In previous weeks, I have focused on family planning options, including IUDs and implants, that allow for prevention of pregnancy. This week, however, I will be talking about hyaluronic acid hydrogel, its use in laparoscopic uterine surgeries, and its ability to reduce post-operative complications, including infertility.

One of the most common type of laparoscopic uterine surgery is a myomectomy, which is the removal of fibroids. Fibroids are noncancerous growths that can appear in women of childbearing age and can cause severe pain and infertility. Removal of fibroids can relieve this pain and also increase a woman’s chance of being able to become pregnant, as removal of the fibroids can allow the embryo to attach to the uterine wall.  

While the surgery is usually successful in removing the fibroids, a primary concern is the potential development of postoperative adhesions, which are abnormal fibrous connections. These adhesions can cause abdominal and pelvic pain and reduced fertility due to disruption of the uterine wall. However, studies have shown that HA hydrogels can reduce adhesion formation by preventing direct contact with adjacent uterine surfaces. 

Hyaluronic acid is a hydrophilic polymer found in the ECM of most connective tissues and is often used in tissue engineering. It can provide scaffold and support to tissues, protect against toxins, aid in wound healing, and act as a lubricant. Hydrogels are networks of cross-linked polymers. Hydrogels are frequently used in tissue engineering due to their properties that are similar to that of human tissue, including gas exchange abilities and water content.

Different concentrations and molecular weights of HA can affect the physiological functions of tissues. Increasing the cross linking of HA can increase the elastic modulus, thereby making the hydrogels stiffer. Work by Mensitieri et al. has shown that auto-crosslinked HA gels can increase the effectiveness of preventing adhesion formation due to the higher level of adhesiveness upon application to the wound site.

In a study by Pellicano et all., a controlled, randomized study was done to assess the ability of HA hydrogels to prevent post-op adhesions following laparoscopic myomectomies in 36 infertile patients. For half of the women in the study, crosslinked HA hydrogel was applied to the sites of the fibroid removal.  60-90 days following the surgery, a laparoscopy was performed to evaluate the post-operative effects, and the rate of adhesion development was significantly lower in the group of women who were treated with HA gel (P<0.01).

In addition, study was done in rabbits by Huberlant et al. to investigate the ability for HA hydrogels to reduce infertility due to adhesions from hysteroscopies, a procedure that is used to look inside the uterus for diagnostic purposes and can sometimes cause adhesions. The procedure was performed in 20 female rabbits. Female rabbits have two uterine tubes, so the HA hydrogel was applied to one uterine tube and the other uterine tube served as the control. The rabbits were then mated after a period of recovery, and there was a significant difference in the number of fetuses conceived in each uterine tube (P<0.05). In the uterine tube that was treated with the HA gel, there was an average of 3.7 fetuses, whereas there was an average of only 2.1 fetuses in the uterine tube that was not treated.

Combine, these results indicate that the implementation of HA hydrogel following laparoscopic uterine surgery can increase fertility due to the decrease in adhesions that develop. The use of HA to prevent adhesion formation is ideal because HA is a natural component of the ECM so there is low risk for an immune response, it embodies many properties of human tissue, it is fairly inexpensive, and it is biodegradable. Going forward, additional modifications could be made to HA in order to further reduce the chance of adhesion formation. The molecular weight or density could be increased in order to increase the crosslinking, which could further increase the residence time of the gel on the uterine surface and ensure all wound sites are covered.

Sources:

Chircov C, Grumezescu AM, Bejenaru LE. Hyaluronic acid-based scaffolds for tissue engineering. Rom J Morphol Embryol. 2018;59(1):71-76.

Pal B. Adhesion prevention in myomectomy. J Gynecol Endosc Surg. 2011;2(1):21-4.

Mensitieri, M., Ambrosio, L., Nicolais, L., and Bellini, D. Viscoelastic properties modulation of a novel autocrosslinked hyaluronic acid polymer. J Mater Sci Mater Med. 1996; 7: 695

Huberlant S, Fernandez H, Vieille P, et al. Application of a hyaluronic acid gel after intrauterine surgery may improve spontaneous fertility: a randomized controlled trial in New Zealand White rabbits. PLoS One. 2015;10(5):e0125610. Published 2015 May 11. doi:10.1371/journal.pone.0125610

This week I am going to talk about the specific interactions that occur at the cellular and tissue level after a hormonal IUD is implanted. The amount of time a hormonal intrauterine device (IUD) is effective in preventing pregnancy is somewhat proportional to the amount of levonorgestrel that it contains. For example, Mirena, the original hormonal IUD, contains 52 mg of levonorgestrel and lasts 5 years, whereas Skyla, which contains 13.5 mg of levonorgestrel, lasts only 3 years. While the hormone concentration is currently the limiting factor to the lifetime of the IUD, if the concentration could be increased without leading to any additional side effects, I’m wondering how long these devices could last. After all, the copper IUD can last for up to 10-12 years. The answer, I would hypothesize, would lie in the interactions of the device with the environment (the uterus) at the cellular and at the tissue level.

As with all biomaterials, once the IUD is implanted, there will be interactions with the device that immediately occur on the cellular level. Specifically, proteins will coat the surface of the device, cells will interact with the device via integrins, and there will be an immune response. The innate immune response will cause an immediate increase in production of neutrophils and leukocytes, and the adaptive immune response, which will kick in after the first day, will cause an increase in production of macrophages. Interestingly, the cellular degradation of these neutrophils and macrophages in particular has been shown to contribute to the anti-fertility effects of IUDs. Furthermore, it has been seen that cells that attach to the surface of IUDs lead to an increase in production of prostaglandin, which also contributes to the anti-fertility effects of IUDs. In this way, the interactions of the IUD itself with the environment on the cellular level contribute to the effectiveness of the IUD in addition to the release of levonorgestrel.

On a tissue level, effects of the material on the environment (the uterus) must be considered. Fortunately, as long as IUDs are inserted correctly, there are few side effects in regards to the material’s effect on the environment. IUDs generally do not cause toxicity or tumorigenesis, and they do not directly cause infection. While there is a slight risk of pelvic inflammatory disease, the infection would be the result of pre-existing bacteria that were disrupted by the insertion of the IUD within the first week. The largest concern in regards to the material-environment interaction is the possibility of a perforated uterus, which occurs in only 0.1% of insertions. Most case studies are isolated and the cause is unknown, but it is thought that the skill of the doctor and improper technique during insertion may play a role. Due to the limited serious adverse effects of the IUD, it is generally considered a safe device. As such, I would hypothesize that a long-term IUD may be considered safe in regards to the material’s on the body.

Finally, when looking at how long the device could last irrespective of the hormonal concentration, the effects of the environment on the IUD, specifically on the polyethylene frame, are the largest considerations. The overall wear and corrosion as a result of uterine contractions and fluid flow are the largest factors that lead to the degradation of the IUD over time. One study I found by Dr. Monica Cirstoiu at the Unviersity of Bucharest used a scanning electron microscope to characterize Mirena IUDs after certain periods of time. After 3 months, only minor degradation signs on the surface were detected. However, after 36 months, signs of severe degradation could be seen. Cirstoiu hypothesized that these cracks over time could affect the function of the device.  I found this very interesting, as I wondered specifically what she meant by that. The effectiveness of the hormonal IUD lies in its continual release of consistent amounts of levonorgestrel, but I wonder if cracks in the polyethylene frame over time can affect the amount released. Copper IUDs are also made of polyethylene, but the composition of the frame is less important, as the copper wound on the surface releases ions over time. Perhaps a different material could allow hormonal IUDs to last longer.

What material could be used? I’m not really sure. However, I do know that polypropylene is a material that is very similar to polyethylene in that it is durable and lightweight. However, Polypropylene is more resistant to corrosion, fatigue, impact, and temperature, meaning it may be able to last longer as an implant in the body. Polypropylene does not stretch as much as polyethylene does though (it has a lower elastic modulus), so given the need of flexibility in an IUD, maybe a combination of the two materials could be tested.

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Sources:

http://www.microbiologyresearch.org/docserver/fulltext/jmm/54/12/JMM5412.1199.pdf?expires=1538842545&id=id&accname=guest&checksum=14FFA56BF8077D0C2CACE8740C2BDD49

https://www.researchgate.net/publication/280944267_Levonorgestrel-releasing_Intrauterine_Systems_Device_Design_Biomaterials_Mechanism_of_Action_and_Surgical_Technique

https://www.dlib.si/stream/URN:NBN:SI:DOC-XJZ8XJU9/04e5a4f0-5f4a-4907-b67e-a8adb297014d/PDF

https://www.healthline.com/health/birth-control/iud-infection#causes

http://www.hunterindustrialsupplies.com.au/blog/polyethylene-vs-polyproylene-which-is-better/

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