The present disclosure relates to systems, devices, and methods to treat a bodily organ and disorders thereof. In particular, the present disclosure describes improved devices and methods for treating a urinary bladder or other bodily organ by partitioning the organ into electrically isolated zones according to a predetermined pattern.
A. The Normal Bladder.
1. Structure:
The urinary bladder is located in the pelvic cavity anterior to the rectum and superior to the reproductive organs of the pelvis. In females, the urinary bladder is somewhat smaller in size compared to males and must share the limited space of the pelvic cavity with the uterus that rests superior and posterior to it.
The urinary bladder functions as a storage vessel for urine, to delay the frequency of urination. It is one of the most elastic organs of the body and is able to increase its volume greatly to accommodate between 600 to 800 ml of urine at maximum capacity.
The bladder wall is made of three distinct layers:
(1) The mucosa (adjacent to the bladder lumen) comprising the transitional epithelium of the bladder (Urothelium) and the underlying lamina propria.                (a) The transitional epithelium with its typical tight junctions, make an impermeable layer, effectively separating the urine from the body. The lamina proporia layer is rich with blood vessels (forming the sub mucosal plexus) and nerve endings, to support the Urothelium. Interstitial Cells of Cagal (a.k.a ICC or myofibroblasts) in the lamina propria form a network of excitable cells, with “nerve like” electrical conduction properties, and intrinsic “pacemaker” qualities (detailed below). Microscopic studies, augmented by immunochemical staining, show these cells are in intimate contact with the nerve ending of the lamina propria, mediating transmission of membrane potential transients from the nerves and the Urothelium to the detrusor.        (b) In addition, the mucosa has important paracrine activities, secreting various growth hormones and cytokines that affect adjacent cells and the underlying detrusor. (Kanai et al., Origin of spontaneous activity in neonatal and adult rat bladders and its enhancement by stretch and muscarinic agonists, Am J Physiol Renal Physiol 292: F1065-F1072, 2007)        (c) Blood vessel plexuses underlie the urothelium (sub endothelial plexus), and the mucosa (submucosal plexus), forming functional anastomoses between adjacent wall areas, important for the paracrine activities of the bladder.        
(2) The muscularis—the middle layer, contains the bulk of the bladder muscle. The muscularis is commonly referred to as the detrusor muscle and contracts during urination to expel urine from the body. Also, the muscularis is rich with ICC cells, arranged along the muscle bundles, forming smaller, more local networks. (McClosekey K D, Interstitial Cells in the Urinary Bladder—Localization ad Function, Neurourology and Urodynamics 29:82-87 (2010))
(3) The adventitia—a connective tissue layer encompassing the bladder, containing the larger blood vessels and nerves of the bladder. Although able to stretch and contract, the adventitia is limited in its elasticity, probably limiting the expansion of other layers, thus protecting the bladder from over expansion. Most blood vessels and nerves enter the adventitia at the bladder neck, and are thus oriented along the longitudinal axis of the bladder, when it is full.
The lower urinary tract is innervated by a complex neural network including sympathetic innervation, parasympathetic innervation, and somatic innervation. The majority of bladder nerves are efferent, however, extensive afferent innervation (mostly unmyelinated C-fibers) carries information from the bladder to the central nervous system. Some of the afferent traffic becomes conscious (bladder sensations), and some terminates at lower CNS levels, as part of the spinal reflexes involved in bladder control.
2. Function
a) Filling Phase
Except for brief micturition episodes, the bladder is constantly filling. In the filling phase, the bladder is in a high compliance state, accumulating urine at changing rates, greatly increasing in volume (˜tenfold), while maintaining a low intraluminal pressure, critical to allow draining from the low pressure renal collecting system.
Grossly, the parasympathetic innervation increases bladder tone and facilitates bladder contraction. The sympathetic autonomic innervation decreases bladder tone, and facilitates bladder relaxation. The cerebral control is predominately inhibitory to bladder contraction, and is normally only temporarily withheld during micturition, to facilitate bladder contraction.
The filling phase is characterized by rhythmic contractile activity of the bladder, producing gentle periodic fluctuations in intraluminal bladder pressure. This periodic activity is pivotal in maintenance of bladder tone and accommodation to changing pressures (luminal as well as external). These contractions are not dependent on external innervation, and persist also in ex-vivo (denervated) bladders, persist in the presence of chemical neural blocks (such as tetrodotoxin), and are seen even in isolated bladder strips.
Interstitial Cells of Cagal (ICC) throughout the bladder, and especially in the Urothelium—Lamina Propria junction, act as pacemakers, initiating these activities. Recently, it has been shown that electrical activity originating in these pacemaker sites propagates through the bladder wall, creating propagating patches of contraction (PPC), important in maintaining bladder shape and pressure. (Chambers et al., Characterisation of the contractile dynamics of the resting ex vivo urinary bladder of the pig, BJU Int 2015 116:973-983.) These PPC's are most frequent on the anterior and superior aspects of the bladder, and less frequent on the posterior aspect of the bladder, and are almost never seen to cross the trigone area. Typically, large PPC may cover up to one fifth of the bladder area.
To note, electrical propagation through the normal detrusor is minimal, mostly limited to individual myocyte bundles. The electrical coupling between normal detrusor muscle cells is poor, and current injected into the detrusor barely travels more than 0.3 mm, in the axial direction, and even less (if at all) transverse to the bladder axis. (Hammad F T, Electrical propagation in the renal pelvis, ureter and bladder, Acta Physiol 2015 213:371-383.) This is substantially different in overactive bladders, as will be detailed below.
b) Micturition
Normal micturition is characterized by voluntary initiation of timely expulsion of urine, with complete emptying the bladder. Since the detrusor muscle itself cannot be consciously contracted, conscious control of voiding is mediated by reflexes originating in the bladder neck, where somatic innervation allows voluntary relaxation of the internal sphincter and bladder neck. Once the bladder neck is relaxed (and thus stretched), coordinated bladder contraction takes place, with almost simultaneous contraction of the entire detrusor, for an average of approx. 20 seconds (average micturition duration). Such rapid coordination of almost simultaneous detrusor contraction during micturition is carried out by the nervous networks (mostly parasympathetic), and not by the relatively slow ICC network.
Normally, the resistance of the lower urinary tract is low, and modest pressures (up to 40 cmH2O) are sufficient for timely urine expulsion. Once the bladder completely empties (residual volumes in the range of up to 30 cc are considered normal), gradual bladder relaxation occurs, with return to the low pressures of the filling phase within minutes.
B. Overactive Bladder (OAB).
1. Causes
Overactive bladder is a disorder of the bladder filling phase. While micturition function is usually preserved, the filling phase exhibits pathological contractile activity, disturbing bladder filling with a sudden, premature urge to urinate.
It is hypothesized that malfunction of any of the normal bladder functions can lead to overactive bladder symptoms. For example “Neurogenic OAB” develops after a stroke, or spinal cord injury, resulting with loss of cerebral inhibition, inducing bladder overactivity. OAB symptoms may also develop in response to bladder outlet obstruction, so called “Obstructive OAB”. In these cases, bladder outlet obstruction by prostatic hypertrophy or pelvic organ prolapse, results with bladder wall myocyte hypertrophy and overactivity. However, in most cases, the reason for OAB remains unknown, and is classified as “idiopathic OAB”.
2. Pathophysiology of OAB
In most cases, there is no obvious pathology that explains the bladder overactivity. Some experts believe the symptoms of OAB reflect normal aging. Some believe that local bladder wall ischemia (in response to bladder hypertrophy and/or micro-vessel arthrosclerosis) is the reason for increased bladder sensations and overactivity. Others attribute the overactivity to local factors, including increased levels of growth hormones and cytokines that act locally (paracrine activity) causing changes in the myocyte function. However, whatever the exact cause, several important observations are commonly seen in OAB, pointing at a common end result that might have different origins in different cases. (Banakhar 2012. Pathophysiology of overactive bladder.) (Brading 2005. Overactive bladder why it occurs.)
Macroscopic changes—On average, overactive bladders have a thicker wall than normally functioning bladders. This is especially pronounced in longstanding neurogenic bladders, and bladders with an obstructed outlet. Although overactive and/or obstructed bladders are usually thicker walled than normal controls, much overlap is reported, and the variability between people (as well as in between studies) is large. (Cruz et al. EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 769-771).) Wall thickness is increased on average by ˜20%, however overactive bladder is quite common also in bladders with normal wall thickness, and increased wall thickness is quite common in normally functioning bladders.
Microscopic changes—Electron microscopy of overactive bladders show alien muscle cell junctions (protrusion junctions or ultra-close abutments) with narrow gaps that mediate abnormal electrical cell coupling. Chain-like linkage of several detrusor muscle cells by such junctions are reported to create erratic irritable foci that readily activate the final common pathway. These changes were reported in overactive bladders of different species, with different underlying causes, and are absent in stable detrusors. (Haferkamp 2003. Structural basis of neurogenic bladder dysfunction. II. Myogenic basis of detrusor hyperreflexia.) (Elbadawi 1997. Structural basis of geriatric voiding dysfunction. VI. Validation and update of diagnostic criteria in 71 detrusor biopsies.) Another microscopic finding seen using light microscopy, is an increased number of ICC cells in overactive bladders. These too, act for increased electrical interconnectivity in overactive bladders.
Contractile behavior—overactive bladders are often characterized by tetanic contractions, of high amplitude, at low bladder volumes. These contractions are symptomatic, and regional, at least initially. Such contractions have been demonstrated in entire bladders, as well as in isolated bladder strips, and even in human biopsy samples. (Drake 2004. Localized contractions in the normal human bladder and in urinary urgency.) (Brading 1997. A myogenic basis for the overactive bladder.)
Increased pacemaker activity and electrical conduction—overactive bladders develop much larger, but less frequent, spontaneous bladder contractions, and intra vesical pressure changes. These enhanced contractions are associated with fewer pacemaker sites that propagate more rapidly and over larger portions of the bladder. (Ikeda 2008. Urotheliogenic modulation of intrinsic activity in spinal cord-transected rat bladders.) (Fry 2004. Spontaneous activity and electrical coupling in human detrusor smooth muscle implications for detrusor overactivity.) In an animal model of neurogenic OAB, PPCs travel the surface of the bladder in various routes, covering approximately a fifth of the bladder surface before spontaneously terminating. Often propagation is circular and re-entrant, much like in cardiac arrhythmia. PPCs exist also in normal bladders, however, their magnitude markedly increases in overactive bladders. (Chambers et al., Characterisation of the contractile dynamics of the resting ex vivo urinary bladder of the pig, BJU Int 2015 116:973-983.)
The crucial role of such electrical connectivity was experimentally demonstrated by a c-kit tyrosine inhibitor that specifically targets ICC cells. When the ICC network was disabled by such an agent, human strips of overactive bladders ceased to exhibit exaggerated responses to carbachol, effectively exhibiting return to normal (control) behavior once the ICC network was disabled. (Biers S M., The functional effects of a c-kit tyrosine inhibitor on guinea pig and human detrusor, BJU International 97:612-616 (2005).)
Thus, the exact reason of OAB is yet unknown and probably more than one condition can cause OAB. While neural autonomic control is crucial for normal micturition and normal inhibition of bladder tone during the filling phase, bladder activity in the filling phase is mostly of myogenic origin, persisting independently of neural control. Over-activity is manifested by uninhibited, generalized tetanic bladder contractions in the filling phase. Such contractions are initiated by independent local pacemakers and propagate through the bladder wall via pathologically increased electrical conduction.
Current pharmaceutical OAB treatments offer only temporary and partial relief for the problem. The only permanent solutions currently available are surgical, and carry significant morbidity. Currently available therapies aim at modulating the activity of the nerves governing bladder function, either by electrical stimulation, by interference with synaptic communication, or by physical disruption of the nerves. While this approach has proven effect, efficacy is limited, and clinically significant OAB remains severely symptomatic in the vast majority of cases.
For at least the above reasons, there remains a major need for a novel treatment for OAB that is safe, effective, minimally invasive, and long lasting.