Surgery for Underactive Bladder Treatment

I. Improve bladder emptying

Cellular therapy:

Intradetrusor application stem cells

Reduction cystoplasty:

Resection of bladder dome reduces capacity by up to 80 % in some cases

Bladder myoplasty:

Microneurovascular free transfer of autologous latissimus dorsi muscle

Bladder replacement:

Regenerative medicine with biodegradable bladder scaffold and cells seeding

II. Decrease outlet resistance

Incision of bladder neck and prostate

External sphincter defeating procedures:

Over dilation

Sphincterotomy

Urethral stent

Sphincter and pelvic floor botulinum toxin injection

Intraurethral prosthesis with a self-contained urinary pump (see Chap. 10)

Cellular Therapy

I have been interested in the development of stem cells to treat bladder and urethral dysfunction since approximately 1997 (Yokoyama et al. 2000). Chancellor et al. (2000) demonstrated successful long-term survival of the injected muscle-derived stem cells in the bladder and urethra, with histochemical evidence that these muscle-derived stem cells can differentiate to smooth muscle. The technology has advanced further with urethral sphincter injection for the treatment of stress urinary incontinence (Carr et al. 2013) and it is currently in international phase 3 multicenter placebo-controlled double-blind studies.

Preclinical Results in Model of Underactive Bladder

Huard et al. (2002) demonstrated that muscle-derived stem cell (MDC) transplantation increased muscle contractility in the cryoinjury UAB model (Figs. 9.1 and 9.2):

Fig. 9.1

Physiological improvement of the injured bladder via muscle-derived cell implantation. Schematic representation of the cryoinjury model and location of the bladder strips (a). A representative contractile curve of bladder strips evoked by electrical stimulation (20 Hz 80 shocks) of control (b) and 30 s cryoinjured (c) rat bladders. Cryoinjured rat bladders with immediate saline and muscle-derived cells (pp6) injection both resulted in a significant (∗P < 0.05) decrease of contractile responses to electrical field stimulation when compared with the control bladder (d). However, the muscle-derived cells (pp6) injected at 1 week after cryoinjury in the rat bladder displayed a significant improvement in bladder contractility versus cryo + saline (1 week) injection (+P < 0.05) for up to 80 % of the normal baseline level, which was not significantly different from the control group (e). The cryoinjured mouse bladder injected with muscle-derived cells (mc13) at 1 week after injury significantly improved bladder contractility in contrast to that observed with early plated myoblasts (pp1/pp2) (f). Compared with control; +compared with cryo + saline (With permission Huard et al. (2002))

Fig. 9.2

Expression of alpha smooth muscle actin (a-SMA) in the injected muscle cells at the injected site. Bladders at 8 weeks (pp6) and 2 weeks (mc13) after injection were stained for b-galactosidase (a, b) and SMA (c, d). Although some of the cells expressing b-galactosidase did not colocalize with SMA (arrowheads e, f), many of the injected MDC expressed both markers (arrows e, f) showing their differentiation into the smooth muscle lineage. Magnification a–f,×200 (With Permission Huard et al. (2002))

Demonstrated the feasibility and survival of MDC injection into the bladder wall
Established improved detrusor contractility with MDC injection
Revealed the maturity of the β-galactosidase-expressing myofibers in the injured bladder by demonstrating the presence of neuromuscular junctions based on the accumulation of AChRs in small segments of their membrane
Supported MDC differentiating into a smooth muscle lineage when injected into the bladder wall

Peclinical data support that autologous MDC injections can be used as a nonallergenic agent to improve bladder contractility (Figs. 9.1 and 9.2) (Huard et al. 2002). Thus, cystoscopic injection of autologous muscle-derived stem cells, under local anesthesia in the outpatient clinic, may be a promising treatment strategy for patients with UAB.

Stem Cell Clinical Trials to Treat UAB

Due to the lack of medical treatment options available for persons with chronic UAB, approval was obtained from the FDA to treat a single patient with regenerative medicine stem cell therapy. The primary objective was to determine the safety of utilizing autologous muscle-derived cells (AMDC) to treat UAB. Additionally, the potential clinical efficacy of AMDC was evaluated.

In a 79-year-old man with chronic urinary retention despite having previously undergone two transurethral resections of the prostate (Levanovich et al. 2015), urodynamic studies demonstrated detrusor areflexia of over 800 ml. Alpha blockers and bethanechol have been tried on multiple occasions without benefit. The patient has been unable to void and has been performing clean intermittent catheterization 4–6 times daily for the past 5 years. The patient has had episodes of gross hematuria requiring bladder irrigation and recurrent febrile urinary tract infections requiring hospitalization.

Approximately 150 mg of the quadriceps femoris muscle was harvested under local anesthesia and the tissue was processed by Cook MyoSite (Pittsburgh, PA). The AMDC were isolated and expanded in culture over several weeks to a final concentration of approximately 250 million. Injections were performed utilizing a flexible cystoscope under direct visualization. The treatments were performed utilizing topical, local anesthesia. There were a total of 30 intradetrusor injections (0.5 ml per injection; 2 mm in depth) throughout the bladder.

No treatment-related adverse events or side effects were reported by the patient. Additionally, there were no complications during biopsy or injection, nor were there any cystoscopic abnormalities at 6 or 12 months. Global response assessment reported “moderate improvement” of UAB symptoms at 6 and 12 months. Reductions in first desire and strong urge to urinate, from 711 to 365 ml and 823 to 450 ml, respectively, were observed. A reduction in maximum cystometric capacity from 844 to 663 ml was noted as well. Using bladder diaries, the patient reported the ability to void a small volume of urine but has continued to require self-catheterization 1-year posttreatment.

The successful completion of this first report of cellular therapy to treat UAB with autologous muscle-derived stem cells has led to the FDA approval of an expanded phase 2 trial. The research study is currently underway and assesses the safety and efficacy of AMDC for UAB. In the future, cellular therapy may be a promising novel treatment for underactive bladder.

Reduction Cystoplasty

Partial cystectomy to reduce excess bladder capacity and potentially decrease the total work the detrusor must perform to adequately empty is conceptually attractive (Fig. 9.3). Over the years the technique of reduction cystoplasty has been intermittently advocated as treatment for excessively large UAB. However, the jury is still out on its efficacy over the long term as there is trend for the bladder to stretch out again over time.

Fig. 9.3

Reduction cystoplasty whereby a segment of the bladder is excised and bladder capacity surgically reduced

How is reduction cystoplasty done? A number of techniques have been described, but most commonly, the most easily accessible portion of the bladder, the bladder dome is widely excised, and bladder closed together. Kinn (1985) reported on 10 patients with UAB and was successful in reducing the bladder capacity, reducing residual urine volume, and reducing frequency of urinary infection, but found no improvement of detrusor contractility after reduction cystoplasty. More encouraging results have been suggested in patients with retained hypocontractile detrusor function (Klarskov et al. 1988). Bukowski and Perlmutter (1994) reported on the long-term outcome of reduction cystoplasty in 11 boys with prune belly syndrome. They found that short-term reductions in bladder volume may have initially contributed to the decreased incidence of urinary infections, but bladder capacity and residual volumes tended to increase over time.

Reduction cystoplasty has not been proven to yield long-term success in UAB patients in controlled studies. Cost and benefit of reduction cystoplasty should be compared with the standard of care, clean intermittent catheterization. Reduction cystoplasty may be considered select patients with diminished detrusor contractility and an excessively large bladder capacity such as a bladder capacity that is 1 or 2 l or more. Perhaps combining reduction cystoplasty with implantation of stem cells may aid toward restoration of adequate bladder contractility after surgery.

Detrusor Myoplasty

Bladder myoplasty is a major surgical method for inducing micturition in UAB patients via augmentation of the bladder with a skeletal muscle wrap (Chancellor 1994; Chancellor et al. 1994a). The method comprises the steps of transecting a patient’s rectus abdominis muscle, preserving the patient’s inferior epigastric artery and 2–4 innervating intercostal nerves, wrapping the muscle around the patient’s bladder, and attaching at least one electrical lead which is attached to a pulse generator similar to the one used for sacral neuromodulation (Fig. 9.4). Electrical stimulation from the signal generator to the bladder myoplasty can facilitate the emptying of the urinary bladder. Initial case report demonstrated encouraging result (Chancellor et al. 1994b), but due to the extensive surgery required, I decided to advance to intradetrusor injection of muscle-derived stem cells as a less invasive method to augment detrusor contractility.

Fig. 9.4

Surgical technique of detrusor myoplasty. Top drawing is a diagram showing the human rectus abdominis muscle including innervation (3) and vascularization (1), the points of attachment of the rectus abdominis muscle to the pubic symphysis (5), and the bladder (4) before detrusor myoplasty. Bottom drawing is a diagram showing the points of attachment of the rectus abdominis muscle (2) and the bladder (4) wrapped with the rectus muscle after detrusor myoplasty. (1) Blood vessels of the rectus muscle; (2) rectus muscle; (3) nerves to the rectus muscle; (4) bladder; (5) pubic symphysis; (6) pulse generator; (7) wire that leads to detrusor myoplasty

Von Heyden et al. (1998) and Van Savage et al. (2000) reported early studies with electrically stimulated detrusor myoplasty in dogs. Von Heyden et al. (1998) described anastomosing the thoracodorsal nerve to the obturator nerve and the vascular supply to the external iliac vessels. The graft was then stimulated by electrodes connected to the anastomosed neural supply and with direct muscle stimulation. Van Savage et al. (2000) described detrusor myoplasty with rectus muscle with the addition of stimulation being achieved with electrodes inserted into the muscle near the nerve entrance. Initial positive results with acute stimulation generating bladder pressures adequate for bladder emptying but bladder emptying did not improve with chronic stimulation.

Stenzl et al. (1998) reported 3 UAB patients treated with a micro-neurovascular free transfer of autologous latissimus dorsi muscle. The main neural and vascular supply to the latissimus dorsi was anastomosed to the lowermost motor branch of the intercostal nerve and to the inferior epigastric vessels supplying the rectus abdominis muscle. The transferred muscle was wrapped around the bladder covering about 75 % of the mobilized bladder and leaving only the area of the trigone and the lateral pedicles uncovered. Patients were actively contracting the lower abdominal musculature when they want to urinate. Short-term follow-up revealed peak flow rates of 18–26 ml/s and residual urine volumes of 0–90 ml. Positive results were reported in a multicenter trial of latissimus dorsi detrusor myoplasty by Gakis et al. (2011) where 24 UAB patients were followed for 46 months (Fig. 9.5). Sixteen of 24 (67 %) regained spontaneous micturition without the need for intermittent catheterization while 3 were able to reduce the frequency of catheterization.

Fig. 9.5

(a) Latissimus dorsi muscle before harvesting. Sutures mark original length of muscle. (b) Fixation of latissimus dorsi muscle in pelvis (broken line). (c) Schematic drawing of position of muscle around bladder with neurovascular connections. (d) Final intraoperative aspect of muscle in pelvis with neurovascular connections (right side) (With permission Gakis et al. (2011))

Regenerative Medicine Bladder Replacement

The term “regenerative medicine” became popularized in the late 1990s, around the time when Atala pioneered bladder regeneration research and reported 7 children with myelomeningocele (4–19 years old) and high-pressure or poorly compliant bladders were treated with an engineered bladder to enhance vascularity (Fig. 9.6) (Atala et al. 2006). A bladder biopsy was obtained from each patient and urothelial and muscle cells were grown in culture. The expanded cells were then seeded on a collagen or collagen/polyglycolic acid-based biodegradable bladder-shaped scaffold. Approximately 7 weeks after the biopsy, the engineered bladder constructs were implanted. Serial follow-up evaluation was done with a mean follow-up of 46 months. Postoperatively, the mean bladder leak point pressure decreases at capacity, and the volume and compliance increase were greater in the composite engineered bladders with an omental wrap. No metabolic consequences were noted and renal function was preserved. No stones or mucus production occurred in the reconstructed bladders.

Fig. 9.6

Construction of engineered bladder scaffold seeded with cells (a) and engineered bladder anastamosed to native bladder with running 4-0 polyglycolic sutures (b). Implant covered with fibrin glue and omentum (c) (With permission Atala et al. (2006))

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