Hydrogel implant technology offers new hope for women seeking reversible sterilization and endometriosis treatment

In a recently published study, Advanced MaterialsResearchers have developed a biocompatible, stimulus-responsive hydrogel implant that could provide reversible fallopian tube blockage, contraception and the prevention of endometriosis (uterine-like tissue growing outside the uterus).

investigation: Reversible mechanical contraception and endometriosis treatment using stimuli-responsive hydrogelsImage credit: Ws Studio1985/Shutterstock.com

background

Because the fallopian tubes are essential for fertility, tubal ligation is a common form of contraception in the United States, but more than 10% of women regret the procedure due to complications and their desire to have children.

Reconnection is complicated and often unsuccessful. Alternatives such as the Essure device face problems. Stimuli-responsive hydrogels offer effective contraception and prevention of endometriosis by preventing retrograde menstruation (backflow of menstrual blood into the pelvic cavity) and show promise for reversible tubal occlusion. Further research is needed to improve it. efficacysafety, and reversibility.

About the Research

All chemicals were obtained from Sigma-Aldrich, except formalin (ROTIHistofix 4%, ROTH) and poly(ethylene glycol) diphotodegradable acrylate (PEGdiPDA) crosslinker. PEGdiPDA was synthesized and stored in the dark.

Purified N-(2-hydroxyethyl)acrylamide (NHEA) and poly(ethylene glycol) diacrylate (PEG diacrylate) were used to prepare hydrogels, which were then injected into Teflon tubing, polymerized, and dried. Fresh oviducts from SBZ Schlachtbetrieb Zürich AG were used fresh or stored at −20 °C. Endometrial cells (12Z) and cell culture material were obtained from Applied Biological Materials Inc (Abm).

Simulated oviductal fluid (SOF) was prepared and the pH was adjusted to 7.2. Hydrogel master mixes containing specific monomers and crosslinkers were stored and used to create gels to test swelling in SOF.

Fourier transform infrared spectroscopy and scanning electron microscopy (SEM) were used for analysis, and the stability of the gel was tested in human ascites fluid. Rheological measurements were used to evaluate the viscoelastic properties and degradation kinetics.

A 3D printed uterus model simulated gel insertion using a hysteroscope. The cytotoxicity of the gel was tested in normal human dermal fibroblasts (NHDFs) using a lactate dehydrogenase (LDH) assay. An in vivo feasibility study in piglets involved implantation of the hydrogel and monitoring for 21 days.

The effectiveness of hydrogel occlusion in the fallopian tube was measured by burst pressure testing. The photolabile gel and thiol-degradable gel were degraded using light and glutathione solution, respectively.

Hydrogel occlusion was assessed by histological analysis and by experiments mimicking retrograde menstruation using endometrial cells and boar semen. Data were statistically analyzed and presented as mean ± standard deviation.

research result

Functional occlusion of the fallopian tubes using stimuli-degradable hydrogels effectively blocks the passage of sperm, oocytes, and endometrial cells, inhibiting fertilization and preventing the formation of an endometrial plug in the abdominal cavity.

Two different but chemically related compositions of stimuli-degradable hydrogels were investigated: both systems consisted primarily of highly absorbent poly(2-acrylamido-2-methyl-1-propanesulfonic acid) sodium salt (PAMPS) and poly(N-(2-hydroxyethyl)acrylamide) (PNHEA).

PAMPS provided high swelling ratios, while NHEA monomers prevented excessive swelling and instability.Using different crosslinkers, two hydrogels with different degradation mechanisms, photoinduced and reduced, were designed.

Photolabile hydrogels (PL-Gel) were formed using a PEG-based crosslinker, PEGdiPDA, in a 40 wt% mixture of PAMPS and PNHEA, and these hydrogels degraded within 30 min under light irradiation (λ = 365 nm).

Thiol-degradable hydrogels (TD gels) were formed in a 25 wt% PAMPS and NHEA mixture using the disulfide crosslinker BAC and degraded within 30 min upon exposure to biocompatible glutathione (GSH). Both hydrogels were designed to degrade on a clinically relevant time scale, ensuring practical application for reversible tubal occlusion.

Hydrogel placement was evaluated using an application similar to the surgical placement of the Essure device: a soft hydrogel was formed, dried, and inserted into the fallopian tube through a hysteroscope.

Upon contact with tissue, the hydrogels expand and block the fallopian tubes within a few hours. If relief of the fallopian tube blockage is required, these hydrogels can be degraded using light or thiol-containing liquids.

The in situ swelling capacity and kinetics of the hydrogels were estimated by immersing the hydrogels in SOF: a swelling plateau was reached within 4–6 h, with final swelling ratios of 12 (PL gel) and 16 (TD gel).

The higher swelling equilibrium of the TD gel is due to the lower polymer weight fraction and crosslinker concentration. The long-term stability of the hydrogel was demonstrated by culturing it in human ascites and SOF, showing that it remained intact for more than 6 months.

The viscoelastic properties and degradation rate of the hydrogel were evaluated by rheological analysis. The storage modulus of the hydrogel was comparable to that of porcine oviduct tissue, indicating that there was no significant strain due to swelling. The degradation rate of the PL-gel increased when it expanded, which is advantageous for clinical application.

Cytocompatibility was assessed using an LDH release assay with fibroblasts, which showed that the cytotoxicity of the hydrogel and its degradation products was negligible. Histological analysis of the porcine fallopian tube after 3 weeks of implantation showed good tissue compatibility and no significant damage or deformation.

Surgical application was simulated in a human-sized uterus model to demonstrate that the hydrogel could be inserted using common gynecological techniques, and ultrasound imaging confirmed that the fallopian tubes were effectively occluded.

Burst pressure tests showed that the fully expanded hydrogel effectively blocked the fallopian tubes and withstood pressures significantly higher than normal physiological pressures.

In vitro experiments demonstrated that the hydrogel could prevent menstrual retrograde and sperm passage, showing that neither cells nor sperm could pass through blocked fallopian tubes.

Conclusion

In summary, in this study we proposed a polymeric material that can induce degradation on demand for reversible swelling-mediated tubal occlusion as a non-hormonal contraceptive method and a mechanical option to prevent endometrial cell migration.

The stimuli-responsive hydrogels exhibited good swelling and viscoelastic properties, complete occlusion under physiological pressure, low stiffness, and negligible cytotoxicity.

Histological analysis of occluded fallopian tubes in a piglet model showed no damage, indicating a low risk of fibrosis. Degradation was achieved using photolabile or thiol-degradable crosslinks.

The hydrogels prevent the passage of endometrial cells and provide firm contact with the fallopian tubes without side effects. These materials represent a promising reversible method of contraception and a potential treatment for endometriosis.