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