RU2803575C1 - Method for prevention of cicatricial deformation of bladder neck after endoscopic removal of prostate hyperplasia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention is related to methods for preventing cicatricial deformity of the bladder neck after endoscopic removal of prostate hyperplasia. The method for preventing cicatricial deformity of the bladder neck after endoscopic removal of prostate hyperplasia consists of introducing a balloon catheter into the scarring area under transrectal ultrasound control by means of an ultrasound machine, inflating the balloon with elastic stretching and tearing of the cicatricial ring of the bladder neck, and exposure to give the desired shape. The contact zone of the balloon with the cicatricial ring contains a drug placed in an elastic sheath made of a polymer film, made with the possibility of releasing the drug under the action of ultrasonic vibrations of the ultrasound machine, and the elastic sheath made of a polymer film is a set of microcontainers formed between two bonded layers of a polymer film, one layer of which has a relief in the form of holes for placing the drug, and the other layer is flat, while said flat layer of the elastic sheath is attached to the body of the balloon.

EFFECT: invention provides prevention of recurrence of cicatricial deformity of the bladder neck due to simultaneous stretching of the neck and delivery of medicinal substances to this area by means of the same ultrasound devices that are used to visualize the affected area of the bladder neck and manipulate the catheter.

9 cl, 1 ex, 6 dwg, 1 tbl

Description

The invention relates to medicine, namely to surgery, and can be used in the prevention and treatment of recurrence of cicatricial deformity of the bladder neck.

It is known that one of the frequent complications of transurethral resection of the prostate (TURP) and laser enucleation of prostate hyperplasia is cicatricial deformation of the bladder neck (0.3-9.2%). Scar-sclerotic changes in the bladder neck that occur after TURP and laser enucleation of prostate hyperplasia necessitate repeated surgical interventions, which significantly reduces the quality of life of patients and negatively affects the condition of the entire genitourinary system of a man.

The most widespread are two approaches to the prevention of this relapse: a combination of endoscopic surgical treatment with the introduction of a cytotoxic agent into the bladder neck (Mitomycin, Prednisolone, Triamcinolone) and a combination of endoscopic surgical treatment with regenerative drugs (injections of hyaluronic acid, installation of collagen preparations).

In Kumar et al., Management of post-radical prostatectomy anastomotic stricture by endoscopic transurethral balloon dilatation. Scandinavian Journal of Urology and Nephrology, 2007; 41: 314315; Ramchandani et al. Vesicourethral Anastomotic Strictures after Radical Prostatectomy: Efficacy of Transurethral Balloon Dilation. Radiology 1994; 193:345-349 describes transurethral balloon dilatation under endoscopic control as a method of treating strictures of the vesico-urethral segment in patients who have undergone prostatectomy, the formation mechanism of which is not identical to cicatricial deformation of the bladder neck. However, these options for using transurethral balloon dilatation are associated with a high risk of urethral trauma, the need for anesthesia, and a high risk of infectious and inflammatory complications.

Studies on balloon dilatation of scar narrowing are described in the work of Sh.A. Abbosov, D.A. Okhobotov, N.I. Sorokin, A.B. Shomarufov, B.M. Shaparov, Ya.S. Nadzhimitdinov, Sh.T. Mukhtarov, F.A. Akilov, A.A. Kamalov. Evaluation of the effectiveness of balloon dilation of scar narrowing of the bladder neck after transurethral interventions on the prostate gland (preliminary results). Journal of Urology, 9(1):5-13, 2021, and also in the review - Sh. A. Abbosov, N.I. Sorokin, A.V. Shomarufov, A.V. Kadrev, K.Z. Nuriddinov, Sh T. Mukhtarov, F.A. Akilov, and A.A. Kamalov. Bladder neck contracture as a complication of prostate surgery: Alternative treatment methods and prospects (literature review). Urological Science, 33(2):49-55, 2022. The described methods involve the use of mechanical stretching of the fibrous-narrowed area of the urinary tract with a balloon-type urethral catheter. However, their effectiveness can be improved.

The closest in technical essence is a method for preventing cicatricial deformation of the bladder neck after endoscopic removal of prostate hyperplasia using a plastic urethral balloon catheter with an increased balloon capacity, described in patent RU 2725549 C1, Kamalov, 07/02/2020) - prototype. Using transrectal ultrasound examination of the prostate gland to identify the condition of the bladder neck, characteristic dimensions and coordinates are measured, the urethral catheter balloon is installed in the lumen of the bladder neck so that the widest part of the balloon is localized in the area of the diameter of the scar ring of the bladder neck. Then it is inflated to a volume corresponding to the diameter of the bed of the removed prostate adenoma with the formation of compression with an hourglass-type scar ring in the widest part of the balloon. Next, it is kept in an inflated state for 5 minutes, ensuring the expanding effect of the elastic force of the catheter balloon on the scar ring of the bladder neck. Maintain in an inflated state for 5 minutes, during which gradual elastic stretching of the scar ring along the length is ensured, the procedure is repeated until the desired condition of the bladder neck is obtained.

In this method, the emphasis in achieving a therapeutic effect is on mechanical stretching of the scar ring and does not involve the delivery of a drug to the scarring area, which reduces the activity of the scarring process.

At the same time, it is known from the prior art that it is possible to use standard ultrasound diagnostic devices (ultrasound) both for visualizing the affected area and for delivering medicinal substances to this area through ultrasound (therapeutic pulses) (see, for example, US 7358226 (B2) - UNIV CALIFORNIA, 04/15/2008). At the same time, differences in imaging modes, as well as in therapy modes (delivery and/or fragmentation of drugs into small particles) are known to specialists and can be established on models. However, this invention did not consider both the possibility of delivering a drug to the area undergoing balloon dilatation, and the means necessary for this purpose.

The present invention is aimed at solving the problem of increasing the effectiveness of treatment - preventing recurrence of cicatricial deformity of the bladder neck with minimal risk and without the need for surgical treatment by delivering drugs to this area using the same ultrasound machines that are used to visualize the affected area of the bladder neck and catheter manipulation.

A patented method for preventing scar deformation of the bladder neck after endoscopic removal of prostate hyperplasia consists of introducing a balloon catheter into the scarring area under transrectal ultrasound control using an ultrasound machine, inflating the balloon to ensure elastic stretching and tearing the scar ring of the bladder neck, and exposing it until the desired shape is achieved .

The difference is that the contact zone of the balloon with the scar ring contains a medicinal substance (DS), placed in an elastic shell made of a polymer film, designed to release the drug under the influence of ultrasonic vibrations of the ultrasound machine.

The method can be characterized by the fact that the elastic shell of a polymer film is a set of microcontainers formed between two bonded layers of polymer film, one layer of which has a relief in the form of holes for placing drugs, and the other layer is flat, with the said flat layer attaching the elastic shell to the body of the cylinder.

The method can also be characterized by the fact that the polymer film is made of polylactic acid and has a thickness not exceeding 1 micron, while the wells have the shape of a cone with a base diameter of 20 microns, a height of 20 microns and an angle of 35° at the apex, and the distance between the wells is 40 microns, and in addition, the fact that the elastic shell is attached to the body of the cylinder using Gluten BF-6 glue.

The method can also be characterized by the fact that the drug is selected from the group containing Prednol-L, Mitomycin, Prednisolone, Triamcinolone, and by the fact that a No. 16 Foley balloon catheter is used.

The method can also be characterized by the fact that an Aixplorer ultrasound machine (SuperSonic Imagine, Aix-en-Provence, France) with an intracavitary SuperSonic Imagine SE12-3 sensor is used, providing an effective bandwidth from 3 to 12 MHz, and also by the fact that an ultrasound machine is used Epiq 5 (Philips Medical Systems B.V., the Netherlands) with a Philips C10-4ec rectovaginal probe with an effective bandwidth of 4 to 10 MHz.

The method can also be characterized by the fact that the course of treatment is 10 sessions lasting 5 minutes, every 2.5-3 weeks with a gradual increase in intervals up to 6 weeks.

The technical result of the invention is the prevention of recurrence of cicatricial deformation of the bladder neck due to simultaneous stretching of the neck and delivery of medicinal substances to this area using the same ultrasound machines that are used to visualize the affected area of the bladder neck and manipulate the catheter.

The patented method implements transurethral balloon dilatation of a scar-deformed bladder neck using a urethral Foley catheter with the possibility of ultrasound-induced drug release under transrectal ultrasound control using a local anesthetic, which avoids anesthesia, and also allows for delivery of the drug directly to the area active scarring.

The creature is illustrated in the figures, where:

fig. 1 - Ultrasound image of the manipulation area;

fig. 2 - diagram of the placement of the catheter and sensor;

fig. 3 - catheter with PV placed in an elastic sheath, side view;

fig. 4 - the same as in Fig. 3 - cross-sectional view in the middle part of the cylinder;

fig. 5 - view of the shell from the outside of the cylinder (enlarged);

fig. 6 - cross-section of the microcontainer structure.

In fig. Figure 1 shows an ultrasound image of the manipulation zone, where the positions indicate: 1 - bladder; 2 - contracture of the bladder neck; 3 - location of the balloon catheter.

In fig. Figure 2 shows a diagram of balloon dilatation: 4 - Foley catheter; 5 - catheter balloon; 6 - shell with drug; 7 - ultrasound sensor; 71-zone of influence of ultrasonic vibrations on the shell 6.

In fig. 3-4 shows the placement of the elastic shell 6 with the drug on the body of the cylinder 5 and fixation with a layer of glue 8.

In fig. 5-6 shows a micrograph of the relief of the elastic shell 6 with holes 9 filled with LVs: relief film 91, flat film 92, thermal fusion zone 93 of films 91 and 92; pos. 93 - LV.

A polydimethylsiloxane (PDMS) stamp for preparing an elastic shell 6 with drugs is made on the basis of a Kapton mold prepared by laser ablation. The light source was Cobolt Tor XS (532 nm, 50 μJ, 1.9 ns) in combination with a focusing lens (Olympus 4x/0.1). To form one well, 25 consecutive laser pulses with an energy of 50 μJ were used. The resulting wells have the shape of a cone with a base diameter of 21±1 µm, a height of 20±2 µm and an angle of ~35°. The distance between wells was set to 40 μm.

The PDMS matrix was prepared by double casting a Kapton master mold. At the first stage, the Kapton master mold was filled with PDMS mixed in a mass ratio of 1:10 (hardener:base). Polymerization of PDMS was carried out at a temperature of 60 degrees Celsius for two hours. After curing, a layer of gold was applied to the resulting PDMS matrix, and a PDMS solution prepared in a similar way was again poured onto the gold-plated surface. The gold release layer prevents positive and negative prints from sticking together. Thus, the final PDMS matrix is formed, which is used for the production of films with microcontainers, exactly repeating the relief of the master mold.

The micro-container film production process consists of several steps. First, the PDMS stamp is immersed in a PLA (polylactic acid)-chloroform solution (1.5 wt%). The stamp is immersed in the solution and kept in it for 10 seconds to ensure wetting of the surface. After this, the stamp was removed at a constant speed of 1 mm/s to form a uniform film on the PDMS surface.

At the second stage, fine Prednol-L powder was loaded into the wells of the relief film. Excess powder was removed with a brush.

At the third stage, the resulting microcontainers were sealed by thermal fusion of relief and flat PLA films for 5 s at 80 C. For this, a flat PLA film (3.5 wt.% in chloroform) was pre-prepared on a glass slide using a thin film applicator (Baker applicator gap 100 µm, 1 mm/s). After thermal melting, the PDMS stamp was cooled to room temperature and separated from the film. The produced films with microcontainers had an area of 6 cm2.

The surface of the Foley catheter balloon 5 was cleaned with alcohol and dried with compressed air. A thin layer of medical glue 7 Gluten BF-6 was applied to the surface of the balloon and left for 30 s, then the film with microcontainers loaded with Prednol-L was wrapped around balloon 5 and carefully pressed to its surface.

The method was implemented using ultrasound devices; the same devices were used to simulate the drug release modes through ultrasonic exposure.

The Aixplorer ultrasound machine (SuperSonic Imagine, Aix-en-Provence, France) with the SuperSonic Imagine SE12-3 intracavitary probe provided an effective bandwidth of 3 to 12 MHz. The ultrasound penetration depth was set to the prostate area. Preset mechanical index Ml 1.6. The device provided grey-scale and SWE imaging.

An Epiq 5 ultrasound machine (Philips Medical Systems B.V., the Netherlands) with a Philips C10-4ec recto-vaginal probe provided an effective bandwidth of 4 to 10 MHz. The ultrasound penetration depth was set to the prostate area. Preset mechanical index MI 1.0.

A method for preventing cicatricial deformation of the bladder neck is carried out as follows.

2 days before the balloon dilatation session, to obtain a systemic antiproliferative effect, the patient is prescribed methylprednisolone 8 mg × 1 time per day in the morning - the intake continues for 5 days. The evening before surgery, the patient takes 3 grams of fosfomycin as antibiotic prophylaxis before the procedure.

Before the manipulation, a preliminary study of the volume of the bladder is performed using transabdominal ultrasound (ultrasound). A volume of 150-200 ml of urine is considered optimal for performing the procedure safely. The patient is positioned on the urological chair in the lithotomy position.

To assess the condition of the bladder neck, before starting the procedure, a transrectal ultrasound examination of the prostate gland and bladder neck is performed in longitudinal and transverse sections, measuring the length and anteroposterior size of the prostate tissue defect (after removal of hyperplasia) in the widest part, the bilateral size of the defect in the widest part, the volume of the defect, the anteroposterior size of the bladder neck.

A balloon-type urethral catheter with a drug coating with ultrasound-induced release of the drug is introduced into the lumen of the bladder with preliminary administration of an anesthetic into the urethra. The most optimal method for this procedure is the use of a No. 16 Foley balloon catheter.

For clear ultrasound visualization and transposition of the catheter in the bladder, the balloon is inflated to 5 ml.

Under transrectal ultrasound control, the urethral catheter balloon is installed in the bed of the removed prostate adenoma.

The balloon of the urethral catheter is inflated until it “fills” the prostate tissue defect, kept in the inflated state for 5 minutes, during which the drug is released due to the action of ultrasonic waves and its direct delivery to the scarring area, as well as gradual elastic stretching of the prostate bed .

Next, the balloon is deflated to 5 ml, after which, under ultrasound control, the balloon of the urethral catheter is installed into the lumen of the bladder neck so that the widest part of the balloon is localized in the area of the diameter of the scar ring of the bladder neck.

The urethral catheter balloon located in the neck is carefully inflated to a volume slightly larger than the diameter of the bed of the removed prostate adenoma, so that the walls of the balloon exert pressure on the scar ring. In this case, an hourglass-type deformation of the balloon is formed in the area of the scar ring. The balloon is left in this position for 5 minutes, during which, due to its elasticity, the balloon tends to take a spherical shape and eliminate compression, due to which gentle elastic stretching and tearing of the scar ring of the bladder neck occurs. In parallel with this, the delivery of the medicinal substance directly to the scarring area continues, which makes it possible to reduce the activity of the scarring process.

After a five-minute exposure, the urethral catheter is deflated and removed.

In order to evaluate the results of the procedure, the length of the removed prostate bed, the anterior-posterior dimension in the widest part, the bilateral dimension in the widest part, the anteroposterior dimension and the volume of the bladder neck defect are re-measured.

The results of these measurements reflect the condition of the cervix before and after the session, that is, they visualize the dilating effect of the procedure. This study allows us to assess the individual dynamics of the patient according to the above indicators.

After completion of the manipulation, uroflowmetry is performed to monitor the patient’s urodynamic status.

This procedure is carried out in several sessions until the desired effect is achieved and the results of stretching the bladder neck are consolidated. The optimal time to start treatment is 3 weeks from surgical treatment for cicatricial deformation of the bladder neck and repeated sessions of balloon dilatation of the bladder neck with a gradual increase in the time between repeated sessions to 4-6 weeks with a course of at least 6 procedures.

The clinical effect of this method is achieved by stabilizing the scar ring at a hydrodynamically acceptable level. The scar ring in case of systematic mechanical tear, which is achieved through several sessions of gradual elastic stretching of the fibrous ring with a catheter balloon, should be stabilized due to fibrosis of the tear areas. In this case, the catheter balloon provides gradual elastic stretching of the fibrous ring, preventing its excessive trauma and protecting against aggressive scarring of the bladder neck. An improvement in the effect compared to standard bladder neck dilatation is provided by a urethral catheter with V3-induced drug release, which is contained in the coating of the urethral catheter balloon. In this case, the danger of uncontrolled exposure to ultrasonic vibrations on tissue is ensured by the choice of the energy index Ml in the range of 1.0-1.6.

Clinical example. Patient B., 53 years old.

The patient has a history of dysuric symptoms for 4 years; conservative therapy with alpha-blockers was without effect.

Upon admission to the patient: Prostate volume - 59 cm ³ ; The volume of residual urine is 10 ml; Maximum urination rate - 6.6 ml/sec, Average urination rate - 4.3 ml/sec; IPSS - 22 points; QoL - 4 points.

The patient underwent laser enucleation of prostate hyperplasia on January 13, 2021, and 3 months later, due to the development of cicatricial deformation of the bladder neck, laser incision of the bladder neck was performed. Two months later, due to recurrence of cicatricial deformity, the patient underwent bipolar transurethral resection of cicatricial deformity of the bladder neck.

According to uroflowmetry data from June 24, 2021 (the day the patient visited the clinic): Qmax - 11.2 ml/sec; Qave - 6.7 ml/sec. During cystoscopy, the bladder neck is patent, the area of the TUR defect and the bladder neck are covered with fibrin.

3 weeks after the operation, on June 25, 2021, the patient underwent the first session of balloon dilatation of the bladder neck with a urethral catheter with ultrasound-induced release of the drug - prednisolone (Prednol-L) in saline solution. Session duration - 5 minutes. A shell made of a polylactic acid film with a thickness of 0.7 microns is attached to the surface of the cylinder. The holes have the shape of a cone with an angle of 35°° at the apex; base diameters and heights are 20 µm, and the distance between wells is 40 µm. Coverage area is approx. 6 sq.cm. A single dose of prednisolone (Prednolom-L), located in the wells of the membrane and released into the body of the cervix, is approx. 102±33 mcg.

The ultrasound system “Epiq 5” (Philips Medical Systems B.V., the Netherlands) was used. Studies of the urinary tract were carried out in a known manner.

Ultrasonic vibrations for drug release were supplied from the Epiq 5 system through a Philips C10-4ec recto-vaginal sensor with an effective bandwidth of 4 to 10 MHz. Settings were made for the depth of penetration into the prostate area: the mechanical index (MI) was set to 1.0.

Subsequently, the patient underwent another 9 sessions of balloon dilatation with a drug.

Changes in urodynamic parameters during observation for 10 months demonstrate the absence of deterioration in the patient's urodynamics.

At the beginning of treatment, balloon dilatation sessions were performed every 2.5-3 weeks with a gradual increase in intervals up to 6 weeks, the last procedure was performed on the patient on 04/08/2022 (see table).

Claims (8)

1. A method for preventing scar deformation of the bladder neck after endoscopic removal of prostatic hyperplasia, which consists of introducing a balloon catheter into the scarring area under transrectal ultrasound control using an ultrasound machine, inflating the balloon to ensure elastic stretching and tearing the scar ring of the bladder neck and exposing it to the desired shape , characterized in that the area of contact of the balloon with the scar ring contains a medicinal substance (drug) placed in an elastic shell made of a polymer film, configured to release the drug under the influence of ultrasonic vibrations of an ultrasound machine, while the elastic shell of a polymer film is a set of microcontainers, formed between two bonded layers of polymer film, one layer of which has a relief in the form of holes for placing drugs, and the other layer is flat, with the said flat layer attaching the elastic shell to the body of the cylinder. 2. The method according to claim 1, characterized in that the polymer film is made of polylactic acid and has a thickness not exceeding 1 micron, while the wells have the shape of a cone with a base diameter of 20 microns, a height of 20 microns and an angle of 35° at the apex, and the distance between wells is 40 µm. 3. The method according to claim 1, characterized in that the elastic shell is attached to the body of the cylinder using Gluten BF-6 glue. 5. The method according to claim 1, characterized in that the drug is selected from the group containing Prednol-L, Mitomycin, Prednisolone, Triamcinolone. 6. The method according to claim 1, characterized in that a No. 16 Foley balloon catheter is used. 7. The method according to claim 1, characterized in that the Aixplorer ultrasound machine is used with the SuperSonic Imagine SE12-3 intracavitary sensor, providing an effective bandwidth from 3 to 12 MHz. 8. The method according to claim 1, characterized in that an Epiq 5 ultrasound machine with a Philips C10-4ec rectovaginal probe with an effective bandwidth of 4 to 10 MHz is used. 9. The method according to claim 1, characterized in that the course of treatment is 10 sessions lasting 5 minutes every 2.5-3 weeks with a gradual increase in intervals up to 6 weeks.