*5.1. Passive Di*ff*usion*

In an animal study, Khera et al. reported that onaBoNTA failed to reach the muscle layer by direct bladder instillation. Another report from Coelho et al. further supported the lack of effect of onaBoNTA when simply instilled in the bladder with an intact urothelium [13,14]. Bladder instillation of onaBoNTA was less efficient owing to multiple factors. First, onaBoNTA is a large molecule (150 KDa). For targeting the suburothelium and detrusor muscle, passive diffusion is limited by tight junctions [15]. Second, the onaBoNTA agents might be diluted and degraded by urine proteases due to daily urine production of 800 to 2000 mL. Therefore, urologists need a modality that can cross the urothelium barrier, penetrate deep into the bladder, and persist for a sufficient time. Some studies have attempted to overcome the problems with different approaches, as illustrated in Figure 3.

**Figure 3.** Illustration of different approaches for onabotulinumtoxinA delivery in sensory bladder disorder.
