RU2849280C1 - Non-surgical treatment of cervical stenosis - Google Patents

Abstract

FIELD: medicine, specifically gynaecology.

SUBSTANCE: around the circumference of the external axis at points 3, 6, 9, 12 o'clock on the conditional dial, 0.5 ml of the bioimplant "SFERO®gel Medium" is injected into the cervix using a 25G 1 needle to a depth of 3 mm, then, while manipulating the cervix with bullet forceps and a lower speculum, perform a multi-position point injection of 1.5 ml of the bioimplant around the entire circumference and length of the cervical canal at points 3, 6, 9, 12 o'clock points of the conditional dial to a needle depth of 25 mm, and 28 days after the first administration, repeat the course of treatment with the bioimplant "SFERO®gel Medium" in a total volume of 2 ml in the same sequence.

EFFECT: this method allows restoring the patency of the cervical canal and ensuring adequate examination of patients with cervical pathology, creating conditions for the prevention of inflammatory processes and elimination of complaints that reduce the quality of life of patients of reproductive age.

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Description

The invention relates to the field of medicine, namely to gynecology and oncology, and can be used to treat cervical stenosis of various etiologies.

Cervical stenosis occurs as a result of the cicatricial process in the cervical canal, which leads to its narrowing or complete occlusion with obliteration of the external os (Vitale SG, De Angelis MC, Della Corte L et al. Uterine cervical stenosis: from classification to advances in management. Overcoming the obstacles to access the uterine cavity. Arch Gynecol Obstet. 2024 Mar;309(3):755-764).

Cervical stenosis can be congenital or acquired, developing after excision or conization for cervical intraepithelial neoplasia or cervical cancer (Brun J.L., Youbi A., and Hocke C. / Complications, sequelae and outcome of cervical conizations: evaluation of three surgical techniques / J Gynecol Obstet Biol Reprod, Paris. 2002; 31 (6): 558-64), due to traumatic disruption of the anatomical integrity of the cervix during childbirth or invasive manipulations under the influence of thermal, chemical or mechanical factors (Vitale SG, Della Corte L, Ciebiera M, et al. Hysteroscopic endometrial ablation: from indications to instrumentation and techniques - a call to action. Diagnostics. 2023; 13: 339), after radiation therapy for malignant neoplasms of the pelvic organs (Christianson MS, Barker MA, Lindheim SR. Overcoming the challenging cervix: techniques to access the uterine cavity. J Low Genit Tract Dis. 2008). The risk of developing cervical stenosis increases in the presence of endometriosis, recurrent vaginal infections, and nabothian cysts (Barbieri RL. Stenosis of the external cervical os: An association with endometriosis in women with chronic pelvic pain. Fertil Steril. 1998;70:571-573).

In addition, progressive narrowing of the cervical canal can be caused by atrophic and/or dystrophic processes arising as a result of estrogen deficiency in the peri- and postmenopausal periods (Debby A, Malinger G, Glezerman M, Golan A. Intra-uterine fluid collection in postmenopuasal women with cervical stenosis. Maturitas. 2006;55:334-337. doi: 10.1016/j.maturitas.2006.04.026).

Cervical stenosis is often asymptomatic, especially with incomplete cervical occlusion, where menstrual blood flow is preserved. The severity of clinical symptoms correlates with the degree of cervical canal narrowing and may include pelvic pain, menstrual irregularities such as amenorrhea (absence of menstruation), dysmenorrhea (painful menstruation), abnormal intermenstrual bleeding, and discomfort and pain during intercourse. With complete cicatricial fusion of the cervical canal, menstrual flow is delayed and accumulates in the uterine cavity (hematometra), leading to the development of inflammatory and purulent processes (pyometra), accompanied by acute pain. Retrograde menstrual blood flow through the fallopian tubes into the abdominal cavity can contribute not only to an increased risk of endometriosis but also to pelvic peritonitis.

In women of reproductive age, cervical stenosis is a cause of infertility (Izhar R, Husain S, Tahir MA, Husain S. Cervical stenosis and pregnancy rate after ultrasound-guided cervical dilation in women undergoing saline infusion sonography. J Ultrason. 2020;20:e116). Replacement of the columnar epithelium of the endocervix with fibrous tissue leads to disruption of cervical mucus production, which can hinder the movement and survival of sperm. When the cervical canal adhesions, mechanical barriers arise not only for the spontaneous movement of sperm but also for the transfer of embryos as part of ectopic reproductive technologies.

An obliterated external os and/or occluded cervical canal limits access to the uterine cavity and creates difficulties in performing a number of diagnostic and/or therapeutic procedures, including hysteroscopy, endometrial biopsy (curettage), sonohysterography, hysterosalpingography, etc. Thus, in patients during menopause, due to cervical stenosis, ultrasound examination reveals fluid in the uterine cavity (serosometra); in combination with an endometrial thickness of > 3 mm, an examination of the endometrial cavity and a biopsy are recommended due to the risk of endometrial malignancy, which is complicated by cervical canal obstruction.

In addition, the inability to obtain biomaterial directly from the cervical canal limits population-based screening for cervical cancer and hinders effective monitoring of patients with cervical pathology after organ-preserving surgical interventions (excision or conization).

Thus, cervical stenosis is an important obstetric-gynecological and oncological problem and requires the search for adequate treatment methods available for implementation in outpatient settings.

The main non-surgical methods of treating cervical stenosis include the use of medical devices or instruments for stenting the cervical canal or mechanical separation of scar tissue. Urological catheters (Tan Y., Bennett M. Urinary catheter stent placement for the treatment of cervical stenosis. Aust N Z J Obstet Gynaecol. 2007;47:406-9) or intrauterine devices with or without hormones (Nasu K., Narahara H. Management of severe cervical stenosis after conization by detention of nylon threads tied up to an intrauterine contraceptive device. Arch Gynecol Obstet. 2010; 281: 887-9; Motegi E., Hasegawa K., Kawai S. et al. Levonorgestrel-releasing intrauterine system placement for severe uterine cervical stenosis after conization: two case reports. J Med Case Rep. 2016;10:56), traditional Hegar dilators or special intracervical devices (Park JY, Lee YH, Chong GO, Hong DG. A uterine cervix supporting device (Con-CapTM) for reducing canal stenosis after Loop Electrosurgical Excisional Procedure. Technol Health Care. 2021;29(5):955-962; Vieira MA, de Araüjo RLC, da Cunha Andrade CEM, Schmidt RL, Filho AL, Reis RD. A randomized clinical trial of a new anti-cervical stenosis device after conization by loop electrosurgical excision. PLoS One. 2021;16(1) ensure the outflow of menstrual flow, thereby preventing the occurrence of inflammatory processes and pain syndrome.

However, all these means do not act on the structure of fibrous tissues of the cervix and are a temporary measure; in addition, their implementation often requires inpatient conditions and/or anesthesia using lidocaine-containing agents, which have a number of side effects.

Non-surgical treatment also includes the use of dried seaweed, Laminaria, as an osmotic dilator. In obstetrics and gynecology, Laminaria sticks, made from the stems of Laminaria digitata and Laminaria japonica, are often used to dilate the cervix. Due to its hygroscopic properties, Laminaria absorbs fluid from the cervical tissue and swells in diameter, reaching its maximum dilation of 9-12 mm within 24 hours.

A method for producing kelp sticks for obstetrics and gynecology is known (RU 2043119 C1). A new species of seaweed, Laminaria saccharina, is used to produce the kelp sticks. Its primary property, used for cervical dilation—swelling—is 1.5-2 times greater than that of known kelp species. Several kelp rods are inserted into the cervical canal, each one strictly parallel to the previous one and held in place for approximately 15 seconds to prevent it from being expelled from the cervical canal by uterine contractions.

Suppositories containing micronized powder of Japanese or saccharinate laminaria with a particle size of no more than 200 microns and a 1:1 ratio of active ingredient to suppository base (RU 2319495 C1) are also used for cervical dilation. Unlike sticks, suppositories can be inserted into the cervical canal without the assistance of medical personnel.

However, to accommodate both sticks and suppositories, a certain degree of expansion of the external os is necessary, i.e., when the latter is obliterated, the use of laminaria-containing products is impossible (Lichtenberg ES. Complications of osmotic dilators. Obstet Gynecol Surv. 2004;59:528-536. doi: 10.1097/00006254-200407000-00022).

Various devices and agents located in the cervical canal can facilitate the access of vaginal microflora, including pathogenic ones, into the uterine cavity, thereby increasing the risk of infection.

To expand the cervical canal, medications are used - prostaglandin analogues that cause luteolysis and the elimination of the progesterone block, leading to structural changes in the cervix due to the effect on the contractility of the smooth muscle tissue of the uterus, the consistency of the cervix and the degree of patency of the cervical canal. Thus, misoprostol, an analogue of prostaglandin _E1, when used at a dose of 200 mcg vaginally 3 hours before hysteroscopy, facilitates the passage of the device tube through the cervical canal in 75.41% of cases versus 27.87% in the group without the use of the drug (Nandhini B, Maurya DK, Keepanasseril A, Kubera NS. Effect of cervical priming with misoprostol on cervical entry in women undergoing vaginoscopic hysteroscopy for evaluation of abnormal uterine bleeding: a randomized controlled trial. Arch Gynecol Obstet. 2018;298:133-137. doi: 10.1007/s00404-018-4764-y). The effectiveness of Dinoprostone, a prostaglandin _E2 analogue, in cervical ripening before office hysteroscopy is reported (Inal HA, Ozturk Inal ZH, Tonguc E, Var T. Comparison of vaginal misoprostol and dinoprostone for cervical ripening before diagnostic hysteroscopy in nulliparous women. Fertil Steril. 2015;103:1326-1331. doi: 10.1016/j.fertnstert.2015.01.037).

However, medications require long-term use, often have a number of side effects, and are a temporary measure that requires repeated dosing before each intrauterine procedure.

A method is known for activating regeneration processes with autologous platelet-rich plasma (RU 2781150 C1) for the purpose of scarless restoration of the cervical canal after surgery for cervical intraepithelial neoplasia of varying severity, in which blood, 28 days after surgery on the cervix, is drawn into a 20 ml syringe with 2 ml of a hemopreservative with sodium citrate, then 13 ml of the patient's blood is collected into the same syringe, the blood and hemoconcentrate are mixed, the resulting mixture is introduced into a test tube and centrifuged at 3500 rpm for 8 minutes, then a targeted collection of a layer of platelet-rich plasma - 0.5 ml is performed into a sterile syringe, after which an echogenic spinal needle with a cut thickness of 25G and a length of 80 mm is attached to the syringe, which is inserted into the cervical canal under ultrasound control The canal is then visualized with an echogenic needle in the cervical canal and autologous plasma is injected into the papules along the entire circumference and length of the cervical canal. This method promotes postoperative healing by primary intention of the cervical tissue and ensures cervical canal patency.

However, this method is used postoperatively and is intended to prevent cervical stenosis by accelerating tissue regeneration by primary intention after cervical manipulation. Its use in therapeutic interventions for cervical stenosis involves initial surgical excision of tissue followed by the administration of platelet-rich plasma. Furthermore, the production of platelet-rich plasma not only requires specialized equipment (hourglass-shaped tubes, centrifuge) but may also have a number of contraindications related to the patient's medical condition, which prevents both blood collection and the production of complete plasma. Delivery of plasma to the walls of the cervical canal also requires additional instrumentation and hardware (ultrasound, echogenic needle), which may not always be available in outpatient settings.

The closest (prototype) is the method of treating fibrous degeneration of the skin, subcutaneous connective tissue and oral mucosa with the biomimetic SFERO®gel (Zorkina S. Treatment of multifactorial fibrous degeneration of the skin and subcutaneous connective tissue using the bioimplant SFERO®gel / Aesthetic medicine. - 2023, 1. - pp. 77-81). Biodegradable implant made of biological polymeric materials (biopolymers) - a composition of the heterogeneous implantable gel SFERO®GEL is a microstructured biopolymer hydrogel (FSR 2012/13033 dated 01.02.2012) (V.I. Sevastyanov, N.V. Perova Practical medicine. - 2014, 8 (84) - pp. 110-116). Sphero®GEL is obtained from the hydrolyzate of collagen-containing tissues of animal origin, using the technology of ultradispersion of hydrogels with subsequent radiation cross-linking. In essence, Sphero®GEL, containing virtually all components of the extracellular matrix of tissues of animal origin, belongs to bioactive biomimetic hydrogels. The composition of the drug includes both the main components of the extracellular matrix (collagen, proteoglycans and glycoproteins), and other biologically active substances, including peptides, amino acids, uronic acids, monosaccharides, growth factors, etc. The biological safety of Sphero®GEL has been proven in vitro and in vivo experiments (D.V. Davydov, L.K. Brizhan, A.A. Kerimov et al. Application of orthobiological methods in the treatment of gunshot wounds of the extremities / Traumatology and Orthopedics. - 2023, 59. - pp. 21-26).

The established method involved administering a Light version of SFERO®gel using a needle technique to separate fibrotic tissues of the cheeks, lips, and chin. The Light version was then administered in areas of severe fibrosis, while the Medium version was additionally administered in more pliable areas, allowing for larger amounts of gel. The volume of injected gel varied from 2 to 16 ml. After two months, positive results were noted, with increased facial tissue mobility and a reduction in the defect in the right commissure and lower lip. This allowed the transition to a cannula technique for administering the previously used SFERO®gel bioimplant, supplemented by invasive RF treatments using the Innofill device. After 6 months of therapy, restoration of the mucous membranes and underlying tissues of the lips and gums was achieved with the participation of a dentist using the sequential application of SFERO®gel Long, SFERO®gel Medium, and SFERO®gel Light in 0.5 ml doses. After 9 months of bioregeneration with SFERO®gel, positive dynamics were noted: a change in skin color to a flesh-colored pink, a decrease in tissue tension and facial stiffness (according to the patient), restoration of their mobility with the ability to form skin folds in the cheek area, an increase in the amplitude of oral opening and the ability to retain water, and improved articulation. The use of this method made it possible to correct fibrous degeneration of the skin and subcutaneous fat with restoration of the structure of the epidermis, dermis, and hypodermis, as well as the mucous membranes of the oral cavity.

However, the disadvantage of this method is that the cervical canal, on the one hand, has a different functional structure - stroma covered with columnar epithelium, on the other hand, when correcting fibrously altered cervical tissue, it is necessary to achieve complete resorption of the latter and restoration of the tubular shape of the cervical canal in order to ensure its physiological function - access to the uterine cavity.

The technical result is achieved by the fact that, just as in the known method, SFERO®gel is administered using a needle technique.

The peculiarity of the claimed method is that 0.5 ml of the bioimplant "SPHERO®gel Medium" is pointwise introduced into the stroma of the cervix at the 3, 6, 9, 12 o'clock positions of the conventional clock face using a 25G 1 needle to a depth of 3 mm, then, while simultaneously manipulating the cervix using bullet forceps and a lower speculum, a pointwise multi-positional introduction of the bioimplant of 1.5 ml is carried out along the entire circumference and length of the cervical canal at the 3, 6, 9, 12 o'clock positions of the conventional clock face to a depth of 25 mm of the needle and 28 days after the first introduction, a repeated course of treatment with the bioimplant "SPHERO®gel Medium" is carried out in a total volume of 2 ml in the same sequence.

The invention is explained by a detailed description, a clinical example and illustrations, which depict:

Fig. 1 - photo illustration of patient M.: external os of the cervix before treatment of stenosis.

Fig. 2 - photo illustration: syringe with bioimplant "SPHERO®gel Medium", needle size 25G 1.

Fig. 3 - photo illustration of patient M.: at a follow-up examination 1 month after 2 courses of treatment: the cervix is fully formed, with complete epithelialization; the width of the external os and cervical canal is 4 according to Hegar, no signs of stenosis were detected.

Fig. 4 - photo illustration of an ultrasound scan of patient M., at a follow-up examination 3 months after treatment: the cervical canal can be traced throughout its entire length.

The method is carried out as follows.

The patient undergoes a gynecological examination. After the patient's external genitalia are cleaned, the cervix is exposed using a sterile metal Otto speculum and an anterior vaginal wall elevator. It is then treated with a 0.05% aqueous chlorhexidine solution and secured with a 2 ml syringe containing the SFERO® gel Medium bioimplant (Fig. 2). Anesthetic gel is applied to the cervix. Under visual control, the cervix is pulled toward the vaginal introitus using a 2 ml syringe filled with the 2 ml syringe containing the SFERO® gel Medium bioimplant (Fig. 2). A 25G 1 (0.5x25) needle with no more than 0.5 ml of the SFERO®gel Medium bioimplant is inserted into the cervical stroma along the circumference of the external os at the 3, 6, 9, and 12 o'clock positions on a conventional clock face to a depth of 3 mm. Next, while simultaneously manipulating the cervix with bullet forceps and a lower speculum, the remaining volume of the biomimetic (1.5 ml) is administered pointwise (papularly) in a multi-positional manner along the entire circumference and length of the cervical canal at the 3, 6, 9, and 12 o'clock positions on a conventional clock face to a depth of 25 mm. The total injection volume is 2 ml. A repeat course (procedure) is performed 28 days after the first injection in the same sequence.

Due to the shortening of the cervical canal following cervical resection, the specified needle length is sufficient for circumferential injection of the drug into the walls of the cervical canal, reaching the internal os. The 0.5 mm needle diameter minimizes damage to the capillaries of the cervical mucosa, ensuring a minimally invasive and bloodless procedure.

Clinical case.

Patient M., 38, diagnosed with carcinoma in situ of the external cervix. Cervical resection scheduled for 2022. No evidence of progression.

She presented herself in September 2024 to the outpatient department of the A.F. Tsyb Medical Research Center for Gynecological Diseases for a preventive gynecological examination as part of her regular follow-up care. The patient complained of nagging lower abdominal pain during the premenstrual period and painful menstruation during the first two days of her menstrual cycle. Her medical history included: in 2022, a histological examination of a cervical biopsy revealed CIN III (squamous cell carcinoma in situ), and she underwent radiosurgical conization of the cervix at her place of residence.

A standardized examination at the place of residence was conducted only within a year after the surgical procedure. According to the examination data: Cytological examination of a scraping from the surface of the cervix and cervical canal - conclusion: NILM (normal); PCR analysis for HPV - not detected.

At her regular checkup at 18 months, cervical stenosis (narrowing of the external os) was diagnosed. As part of the examination, a cytological examination of a cervical scraping was performed, with the result being NILM. Cervical cytological data are missing. According to the patient, adequate examinations had not been performed over the past year due to the technical impossibility of collecting biopsy material from the cervical canal due to the stenosis, and preliminary bougienage was not offered.

Gynecological examination on day 7 of the menstrual cycle revealed normal development of the external genitalia. The vagina is capacious, the vaginal walls are prolapsed, and the mucosa is normal. Speculum examination revealed a formed cervix, the mucosa is visually unchanged, and the external os is pinpoint (it passes Hegara 1 with difficulty) (Fig. 1). The uterine body is not enlarged, and the appendages are normal.

A vaginal swab was taken to determine the degree of purity. Based on the satisfactory results, the patient underwent treatment for cervical stenosis with the insertion of a 2 ml SFERO®gel Medium bioimplant (Figure 2).

After the patient's external genitalia were treated, the cervix was exposed using a speculum, treated with a 0.05% aqueous chlorhexidine solution, and grasped with forceps. Topical anesthesia was administered. Using forceps positioned around the external os at the 3, 6, 9, and 12 o'clock positions, 0.5 ml of the preparation was injected into the cervical stroma using the papular technique to a depth of 3 mm. Next, 1.5 ml was injected around the entire circumference of the cervical canal using papular techniques at the 3, 6, 9, and 12 o'clock positions along the cervical canal to the internal os (20 mm). The needle used ensured delivery of the biogel across the surface of the cervix and along the cervical canal to the internal os.

On the 28th day after the first administration of the drug, a second injection of the bioimplant “SFERO®gel Medium” was performed in a volume of 2 ml using a similar method and technique.

At a follow-up examination, one month after two courses of SFERO®gel Medium bioimplant injections, the patient had no active complaints and reported no pain in the pre- or perimenstrual periods. Gynecological examination revealed normal development of the external genitalia. Speculum examination revealed a spacious vagina with a normal mucosa. The cervix was fully formed and fully epithelialized. The width of the external os and cervical canal was 4 according to Hegar, with no signs of stenosis (Fig. 3).

Under conditions of the restored cervical canal, scrapings were obtained from both the surface of the cervix and the cervical canal. Cytological examination revealed NILM. PCR analysis for HPV (HCR) was negative.

At 3 months, a pelvic ultrasound with cervicometry was performed to confirm cervical canal patency. Cervicometry revealed the endocervix to be up to 6 mm, with minor hypoechoic areas. Vascularity (color and echometry) was within normal limits. The cervical canal was traceable throughout its entire length (Figure 4).

Thus, in a patient with stenosis of the external os and cervical canal, which developed as a complication following surgery (cervical conization) for carcinoma, the SFERO®gel Medium bioimplant was inserted to restore cervical canal patency. This goal is achieved through the ability of the biomimetic to restructure fibrously altered tissues of the cervical canal, restoring its original structure.

This method allowed for differentiated, targeted insertion of the bioimplant along the surface of the cervix (exocervix) and along the circumference of the cervical canal walls (endocervix) using the papular technique, extending to the internal os. The 25G needle, 1-25 mm in length, is sufficient to treat the entire length of the cervical canal, shortened after resection. Its 0.5 mm diameter minimizes damage to capillaries, which become more fragile and branched due to the healing process after conization, thereby ensuring a bloodless and minimally invasive procedure.

The proposed method allows for the restoration of cervical canal patency and ensures adequate examination of patients with cervical pathology. Furthermore, allowing unimpeded menstrual flow has created conditions for preventing inflammation and alleviating complaints that reduce the quality of life of reproductive-age patients.

The ease of implementation, minimally invasive nature, and absence of blood loss made it possible to perform the procedure on an outpatient basis without the need for additional equipment and consumables, or medical personnel with different skills.

Claims (1)

A method for non-surgical treatment of cervical stenosis, including the introduction of SFERO® gel using a needle technique, characterized in that 0.5 ml of the SFERO® gel Medium bioimplant is pointwise introduced into the cervical stroma at the 3, 6, 9, 12 o'clock positions of a conventional clock face, using a 25G 1 needle to a depth of 3 mm, then, while simultaneously manipulating the cervix using bullet forceps and a lower mirror, 1.5 ml of the bioimplant is pointwise multi-positionally introduced along the entire circumference and length of the cervical canal at the 3, 6, 9, 12 o'clock positions of a conventional clock face to a needle depth of 25 mm, and 28 days after the first introduction, a repeated course of treatment with the SFERO® gel Medium bioimplant is carried out, in a total volume of 2 ml in the same sequence.