implants in-vivo were assessed in murine syngeneic transplants.

With a constant surface area-to-volume ratio (SA/V) among geometries, dexamethasone release profiles were comparable. Release studies exhibited an initial burst (1-3 d), followed by sustained release levels that linearly correlate with percent drug loading of the construct, with plateau values from 0.5-0.1 μg/day/construct. Computational models predict sustained drug release from 1-12 months, depending on the drug load and construct volume. Urine and blood measurements of mice implanted with 5–20% Dex-PDMS disks support in-vitro data, with similar burst (1-7 days) and plateau profiles (>90 days). In-vitro activity studies of PDMS-Dex disks (5-20%) with THP-1 monocytes or macrophages resulted in substantial suppression of inflammatory activation, indicating a therapeutic level of release. Preliminary studies in diabetic mice recipients of syngeneic islets using Dex-PDMS rods showed reversal of diabetes and sustained graft function.

Sustained drug release from Dex-PDMS constructs was confirmed at therapeutic levels with the ability to release long-term (>1 year). The rate and duration of the release can be modified by varying the surface/volume, total volume, and drug loading parameters. Supported by JDRFand DRIF.