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Preclinical Testing of a New Urethral Bulking Agent in a Rat Animal Model
Benjamin J. King, MD1, Travis K. Mann-Gow, BSc1, Cameron S. Sikavi, BSc1, Ahmed El-Ghannam, PhD2, Christine Knabe, PhD3, Michael K. Lam, MD1, Jerry Blaivas, MD4, Mark K. Plante, MD1, Peter Zvara, MD, PhD1.
1University of Vermont, Burlington, VT, USA, 2UNC Charlotte, Charlotte, NC, USA, 3Philipps-University, Marburg, Germany, 4Weill Cornell Medical College, New York, NY, USA.
While endoscopic injection of a bulking agent into the proximal urethra provides a minimally-invasive and safe alternative to open surgery for those suffering from stress urinary incontinence, the ideal injectable material has yet to be identified. In preliminary studies, alumina ceramic beads (ACB), 75-105μm in diameter suspended in hyaluronic acid sodium salt were injected into rat urethras. Adequate volume retention one-month post-injection was observed, but the ACB fell out of suspension, causing frequent injection needle plugging. The aim of this study was to develop the optimal composition of alumina beads, suspended in hyaluronic acid (HA), that could be easily stored, injected via a 22G needle, and resist degradation during sterilization. A rat model was used to assess long-term volume retention and effect on lower urinary tract function. Finally, ACB integrity and host tissue response was evaluated prior to and 6 months following injection.
Materials & Methods
Multiple formulations of HA and varying ACB-HA ratios were used to create a bulking agent that is both stable and easily injectable with a 22G needle. Using a midline abdominal incision under an operating microscope with direct visualization, ACB-HA solution was injected into the wall of the mid-urethra using a 22G needle. Microphotographs were taken during injection, and again upon removal of the urethra. Flow rate and voiding frequency were assessed for a 12-hour period, by placing the animal into a metabolic cage with free access to food and water, before injection, and again at 1 and 3 months post-injection. At 6 months, the urethra was removed, fixed and processed for hard tissue histology, using light and scanning electron microscopy (SEM).
Cross-linked HA (Novoenzymes, Bagsvaerd, Denmark) proved to be the optimal suspension media, showing a minimal and predictable decrease in viscosity following sterilization. A 1:4 ratio of ACB (Dakot Milling Media, KwaZulu-Natal, South Africa) to cross-linked HA provided uniform bead suspension, allowing intraurethral injection through a 22G needle without plugging. There was no significant difference between the 12-hour average urinary frequency (19.9±1.52, 18.1±1.75, 20.7±3.03 voids/12 hr) and mean urinary flow rate (0.095±0.027, 0.078±0.008, 0.078±0.009 ml/min) at 1 and 3 months post-injection compared to baseline. SEM visualization indicated ACB were unstable in vivo, disintegrating into smaller particulates. Micropores in beads were too small to allow for tissue ingrowth. Histological analysis demonstrated fibrous encapsulation of the beads, release of particulate matter and local inflammatory response.
UBT is a grossly underutilized treatment of SUI. This study used a readily available and cost-effective animal model to investigate critical issues involved with UBT. Alumina beads used in this study lacked consistent size and were unstable in vivo. Our research will continue investigating porous silica-calcium phosphate bioceramic particles (SCPC10). The SCPC10 is a bioactive ceramic that stimulates tissue attachment to its surface. The migratory effects of beads into lymph nodes, liver, spleen and lungs will also be examined.
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