Since its release in the 1960s, the IUD has grown to be one of the most popular contraceptive methods after the birth control pill. While hormonal and copper IUDs are both over 99% effective in preventing pregnancy, hormonal IUDs are more popular due to their relatively limited side effects. Copper IUDs work to prevent pregnancy by releasing copper ions from a copper wire into the uterus via corrosion, which leads to inactivation of sperm and an inflammatory response that creates a toxic environment and prevents conception.

Figure 1. Currently there is only one Copper IUD that is FDA approved in the US, ParaGard. ParaGard has a polymeric body with a metallic copper wire that releases copper ions.

Significant side effects, however, come with this release of copper ions, including heavier and more painful periods as well as abnormal bleeding and pelvic pain. Intense pain in the first few days following insertion is very common due to the initial “burst” of copper ions following insertion. This burst is due to the fact that there is a high concentration gradient and ions are able to readily diffuse through release channels since they are not obstructed by corrosion deposits, a product of the oxidation of copper ions. It is also noted that consistently around one third of copper ions released are oxidized and deposited as a product of corrosion on the surface of the IUD frame as Cu₂O, rendering their contraceptive abilities ineffective, while still contributing to side effects.

Figure 2. Corrosion of copper and deposition of Cu2O

Despite these side effects, for women who want a reliable and long-lasting contraceptive option without exposure to hormones, the copper IUD is one of the best options. As such, there has been recent efforts to improve the copper releasing mechanism of the copper IUD. One of the most promising approaches is to use a polymer matrix composite rather than just a copper wire, which allows for a more controlled release of copper ions. The benefit of a composite is that the device is able to take on the constitutive properties of both materials.

In a study done by Li et al., the polymer matrix selected was poly vinyl alcohol (PVA), a polymer known to have high strength, good processability, and long-term stability in biological conditions. To form the composite, a solution of PVA and water was heated with SiO2 (to decrease the solubility of PVA) to create a homogenous solution. CuCl2 was then added, and the solution was solidified on a glass plate. When release studies were done in vitro, the release rate of copper ions from the composite was 12 times less than from metallic copper due to the fact that the diffusion of ions was limited by the polymeric network. After the third week, the release of cooper ions was comparable to metallic copper, showing the stability and consistent rate of release of copper ions via corrosion. In addition, there were no Cu₂O depositions on the surface of the composite, which indicates that all of the Cu ions released would have contraceptive effects. This points to the possibility of engineering a composite IUD with a lower concentration of copper because all copper released would contribute to contraceptive effects.

Figure 3. Release of copper over time for metallic Cu and for Cu-PVA composite

In another study done by Xu et al., a composite of Cu and polydimethiylsiloxane (PDMS) was constructed. PDMS was selected because it is easy to be mechanically tuned and is biocompatible. Unlike Li et al., this composite used Cu nanoparticles, which release Cu ions. The composite was made by pouring the Cu nanoparticles into a PDMS cross-lined matrix at a high temperature. Similar to Li et al., there was also a reduction in the initial burst of Cu ions and no Cu₂O deposits were observed on the surface in in vitro studies. There was also a steady release of Cu nanoparticles over time, pointing to the long-term abilities of the device as a contraceptive agent.

Figure 4. Surface imaging of copper nanoparticle-PDMS composite

As such, an IUD made of a copper-PVA or copper-PDMS composite could lead to fewer side effects both immediately after insertion and long term due to the reduction in the initial burst of copper ions and the possibility of the lower concentration of copper ions in total, respectively. Since the copper IUD can last up to 10 years, two times longer than the hormonal IUD, a new copper IUD with fewer side effects could have significant implications for women seeking family planning options in rural and less developed communities who may not have the resources to receive a new hormonal IUD every three to five years.

Works cited:

Li J, Suo J, Huang X, Ye C, Wu X. Release behavior of copper ion in a novel contraceptive composite. Contraception. 2007;76(3):233-7.

Xu XX, Ding MH, Zhang JX, Zheng W, Li L, Zheng YF. A novel copper/polydimethiylsiloxane nanocomposite for copper-containing intrauterine contraceptive devices. J Biomed Mater Res Part B Appl Biomater. 2013;101(8):1428-36.

Ramakrishnan R, B B, Aprem AS. Controlled release of copper from an intrauterine device using a biodegradable polymer. Contraception. 2015;92(6):585-8.

Bulk metallic glasses (BMGs) are amorphous metallic alloys with high corrosion resistance, high strength, and high flexibility at high temperature. As such, when heated, BMGs become flexible and can expand into a mold, allowing them to take on the shape and topography of the mold. One interesting thing that can be done with BMGs is the creation of nano-patterns on the surface. The amount of pressure applied during this molding process determines the stiffness and diameter of the nano-rods, with a greater force resulting in smaller and less stiff rods. These nano-patterns can act as reservoirs for controlled release of drugs. Given the fact that the strength and corrosion resistance of BMGs is much greater than that of polymers, this drug-releasing ability points to BMGs as an attractive material for long-lasting implants. This week, I will be talking about BMGs as a material that could be used in hormone-releasing reservoir of hormonal IUDs

In the hormonal IUD, the steroid reservoir continuously releases levonorgestrel into the uterus in order to prevent pregnancy. This reservoir is made of dimethylsiloxane cross linked elastomer and is covered in a rate-limiting membrane composed of semi-opaque tubing, allowing for the continuous release of levonorgestrel via diffusion over time. The lifespan of an IUD depends, in part, on the amount of hormone that the reservoir contains, with the 13.5 mg IUD lasting 3 years and the 52 mg IUD lasting 5 years. Nevertheless, one of the great barriers to the lifespan of the hormonal IUD is the degradation of the polymeric surface, which affects the ability of the hormone reservoir to release a continuous dose of levonorgestrel over time.

Degradation of the polymeric materials of hormonal IUDs

BMGs could be a solution to this problem of degradation given the strong corrosion resistance and slower degradability of the metallic alloys. Given that the arms of the IUD still need to have elastic properties at body temperature in order to be inserted properly and exhibit flexibility within the uterus, the body of the IUD would still be made of polyethylene. However, a hormone reservoir made of BMGs could allow the device to continuously release hormones for a longer period of time, preventing the need for the IUD to be replaced every 3-5 years.

As was discussed in lecture, BMGs can be used as reservoirs for controlled drug release. The material is heated and put in a mold with micro-sized protrusions in it, forming a material that has micro-sized holes in it. These micro-sized holes can then become functional by adding drugs. While there is not a lot of published research on this, I envision an approach that would use BMGs as the primary material of the IUD hormone reservoir. The hormone reservoir would be shaped into an appropriately sized cylinder with micro-sized holes using blow molding, and levonorgestrel could be covalently attached to the mirco-pores. The reservoir could then be coated in a hydrogel, which would allow for controlled diffusion of levonorgestrel over time. Given the BMG composition, the reservoir would be able to last a longer time than the polymeric structure of current reservoirs, extending the life of the IUD. In addition, given the fact that micro-pores increase the surface area of the device, the amount of drug loaded in the IUD could be increased, which would also extend the life of the IUD.

The hormone reservoir would be composed of micro-patterned BMGs

Furthermore, in this application for IUDs, micro-sized patterning has an advantage over nano-sized patterning in terms of the immune response. In research done by Padmanabhan et al., it was shown that nano-patterning induces a decrease in the inflammatory response compared to micro-patterning. This is because macrophages are unable to detect nano-patterns of 150 nm or smaller. This has important applications for many types of implants where an immune response is not wanted, such as in a stent or in a bone implant. However, in the case of IUDs, the immune response of an implanted device from macrophages and neutrophils (as part of the foreign body response) actually contributes to the anti-fertility effects of IUDs. In one study, it was estimated that there are 100 million to 1 billion macrophages in the uterus of a woman with an IUD, and these macrophages play an important role in the phagocytosis of sperm. As such, if an IUD were to be created out of BMGs, the idea size of the drug reservoirs would be micro sized so as to induce a greater immune response than nano-sized reservoirs.

Surface patterning on BMGs

Sources

Padmanabhan J, Kinser ER, Stalter MA, et al. Engineering cellular response using nanopatterned bulk metallic glass. ACS Nano. 2014;8(5):4366-75.

National Collaborating Centre for Women’s and Children’s Health (UK). Long-acting Reversible Contraception: The Effective and Appropriate Use of Long-Acting Reversible Contraception. London: RCOG Press; 2005 Oct. (NICE Clinical Guidelines, No. 30.) 5, Intrauterine system (IUS) Available from: https://www.ncbi.nlm.nih.gov/books/NBK51042/

Cirstoiu, Monica & Cirstoiu, Catalin & Antoniac, Iulian & Munteanu, Octavian. (2015). Levonorgestrel-releasing Intrauterine Systems: Device Design, Biomaterials, Mechanism of Action and Surgical Technique. MATERIALE PLASTICE. 52.

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

https://www.popline.org/node/449215