As in previous weeks when the topics discussed in class do not relate well to contraceptive devices, I turn to the opposite topic of engineering approaches to improve fertility. This week, I am going to be talking about decellularized uterus scaffolds to treat female infertility.

Infertility due to uterine conditions can occur due to a multitude of reasons, including endocrine and structural abnormalities as a result of congenital conditions, cancer, chemotherapy, and injury. Complete or partial transplants have successfully taken place, but as with any transplant from an allogenic donor, there runs the risk of rejection by the immune system. In addition, even if rejection does not occur, a life-long dependence on immunosuppressive drugs can lead to nephrotoxicity, diabetes, and severe infections. Therefore, tissue engineering approaches are a promising approach and do not carry the same risk of rejection.

In particular, biological scaffolds obtained through decellularization are an area of research. Biological scaffolds have an advantage over synthetic scaffolds because they are more similar to natural tissue from a mechanical and biological stance, meaning they are more able to replicate the structure and function of the natural organ. During decellularization, immune cells are removed from the donor tissue and the extracellular matrix (ECM) is isolated to create the scaffold. This decellularization process can be accomplished through chemical, biological, and physical processes. The remaining ECM architecture resembles that of the natural tissue. It also retains vital proteins such as collagens, fibronectin, laminin, and elastin. As such, functions of the specific tissue are maintained, including cell signaling, adhesion, differentiation, and proliferation abilities, all while avoiding rejection by the immune system. The scaffolds can be implanted in vivo on their own, or, in the process of recellularization, stem cells can be integrated into the scaffold prior to implantation in order to populate the scaffold with cells crucial to the functioning of the organ.

Figure 1. Process of decellularization and recellularization for uterine scaffolds

In the case of a uterus, the key functions include the ability to implant an embryo and nourish the fetus, and then contract once the fetus has reached term and allow for delivery. In a study by Drs. Roger Young and Gabriela Goloman, the myometrium, the smooth muscle of uterine tissue, of both humans and rats was decellularized using an ethanol and trypsin protocol, which removed the immune cells and maintained the ECM of the myometrium. Then, the myometrium scaffolds were recellularized using isolated myocytes, the functional cells of the uterus, to create a “neo-myometrium” (stem cells were not used). Three experimental group types of neo-myometriums were created: human scaffold / human myocytes, rat scaffold / rat myocytes, and rat scaffold / human myocytes. Seeded scaffolds in all groups demonstrated ability for the myocytes to attach and grow, showing a successful recellularization process. However, in the case of the human scaffold / human myocyte group, the myocytes could not stay attached to the scaffold for a long period of time, and a thick layer was never achieved. As such, coordinated contractions of the tissue could not be observed in isometric contractility experiments. Nevertheless, for the rat scaffold / human myocyte group, the myocytes grew well into the scaffold. As a result, coordinated contractions were observed in vitro, showing the potential of the recellularized scaffold to embody the functional characteristics of the myometrium. In the future, it would be interesting to gain a better understanding of why the human myocytes did not grow well into the human scaffold, as this is not well explained in the paper.

Figure 2. Decellularized rat and human scaffolds (prior to recellularization)

Furthermore, a study by Dr. Kaoru Miyazaki and Dr. Tetsuo Maruyama did a similar experiment with decellularization with whole rat uteri. In the experiment, the decellularization process was carried out using perfusion of SDS (a detergent) that was infused through the aortic artery. The decellularized uterine scaffold was then recellularized through injection of rat uterine cells and mesenchymal stem cells (from bone marrow), allowing for proliferation of cells throughout. Then, a portion of the uteri of living rats was excised and replaced with a portion of the newly created uterine scaffold. There was also a control group and a group that only had excised uteri, a model of uterine damage. The rats were then mated 28 days after surgery. A histological analysis was performed to determine the extent of tissue regeneration in the experimental group, and it was found that the regenerated tissue was thick and the scaffold was well recellularized. In addition, fetuses were observed in 6 out of the 8 rats in the experimental group, whereas they were only observed in 1 out of the 8 rats in the group with excised uteri.

Figure 3. Rat uteri before, during, and after the decellularization process using a detergent. It can be seen that the resulting scaffold maintains the original shape of the uteri due to preservation of the ECM.

Figure 4. Rat uteri after decellularization and after recellularization with rat uterine cells and mesenchymal stem cells. The recellularized scaffold was the implanted into excised portions of the uteri of living rats.

These results show the potential for the decellularized scaffolds to not only replace and regenerate uterine tissue, but to embody the natural function of the tissue by allowing for implantation and growth of fetuses. This could have implications for women who have damaged portion of their uterus due to cancer, chemotherapy, or other injury.

Nevertheless, one of the main disadvantages of decellularization in general is that smaller structures within the organ may be disrupted, which can impair the function. In addition, residual cellular components, such as nucleic acid from the DNA of immune cells, may have unknown and unintentional effects and consequences on the function of the organ. These all need to be taken into consideration for future studies.

Sources:

Hellström M, Bandstein S, Brännström M. Uterine Tissue Engineering and the Future of Uterus Transplantation. Ann Biomed Eng. 2017;45(7):1718-1730.

Miyazaki K, Maruyama T. Partial regeneration and reconstruction of the rat uterus through recellularization of a decellularized uterine matrix. Biomaterials. 2014;35(31):8791-8800.

Young RC, Goloman G. Allo- and xeno-reassembly of human and rat myometrium from cells and scaffolds. Tissue Eng Part A. 2013;19(19-20):2112-9.

Kuo CY, Baker H, Fries MH, Yoo JJ, Kim PCW, Fisher JP. Bioengineering Strategies to Treat Female Infertility. Tissue Eng Part B Rev. 2017;23(3):294-306.

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

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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This week I am going to focus on the contraceptive implant. As mentioned in the first blog post, the birth control implant is a flexible rod, composed of non-biodegradable ethylene vinylacetate co-polymer, that continually releases the hormone etonogestrel. Nexaplanon is currently the only FDA approved birth control implant, and it must be removed after three years.

While it is fairly easy to insert the rod, as it is packaged with an applicator that allows a trained medical professional to smoothly insert it into one’s upper arm, removal requires a slightly more complicated medical procedure. A scalpel is used to make an incision and cut the implant out, a procedure that can be frightening for some women. Furthermore, as with any procedure, there is a risk of infection.

Contraceptive implants have been rising in popularity in less developed countries where there is a need for family planning solutions. However, for women who have limited access to medical care, it can be challenging for women to find a trained professional who is able to remove the implant after 3 years.

For these reasons, there have been recent initiatives to develop biodegradable contraceptive implants, which would eliminate the need for the implant to be removed after three years! In addition, the implant would not start to degrade until one year after implant, allowing a woman to have the implant surgically removed if she experiences adverse side effects. This research, sponsored by the Gates Foundation and USAID, is actually being done here at Yale in the Saltzman Lab – how cool!

Composition

The biodegradable contraceptive currently being developed is made of a non-toxic polymer called poly(ω-pentadecalactone-co-p-dioxanone) [poly(PDL-co-DO)]. That’s a mouthful, but here’s a picture of its chemical structure:

Basically, a polymer is a large molecule that is composed of many small, repeating molecules that are bound together by covalent bonds. Covalent bonds result from the sharing of electrons between atoms that are directly adjacent to one another. Polymers also have secondary bonds, such as hydrogen bonds, which gives polymers properties such as elasticity and mobility – that’s a vital characteristic for contraceptive implants.

Biodegradability

A biodegradable material is a material that is able to decompose (i.e. the covalent bonds are cleaved) into molecules that are naturally found in the body, rendering the products to be non-toxic to the body.  Degradation can occur through surface erosion (degradation from the edges moving inward) or through bulk degradation (slow degradation of materials throughout). When the material is fully degraded, the products are processed by the body’s metabolism.

In the case of the contraceptive implant, this would mean that the device would completely disappear after a given period of time, making it seem as if it had never been implanted. This biodegradable component may be a solution to the issues associated with non-biodegradable implants and the need for them to be removed. Nevertheless, in order to allow women to remove the device if they are experiencing adverse side effects, the bonds in the polymers must be able to stay intact for an initial period of time.

Slow release of etonogestrel

As mentioned above, etonogestrel is slowly and continuously released from the implant. So how would this work? Nanoparticles.

Nanoparticles are solid, submicron-sized particles that can be used as a therapeutic agent. A nanoparticle consists of a bulk material (e.g. a polymer) that encapsulates and carries an active substance, such as a drug, to a target location. As the polymer degrades, the drug (e.g. etonogestrel) is released into the bloodstream over a period of time, allowing for controlled delivery of drugs. This is especially important in the case of LLRCs, as the goal is to have continuous release of low amounts of etonogestrel in order to prevent pregnancy over an extended period of time. If all of the etonogestrel were released at once, that would not be good.

Stress and Strain

One final consideration is the fact that the implant is injected into the muscle tissue in the inner arm, subjecting it to tensile and compressive forces as the arm moves around. The implant must have properties that prevent it from breaking or snapping when subjected to these forces. As such, its elastic modulus must be fairly low, because it must be able to stretch and condense as a result of tensile and compresses forces without deforming (i.e. without permanently changing the molecular structure). Nevertheless, the elastic modulus cannot be too low, as it needs to be firm enough so as it doesn’t dislodge from the position in the muscle it is placed.

So, is this feasible?

Overall, a biodegradable contraceptive implant would provide an excellent solution to the issues related to the removable of non-biodegradable contraceptive implants. These issues include, but are not limited to, pain and discomfort associated with the procedure, the risk of infection, and the inability to have access to a trained professional to remove the device.

Nevertheless, I think one of the largest considerations may be efficacy of the device. Hormonal birth control relies on the continuhttps://www.nexplanon.com/nexplanon-removal/ous release of hormones, but I wonder how the degradation process may affect this release. If the implant starts degraded after year 1 and is completely degraded by year 3, do the levels of etonogestrel change at all as year 3 approaches? And at one point would women have to begin using alternative forms of birth control? These are questions to ask going forward and something that I’m sure is being considered in the development of biodegradable implants.