Abstract
Type-1 diabetes (T1DM) is a chronic metabolic disorder resulting from the autoimmune destruction of β cells. The current standard of care requires multiple, daily injections of insulin and accurate monitoring of blood glucose levels (BGLs); in some cases, this results in diminished patient compliance and increased risk of hypoglycemia. Herein, we engineered hierarchically structured particles comprising a poly(lactic-co-glycolic) acid (PLGA) prismatic matrix, with a 20 × 20 μm base, encapsulating 200 nm insulin granules. Five configurations of these insulin-microPlates (INS-μPLs) were realized with different heights (5, 10, and 20 μm) and PLGA contents (10, 40, and, 60 mg). After detailed physicochemical and biopharmacological characterizations, the tissue-compliant 10H INS-μPL, realized with 10 mg of PLGA, presented the most effective release profile with ∼50% of the loaded insulin delivered at 4 weeks. In diabetic mice, a single 10H INS-μPL intraperitoneal deposition reduced BGLs to that of healthy mice within 1 h post-implantation (167.4 ± 49.0 vs 140.0 ± 9.2 mg/dL, respectively) and supported normoglycemic conditions for about 2 weeks. Furthermore, following the glucose challenge, diabetic mice implanted with 10H INS-μPL successfully regained glycemic control with a significant reduction in AUC0–120min (799.9 ± 134.83 vs 2234.60 ± 82.72 mg/dL) and increased insulin levels at 7 days post-implantation (1.14 ± 0.11 vs 0.38 ± 0.02 ng/mL), as compared to untreated diabetic mice. Collectively, these results demonstrate that INS-μPLs are a promising platform for the treatment of T1DM to be further optimized with the integration of smart glucose sensors.
Highlights
Type-1 diabetes (T1DM) is a chronic metabolic disorder characterized by elevated blood glucose levels (BGLs).[1]
We propose five different configurations of microparticles made with different thicknesses and poly(lacticco-glycolic) acid (PLGA) concentrations, namely, 5 μm thick with 10 mg of PLGA (5H insulin granules (INS)-μPL); 10 μm thick with 10 mg of PLGA (10H INS-μPL); and 20 μm thick with 10, 40, and 60 mg of PLGA (20H INS-μPL with either 10, 40, or 60 mg of PLGA)
Insulin (5 mg/mL) was dissolved in acidified water (HCl 10 mM, pH = 2.5), whereupon zinc acetate (0.05 M), trisodium citrate (0.05 M), and acetone 15% were added at room temperature under magnetic stirring (250 rpm) for 90 min
Summary
Type-1 diabetes (T1DM) is a chronic metabolic disorder characterized by elevated blood glucose levels (BGLs).[1]. SEM and fluorescent microscopy images were obtained at predetermined time points after INS-μPL exposure to physiological conditions (0.5 mL of PBS, pH = 7.4 at 37 °C) and confirmed that the typical μPL prismatic shape with a 20 × 20 μm base was preserved for long incubation periods This proves that, within the 1 month observation time, insulin release is largely affected by the progressive dissolution of insulin granules and diffusion of molecular insulin out of the μPL matrix into the surrounding aqueous environment.[36,37] It is just important to note that differently from several other conventional PLGA microparticles, the μPLs exhibit a less compact structure that would allow water molecules to slowly permeate into the matrix without requiring extensive hydrolysis of the constituting polymer. This could be due to the combination of multiple factors including enzymatic reactions that could accelerate insulin release and PLGA degradation, as well as an effective larger release volume than that considered in vitro.[46,47]
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