AB304. SPR-31 Controlled release of IGF1 enhances urethral sphincter function and histological structure in the treatment of female stress urinary incontinence in a rodent model

OBJECTIVE: IGF1 plays a key modulatory role in promoting angiogenesis, as well as muscle and nerve regeneration. Although systemic administration of IGF1 improved urinary sphincter function in vivo, this therapy has several pitfalls, including limited effects due to the short half-life of IGF1 and potential dose-related toxicity. It is important to use a delivery system that slowly releases suitable amounts of IGF1 over time. The goal of this study was to determine the effects of controlled release of IGF1 from alginate-gelatin microbeads (IGF1-A-G-beads) on sphincter tissue repair in a rat model of stress urinary incontinence (SUI). METHODS: Forty-four female SD rats were randomized into four groups (G) and underwent vaginal distension (VD) followed by periurethral injection of IGF1-A-G-beads (1×10(4) beads/1 mL normal saline) (G1), VD + empty microbeads (G2), VD + normal saline (NS), or sham VD + NS. Urethral function [leak point pressure (LPP)] and histology were assessed one week after VD injury. Quantitative data was analyzed using ANOVA on Ranks followed by a Tukey post hoc test with P<0.05 indicating a statistically significant difference between groups. Data is presented as mean ± standard error of the mean. RESULTS: LPP was significantly decreased with VD when treated with saline (23.9±1.3 cmH(2)O) or with empty microbeads (21.7±0.8 cmH(2)O) demonstrating that the microbeads themselves do not create a bulking or obstructive effect in the urethra. LPP significantly increased in rats with VD treated with IGF1-A-G-beads (28.4±1.2 cmH(2)O), compared to those treated with empty microbeads and was not significantly different from LPP of rats with sham VD (44.4±3.4 cmH(2)O), demonstrating initiation of a reparative effect even 1 week after VD. Histological analysis demonstrated well-developed, well-organized skeletal muscle fibers in the external urethral sphincter of rats with VD treated with IGF1-A-G-beads, similar to that of sham-injured animals. In contrast, substantial muscle fiber attenuation and disorganization was observed in VD injured, NS- or empty microbeads-treated rats. CONCLUSIONS: Periurethral administration of IGF1-A-G-beads facilitated recovery from SUI induced by simulated childbirth injury (VD). IGF1-A-G-beads thus represent an attractive, alternate approach for the treatment of female SUI. FUNDING SOURCE(S): NIH NIDDK R56 DK100669-01A1