Periurethral bulking agents are substances that are injected periurethrally to increase tissue bulk as a treatment of stress urinary incontinence (SUI). Patients receive one or several treatment sessions. A number of products have been developed and are commercially available; key factors in determining the optimal product are biocompatibility, durability, and absence of migration.
Improvement in stress incontinence with bulking agents is achieved by increasing the tissue bulk and thereby increasing resistance to the outflow of urine. The bulking agent is injected into the periurethral tissue as a liquid that then solidifies into a spongy material to bulk the urethral wall. Bulking agents may be injected over a course of several treatments until the desired effect is achieved. Periurethral bulking agents have been widely used for incontinence in women. Men have also been treated, typically those with post-prostatectomy incontinence. Except for Contigen®, however, bulking agents are indicated by the U.S. Food and Drug Administration (FDA) for use only in women, specifically those with stress urinary incontinence due to intrinsic sphincter deficiency.
Biocompatibility, durability, and absence of migration are key factors in the success of bulking agents. Cross-linked collagen (e.g., Contigen) has been commercially available for many years. Collagen is slowly absorbed over time, and symptoms may recur, requiring additional injections. Carbon-coated beads (e.g., Durasphere) and ethylene vinyl alcohol copolymer implants (e.g., Uryx®, marketed under the trade name Tegress® starting in 2005) received approval (1999 and 2004, respectively) from the FDA for use as periurethral bulking agents. Both were thought to be more durable than collagen. Tegress was later voluntarily removed from the market due to safety concerns.
In 2005, a bulking agent composed of spherical particles of calcium hydroxylapatite (CaHA) in a gel carrier (Coaptite®) received FDA approval for use in women. Polydimethylsiloxane (silicone, Macroplastique®) received FDA approval in 2006 “for transurethral injection in the treatment of adult women diagnosed with stress urinary incontinence (SUI) primarily due to intrinsic sphincter deficiency.” The FDA approvals are conditional on the enrollment of a minimum of 200–250 patients in a 5-year registry to further evaluate safety and efficacy.
In Europe, Q-Med has marketed a dextranomer/hyaluronic (Dx/HA) copolymer (Zuidex™) together with an injection system (Implacer™) for treatment of urinary incontinence. A Dx/HA formulation (Deflux™) from the same company has been commercially available for a number of years for the treatment of vesicoureteral reflux in children (see policy No. 7.01.102 on the treatment of vesicoureteral reflux with bulking agents).
Autologous fat and autologous ear chondrocytes have also been used as periurethral bulking agents; autologous substances do not require FDA approval. Polytetrafluoroethylene (Teflon®) has been investigated as an implant material but has not received FDA approval.
A more recently explored alternative is cellular therapy with myoblasts, fibroblasts, or stem cells (muscle-derived or adipose-derived). In addition to their use as periurethral bulking agents, it is hoped that transplanted stem cells will undergo self-renewal and multipotent differentiation, which could result in regeneration of the sphincter and its neural connections.
Several periurethral bulking agents have been approved by the FDA through the premarket approval process. These devices are indicated for the treatment of stress urinary incontinence due to intrinsic sphincter deficiency; other than Contigen, approval is only for use in adult women. Products include:
- In 1993, Contigen (Allergan, Inc.), a cross-linked collagen, was approved. A supplemental approval in 2009 limited the device’s indication to treatment of urinary incontinence due to intrinsic sphincter deficiency in patients (men or women) who have shown no improvement in incontinence for at least 12 months.
- In 1999, Durasphere (Advanced UroScience), pyrolytic carbon-coated zirconium oxide spheres, was approved.
- In 2004, Uryx (CR Bard), vinyl alcohol copolymer implants, was approved. In 2005, approval was given to market the device under the trade name Tegress. In 2007, Tegress was voluntarily removed from the market due to safety concerns.
- In 2005, Coaptite (BioForm Medical, Inc.), spherical particles of calcium hydroxylapatite, suspended in a gel carrier, was approved for soft tissue augmentation in the treatment of stress urinary incontinence due to intrinsic sphincter deficiency in adult females.
- In 2006, Macroplastique (Uroplasty), polydimethylsiloxane, was approved.