Corrosion of copper intrauterine devices: review and recent developments
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David M. Bastidas
David M. Bastidas is an associate professor of corrosion engineering at The University of Akron. He received his PhD in materials science and engineering and BSc in chemistry from the University of Barcelona (Spain). His research focuses on the corrosion of steel in concrete, inhibition, and Cu-IUD corrosion. He is a member of research and infrastructure committees of NACE and the vice chairman of corrosion of steel in concrete WP of EFC.
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Benjamin Valdez
Benjamin Valdez is a professor at the Institute of Engineering, UABC and was the Institute’s director from 2006 to 2013. He has PhD and MSc in chemistry and BSc in chemical engineering. He was appointed a member of the Mexican Academy of Science and the National System of Researchers in Mexico. He was a guest editor of
Corrosion Reviews . His activities include corrosion research, consultancy, and control in industrial plants and environments.
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Michael Schorr
Michael Schorr is a professor (Dr. honoris causa) at the Institute of Engineering, UABC. He received his PhD in materials engineering and BSc in chemistry from the Technion-Israel Institute of Technology. He was an editor of
Corrosion Reviews (1986–2004). His research focuses on volatile corrosion inhibitors in industrial environments. He is a corrosion consultant and a professor in Israel, United States, Latin America, and Europe.
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Jose M. Bastidas
Jose M. Bastidas is a full professor at the CENIM, CSIC. He received his PhD in chemistry from Complutense University of Madrid, Spain. He was a postdoctoral Ramsey fellow at the University of Manchester (UK). His research focuses on corrosion and inhibition mechanisms, protection methods and numerical modeling in biomedical materials, chemical industry, heritage science, construction, and transportation.
Abstract
A systematic review of the literature about the corrosion of copper in intrauterine devices (IUDs) was conducted, an important topic of copper application that apparently may not be well known to a broad corrosion audience. Copper IUDs (Cu-IUDs) are one of the most widely used contraceptive methods around the world, particularly in China, India, and Latin America. The contraceptive method is based on the release of copper ions from a Cu-IUD. Copper ions enhance the inflammatory response in the uterine cavity and reach concentrations in the luminal fluids of the genital tract, which are toxic for spermatozoa and embryos. A description is made of the different types of Cu-IUD used, the traditional T-shaped device, copper nanoparticles inside a polymeric matrix, and other shapes. This review aims to discuss the main parameters affecting the efficiency of a Cu-IUD, the contraceptive mechanism, and the shape of the device. The high copper corrosion rate immediately after insertion in the uterus (“burst release”) is discussed, which presents values of the order of up to 296 μg/day, causing side effects such as bleeding and pain, with an exponential decay defining a steady-state plateau after 1–2 months of insertion with values of 40 μg/day for a 200 mm2 Cu-IUD. This plateau is maintained over the life span of a Cu-IUD, in which the copper dissolution rate is as low as 2 μg/day for a Cu-IUD with indomethacin keeping up the contraceptive action mechanism, the concentration of copper that needs to be higher than 10−6 mol/l.
1 Introduction
Nowadays, intrauterine devices (IUDs) are considered as the second most widely used contraceptive method (Sitruk-Ware, 2006; Winner et al., 2012; Wright et al., 2012; Tatum & Connell, 2013). The distribution of IUD users for women ages 15–49 years is 83% in Asia (64% of them are in China), 8% in Europe, 4% in Latin America, 4% in Africa, 1% in the United States, and 0.03% in Oceania (Buhling et al., 2014; Norman et al., 2015; Kavanaugh & Jerman, 2018).
Copper-bearing IUDs (Cu-IUD; TCu380A), which are recommended by the World Health Organization, consist of a T-framed plastic body to which copper is attached, the copper sleeves are located on the horizontal arms, and the vertical stem is wound around the copper wire (Figure 1, right; Bastidas et al., 2010). The number of Cu-IUD indicates the copper surface area, for instance, 380 mm2 for a TCu380A and 300 mm2 for a CuT300. A direct relationship has been reported between the size of a Cu-IUD (higher contact surface with the endometrium) and the quantity of synthesized prostaglandin E2 (PGE2) (Timonen, 1976; Roldán Rodríguez-Marín et al., 1993). According to the ASTM B170–99 (2015) standard and the unified numbering system (UNS), the copper wire is referred to as grade 1 (also designed as C10100) of about 0.40±0.01 mm in diameter, has a purity of at least 99.99%, and is the highest purity oxygen-free electronic copper with a maximum limit of 0.0005%. The copper sleeves are of the same UNS C10100 grade as the wire.
Cu-IUD: (left) IUB-shaped Cu-IUB and (right) T-shaped Cu-IUD.
Several shapes of Cu-IUDs are frequently used. Most countries used at least one T-shaped Cu-IUD. For instance, Mona Lisa in France and Belgium, Mirena in Argentina, Australia, Brazil, Canada, Colombia, Germany, Mexico, New Zealand, Peru, Spain, Sweden, The Netherlands, United Kingdom, and Para Gard and Skyla in the United States and China use stainless-steel rings despite their higher failure and expulsion rates (up to 10% per year; Bernstein et al., 1972; Orlans, 1974; Buhling et al., 2014).
Throughout the world, about 100 million Cu-IUDs are used as follows: China (more than 80 million), Vietnam (~4 million), Indonesia (3.5 million), Egypt (3 million), Mexico (2.5 million), Turkey (2.2 million), Colombia (0.7 million), Cuba (0.6 million), and Peru (0.5 million; Arancibia et al., 2003). Alvarez et al. (2012) indicated that approximately 162 million women worldwide used Cu-IUDs.
2 History and woman’s uterus
In all the treatises on IUDs, it is mentioned that Bedouin camel drivers had the habit of introducing in the uterus of the camels a rounded and smooth stone, the size of an almond, so that they would not be pregnant in the crossings of the desert (Margulies, 1975).
Towards 1930, the devices began to be used. The first consisted of a piece of silkworm gut of about 5 cm in length with a silver thread. Later, it was used in the form of a ring surrounded by silver. To introduce the device, a small fork was used, with which it forced to deform the ring in a guaranteed way; when removing the fork, it recovered the primitive round form.
Oppenheimer in Israel (1959) used polyethylene (PE) plastic material that has good “memory” and designed the IUD Margulies spiral-shaped, with a tail also of plastic, which was outside the uterus to allow extraction (Oppenheimer, 1959). Lippes designed an S-shaped IUD and the applicator was a thin plastic tube into which the S was inserted that was straight; when the applicator was removed, the device recovered the S-shape inside the uterus (Lippes, 1965). With these three basic ideas, the plastic, the applicator, and the tractor wire, different models were designed, so that almost every country has its own.
Anatomical and functional considerations of the uterus led Tatum (1974) to devise an IUD in the form of a T. IUDs with metals (copper, silver, and zinc) began to be used with good results. Van Os in Holland (Rhemrev et al., 1985) designed a model that does not require an applicator, similar in shape to the Dalkon shield, endowed with lateral spicules that hinder its expulsion and also with copper wire in the central stem (Zipper et al., 1976). Although Zipper et al. (1969) described the contraceptive effect of Cu-IUDs and zinc-bearing IUDs on rabbits, and different models of Cu-IUDs were proposed (Tatum, 1974), copper was known as a potent spermicide for more than 130 years (Roblero et al., 1996).
The woman’s uterus (womb) is hollow and characterized by a pear shape (typical dimensions of about 7.6 cm long, 4.5 cm broad, and 3.0 cm thick; weights about 60 g) in the lower abdomen between the bladder and the rectum. The measurement of the uterine cavity is an important but not definitive means to decrease the rates of unwanted effects (Kurz, 1985). The broader, upper part of the uterus is the corpus (with two layers of tissue; the outer layer is the myometrium), and the narrow lower part is the cervix. In women of childbearing age, the inner layer of the uterus (endometrium) goes through a series of monthly changes, because of menstrual cycle (Diez-Febrer et al., 1993).
3 Cu-IUDs
Cu-IUDs are classified as nonhormonal IUDs. These devices deliver cupric ions that serve as antifertility agents. A minor percentage of copper is on the surface of the shield and dissociation studies indicated that less than 5% of the total copper is released (Jones et al., 1973). Existing Cu-IUDs, which comprise a PE body and copper wire wound around the stem, are one of the most widely used form of birth control worldwide due to its advantages of safety and reversibility, high efficiency, economy, and long lasting (3–5 years). Nowadays, there are about 150 million IUD users all over the world (Bahamondes et al., 2003).
On the IUD shape, the T-shaped Cu-IUD is the most popular (Figure 1, right). Anchor-, U-, and 7-shaped Cu-IUDs are currently used. Pelvic inflammatory disease (PID) is the great workhorse to Cu-IUD, especially for American authors, from the misfortune that caused the Dalkon shield IUD in the early 1970s (De Castro, 1993). For these devices, shape is one of the main drawbacks, as they become difficult to extract and in some cases they can break a part while inside the uterus. IUD containing a gold or platinum core electrolytically coated with copper has also been used to minimize the wire fragmentation risk (Gal-Or et al., 1982).
3.1 Copper nanoparticles mixed with low-density PE
Although the antifertility efficiency of Cu-IUDs can be comparable to those of female or male sterilization, some side effects of Cu-IUDs are PID, menorrhagia, intermenstrual bleeding, and uterine perforation and so on. Nevertheless, the reaction of cupric ions on the cellular membranes with spermicidal and bactericidal effects is breaking the idea of the Cu-IUD-PID association. To overcome the limitations of conventional Cu-IUDs, copper nanoparticles mixed with low-density PE were proposed as contraceptive devices. Polymer matrix composites were used due to their superiority of controlled release of drug and continuous matrix phase (Ramakrishnan et al., 2015). The composites are filled with copper nanoparticles considering that the size effect of copper nanoparticles can increase the Cu(II) ion transformation ratio in a simulated uterine solution (SUS; Cai et al., 2005b; Xia et al., 2006a; Hu et al., 2013). Ultrafine-grained bulk copper fabricated by severe plastic deformation with excellent mechanical properties (Lugo, 2008) possesses excellent corrosion resistance in SUS (Xu et al., 2004, 2012; Shaamash et al., 2005; Wen et al., 2006; Xia et al., 2006b; Li et al., 2007; Liang et al., 2008).
3.2 Copper intrauterine ball (IUB)
Recently, in the literature, there has been a new IUD, named as IUB, consisting of copper specimens that take a three-dimensional spherical form, and 17 pure copper spheres are threaded over a shape memory alloy NiTiNol wire, a Ti-based alloy with highly pure Ni, and a commercial pure Ti (Baram et al., 2014; Wiebe, 2014; Wiebe & Trussell, 2016; Figure 1, left). NiTiNol presents the ability of deforming force, allowing flexions while always returning to its preset shape. Goldstuck and Wildemeersch (2017) have reported that the IUB has a more physiological fit in both nulliparous and multiparous users because of its extreme flexibility and small dimensions (~12 mm diameter). IUB is 14%–25% smaller than each arm of the common CuT380 IUD, and probably, this new design may reduce the high rate of expulsion in the first year of use (27%; Matsubayashi et al., 2007; Madden et al., 2014; Wiebe & Trussell, 2016). On the contrary, it has been reported that the NiTiNol shape memory alloy, in spite of its high Ni content (49% Ni and 51% Ti), is biocompatible and presents a high corrosion resistance in artificial saliva, and the Ni release is very low (~0.1 ppm; El Medawar et al., 2002).
4 Bactericidal effect of copper
Copper inhibits the growth of some bacteria, such as Neisseria gonorrhoeae and meningococci, preventing the transmission of sexual diseases such as syphilis, gonococci, or soft chancre (Valdéz et al., 2008). Enterobacter are commonly found in vaginal culture. The incidence of the following bacteria is as follows: Staphylococcus aureus 16%, Staphylococcus epidermis 18%, Pseudomonas aeruginosa 5%, Escherichia coli 25%, Candida albicans 20%, N. gonorrhoeae 2%, and Candida dublinieses 12% (Carrillo-Beltrán, 2009). Neisseria gonorrhoeae and Neisseria meningitidis (Meningococcus) have also been reported (De Castro, 1993). Figure 2 shows a scanning electron microscopy (SEM) micrograph of copper surface colonized by Actinomyces israelii biofilm (Valdéz et al., 2008).
SEM micrograph of A. israelii biofilm on the copper surface.
Cu-IUDs inhibit spermatozoa motility, where Cu2+ ions significantly affect sperm incubation (Ullmann & Hammerstein, 1972; Barwin & Tuttle, 1978; Roblero et al., 1996). Copper changes the endometrium and human blastocysts are found to be sensitive to copper as well. It has been tested that the presence of copper is toxic to the embryo, thus playing a contraceptive effect (Brinster & Cross, 1972).
Actinomyces israelii biofilms developed in IUD used for a long time showed a branched growth adhered to the copper surface by its own extracellular polymers as demonstrated by Carrillo et al. (2010). In addition, they found in microbial growths in synthetic medium that A. israelii is capable of surviving copper toxicity due the porous structure of the biofilm.
5 Copper corrosion
A lack of information exits in the literature on the corrosion of Cu-IUDs using native (natural) uterine fluid, the small amount of fluid in the endometrial cavity, 5–35 μl in the midluteal phase and about 80–180 μl in midcycle (Casslén, 1986), and the difficulty associated with the extraction of representative fluid induces the use of SUS (Xue et al., 1998; Zhu et al., 1999; Bastidas et al., 2000).
5.1 Corrosion of copper in acidic and alkaline solutions
Given that, depending on the menstrual cycle and the user, the pH of the uterus cavity has been reported from 5.9 to 8.0 (Sedlis et al., 1967; Johnson Jr et al., 1976), it is of interest to discuss copper corrosion in acid and alkaline media.
The corrosion of copper in hydrochloric acid solution has been widely studied in the literature by different researchers (Crundwell, 1992; Diard et al., 1998; Polo et al., 2003). There is unanimity among different researchers in that chloride, complexes (Cu-CuCl2−), and insoluble products are the parameters that control the corrosion process; the diffusion of different soluble species, mainly CuCl2−, controls the kinetics of the corrosion process. In general, copper oxidizes forming chlorinated complexes of copper (I) at a rate that depends on the existing chloride concentration and is independent of pH and the mass transfer process. Copper does not corrode in nonoxidizing acid environments (Finsgar & Milosev, 2010). In the anodic dissolution of copper in hydrochloric acid solution, it is common to find a passivation of the material. The first stage is an electronic transfer process in which the chloride ion participates in the formation of the CuCl insoluble species adsorbed on the copper surface following the Langmuir isotherm (kc=θ/(1–θ)), where k is the equilibrium constant of the adsorption reaction, c is the concentration of the adsorbed species, and θ the degree of coating of the copper surface; the value of θ is assumed to be very small; θ<<1; Crundwell, 1992; Barcia, 1993; Diard et al., 1998). The second stage is a chemical reaction in which the CuCl species participates in the formation of the complex CuCl2− (Polo et al., 2003).
Copper has also been studied using sulfuric acid solution (Clerc & Alkire, 1991; Tromans & Ahmed, 1998). At low sulfuric acid concentrations, the copper solution is the main anodic process. However, at higher acid concentrations, metal passivation occurs (Bastidas et al., 2003). The passivation process has been related to the formation of a layer of cuprous oxide (Cu2O, cuprite) and another layer of cupric oxide (CuO, tenorite). A more general mechanism has also been proposed consisting of a dissolution-precipitation process. The cuprite and tenorite formed during the anodic polarization in contact with H2SO4 can undergo transformations to Cu, Cu2SO4, and CuSO4 (Tromans & Ahmed, 1998). It has also been reported that passivation occurs through the formation and growth of a CuSO4 layer instead of the corresponding cuprite (Clerc & Alkire, 1991), and copper oxides are stable only in the pH range of 8–12 (Finsgar & Milosev, 2010).
In the chemical treatments of cleaning and pickling of copper and its alloys, the use of organic acids is frequent. Figure 3 shows a Nyquist plot for copper in 5.0% citric acid after 96 h experimentation. A well-defined semicircle and a small tail (diffusion process) at high and low frequencies, respectively, can be observed. Figure 3 (inset) includes the equivalent circuit used to fit impedance data. The solution resistance (Rs) was 36 Ω cm2. The polarization resistance (Rp) was 4780 Ω cm2, which allows the monitoring of the corrosion rate. Using Faraday’s law, the loss of copper was determined to be 0.7 mg/cm2. The CPE parameter (characterized, as a first approximation, by the electrochemical double-layer (Cdl) and the dimensionless n exponent, n=1.0) was 24 μF/cm2. The diffusion process was simulated by the Warburg impedance (Zw; Zw=σ(i – j)ω−½), where σ is the Warburg diffusion coefficient, which was 150 Ω cm2 s−½. The strong acidity of the mineral acids allows a fast and also economic cleaning of the copper-based materials. However, organic acids have the advantage that, being less aggressive than mineral acids, they allow the formation of metal complexes and are not dangerous and are easy to handle and ecologically acceptable (Bastidas & Otero, 1996; 2002; Otero, 1996a; Polo et al., 2002; Cano et al., 2003). Finally, in the cleaning treatment of copper, the use of alkaline solutions is common. The aqueous alkaline solutions containing D(+)glucose and formaldehyde are an alternative to the conventional cleaning solution (Otero & Bastidas, 1996b; Cano et al., 2001b, 2005).
Nyquist plot for copper in 5.0% citric acid after 96 h experimentation at room temperature.
Figure 4 shows a schematic representation of copper corrosion mechanism on a Cu-IUD, which is characterized by a small central zone with restricted access of oxygen (anodic zone) surrounded by a big zone with free access of oxygen (cathodic zone). The presence of corrosion products deposited on the copper surface and the precipitation process of calcite (CaCO3), generated by the presence of sodium bicarbonate and calcium chloride as the components of SUS used (see Table 1), produce aeration differential cells causing pitting corrosion (Oster, 1972; Rosenfeld et al., 1981; Bastidas et al., 2001, 2010; Burstein & Liu, 2007; Alonso et al., 2016):
Copper pitting corrosion mechanism.
Chemical composition of SUS used (Zhang et al., 1996; Mora et al., 2002).
| Reference | Concentration (g/l) |
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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NaHCO3 | NaH2PO4·2H2O | Glucose | Urea | Albumin | CaCl2 | KCl | NaCl | ||||||||
| Zhang et al., 1996 | 0.25 | 0.072 | 0.50 | – | – | 0.167 | 0.224 | 4.97 | |||||||
| Mora et al., 2002 | 0.25 | 0.072 | 0.50 | 0.48 | – | 0.167 | 0.224 | 4.97 | |||||||
| Mora et al., 2002 | 0.25 | 0.072 | 0.50 | – | 35 | 0.167 | 0.224 | 4.97 | |||||||
| Mora et al., 2002 | 0.25 | 0.072 | 0.50 | 0.48 | 35 | 0.167 | 0.224 | 4.97 | |||||||
Reaction inside a precipitated deposit:
Cathodic reaction taking place outside of the amorphous membrane of cuprite (Cu2O), a native oxide spontaneously generated on the copper surface with a porous structure (Cano et al., 2001a,b; Bastidas et al., 2005):
Anodic reaction taking place inside of the amorphous membrane of cuprite:
Reaction between Cu2+, Eq. (3), and the copper from the wall of the pit (Cu(s)):
5.2 Corrosion of copper in SUS
Table 1 includes the chemical composition of SUS used in the literature (Zhang et al., 1996; Mora et al., 2002).
Figure 5 shows copper dissolution rate against albumin content, using SUS (Table 1), for different times of experimentation, albumin content, pH 6.3 and 8.0, and 0.2 atm of oxygen pressure. It can be observed that the behavior is similar for both pH 6.3 and 8.0 with a high dissolution rate up to 500–700 μg/day for 1 day and 110–250 μg/day for 30 days of experimentation. Figure 6 shows an SEM micrograph for the copper specimen of Figure 5 after 1 day of experimentation. It can be observed that there is a broken and nonadherent layer of corrosion products, which allows the diffusion of copper ions for the contraceptive effect. Pitting corrosion was detected on the copper surface after the removal of the corrosion products.
Copper dissolution rate vs. albumin content for copper surface area of 200 mm2 in SUS (Table 1) without albumin (Mora et al., 2002).
SEM micrograph for copper immersed in SUS (Table 1) with urea and albumin, pH 8.0, and 0.2 atm of oxygen pressure (Mora et al., 2002).
It has been reported that there is a much higher release of copper in women during the first two cycles of use and after this a relative constant release for 1 year (Hagenfeldt, 1972, 1987). Previous studies have shown that Cu-IUD devices exhibit fast copper dissolution rates during the early stages of exposure to the uterine fluid, commonly referred to as “burst release” causing bleeding and pain (Zhang et al., 1996; Bastidas et al., 2000; De la Cruz et al., 2005; Gao et al., 2007; Pereda et al., 2008; Zhang et al., 2015). Anomalous bleeding occurs during the first few months after Cu-IUD insertion. This could lead to persistent menorrhagia, where Cu-IUD device removal is recommended. Typical blood loss within the menstrual period is about 35 ml (Barwin & Tuttle, 1978). The accumulation of cupric ions in solution results with time in the deposition of corrosion products in the IUD surface (Bank et al., 1975). This partially protective film decreases the Cu dissolution rate until steady-state Cu release kinetics is observed (Bastidas et al., 2001; Valdéz et al., 2003a,b).
Figure 7 shows the copper dissolution rate vs. time for different pH values using SUS (Table 1; Mora et al., 2002) without albumin and in the absence of additional pressure of oxygen at pH 5.0, 6.3, and 8.0. It can be observed that the behavior is similar for the three pH values with an exponential decay of copper corrosion with time in the first 10 days of experimentation, and after that, a steady state is defined with 0.5–1.5 μg/day copper dissolution. This process is defined as the burst release phenomenon. At the beginning of the experiment, the pits generated increase the copper surface area exposed to SUS originating a high corrosion rate (Figure 8). Copper release in utero reported in the literature varies in a wide range from 44 to 296 μg/day after the first month of insertion (Akinla et al., 1975; Kjaer et al., 1993; Patai et al., 2003) and decreasing to a steady-state value of 7 μg/day after 12 months of insertion (Thiery et al., 1982). In vitro experiments performed by Zhou et al. (2010) reported a copper release rate of as low as 2 μg/day in the steady state and the Cu-IUD with indomethacin was effective for contraceptive use.
Copper corrosion rate vs. time. Copper surface area of 200 mm2 in SUS (Table 1) without albumin (Mora et al., 2002).
Field emission-SEM morphology of a copper specimen exposed to SUS (Table 1) without albumin (Mora et al., 2002). Pits can be observed over the entire surface.
The quantification of in vitro burst release process can be done using different techniques, such as inductively coupled plasma (ICP)-optical emission spectroscopy (OES) with a lower limit of parts per billon, ICP-mass spectrometry (MS), flame atomic absorption spectroscopy (FAAS), atomic absorption spectroscopy (AAS), or diethyl ammonium salt of diethyldithiocarbamic acid (DAD) in spectrophotometric measurements because the sensibility is enough to study the process (Bastidas et al., 2019a,b). Anodic stripping voltammetry has also been used to quantify the amount of copper (Arancibia et al., 2003).
Copper release rate depends on different issues such as copper grade, effective surface area, and pH. An interesting alternative to reduce the undesirable burst release phenomenon is the use of organic inhibitors such as thiourea and benzotriazole. However, research is required to introduce a corrosion inhibitor in the uterus without risks avoiding secondary effects, among others (Thiery et al., 1982; Bastidas et al., 2000; Scendo, 2008; Turok, 2011; Wildemeersch et al., 2014; Zhang et al., 2015). Promising results have been reported by Alvarez et al. (2012) for purine (C5H4N4) with inhibitory efficiency higher than 98%. This heterocyclic compound is present in the structure of RNA and DNA, and probably, it is nontoxic for the body.
A characteristic coloring is one of the most distinguishing features of cupric ion chelates. Visual absorption spectra can be used to quantify the cupric ion content (Mora et al., 2002). The diethyl ammonium salt of DAD acid forms a yellow chelate with the cupric ion. Absorbance measurements performed at a wavelength of 446 nm using an HACH Model DR/3000 spectrophotometer (Figure 9), which shows a calibration of absorbance vs. cupric ion concentration, showed that the absorbance is proportional to cupric ion in the range from 10 to 80 μmol/l.
Calibration plot for copper dissolution, absorbance vs. molar concentration of copper.
The morphology of the corrosion products and deposits is a nonuniform layer, showing some paths through which copper ions can be released, favoring copper to act as a contraceptive device (Patai et al., 1998, 2004; Bastidas et al., 2003; Berthou et al., 2003). Thus, a nonadherent and broken layer is formed, and a compact layer of cuprite is produced underneath, where sulfur and chloride pits were generated. Pitting corrosion is generally observed on the copper surface after the removal of the corrosion product layers. Copper has a contraceptive effect due to cupric ion release into the uterine environment (Ortiz et al., 1996; Cai et al., 2005a).
Pereda et al. (2009) has demonstrated that the early fragmentation of Cu-IUDs cannot be attributed to stress corrosion cracking (SCC). A number of wire samples were metallographically mounted, sectioned, and observed under the optical microscope. No cracks were found. Copper wires are twisted onto an inert plastic rod during the manufacturing process of the Cu-IUD, so that residual stresses are present in the copper wires. This fact, together with the existence of a chloride and organic compounds containing medium like the uterine fluid environment, may lead to SCC. It is known that the presence of Cu2+ ions at high concentrations of the order of 1 m can originate from the SCC of copper (Arancibia et al., 2003; Farina et al., 2005). The shorter fracture times observed in some cases may be attributed to a high uniform corrosion rate that reduces the wire sections and leads to rupture by the overloading of the remaining smaller section. The addition of cupric ions to the solutions at concentrations similar to those measured in uterine fluid (20 mg/l=3×10−3m) did not lead to SCC in copper (Farina et al., 2005).
6 Cu-IUD mechanism
The accurate mechanism of action of the multifunctional effect of a Cu-IUD in the antifertility process is still not known. Pregnancy is prevented by a combination of a metal or plastic frame; a foreign body effect is the most important phenomenon in the antifertility process; the chemical and biochemical reactions are related to the type of material of which the foreign body is composed, causing sterile inflammation that is toxic to sperm; and the specific action of copper is mainly through the release of copper (Zipper et al., 1969; Ortiz et al., 1996; Ortiz & Croxatto, 2007; Chen et al., 2006). For instance, to ensure the antifertility effect of a Cu-IUD, the concentration of the released cupric (Cu2+) ions in uterine solution needs to be higher than 10−6 mol/l (Figure 10; Araya et al., 2003). Copper ions delivered from Cu-IUDs enhance the inflammatory response in the uterine cavity and reach concentrations in the luminal fluids of the genital tract that are toxic for spermatozoa and embryos (Jones et al., 1973; Middleton & Kennedy, 1975; Holland & White, 1998; Linder & Hazegh-Azam, 1996; Ortiz et al., 1996; Bastidas & Simancas, 1997; Bastidas et al., 2001; Sivin, 1997; Mishell, 1998; van Os & Edelman, 1998; Homouda, 2002; Araya et al., 2003; Caliskan et al., 2003). It is believed that the presence of Cu-IUD in the endometrial cavity increases the concentration of Cu2+, accompanied by the synthesis of lipids such as PG that are involved in inflammation and motility effects (Hagenfeldt, 1987), which gains the tubal contractility (higher-frequency intensity), and white blood cells (macrophages, within the uterine and tubal fluids; Kosonen, 1978, 1980; Koch & Vogel, 1980; De Castro et al., 1986; De Castro & González-Gancedo, 1987, De Castro 1993; Grillo et al., 2010). These compounds prevent the encounter of healthy gametes, the formation of viable embryos, and their ability to reach the uterus (motility effect). In other words, they prevent the fertilization of the ovum by interference with sperm function and transport within the uterus and tubes (Carrascosa et al., 2018). In addition, the presence of copper can result in the oxidation of sulfhydryl (-SH) groups of acid fibroblast growth factor causing the loss of the myogenic activity of the protein (Oster, 1972; Oster & Salgo 1975; Beltrán-García et al., 1998, 2000; Lozano et al., 2000; Cunha et al., 2001; Stanford & Mikolajczyk, 2002).
Sperm motility vs. time for a cupric ion concentration of 8 μmol/l CuCl2 in Ringer’s solution (0.72 NaCl, 0.03 KCl, 0.29 MgSO4, and 0.26 Na3PO4, concentration as g/100 ml), pH 7.2, and temperature of 37°C.
The endocrinologic mechanisms of reproductive processes may be summarized as follows (Figure 11). The ovary during the menstrual cycle produces two hormones (H; estrogen and progesterone) carrying information to a specific protein structure, receptor (R), located on the cytoplasmic membrane. Copper ions (Cu2+) from a Cu-IUD may alter the relationship with oligoelements (Cu, Zn, Mo, Nb, and Mn) having a negative impact on the motility (Figure 11, bottom; De Castro, 1993). The H reaches the endometrial territory through the arteries that irrigate the uterus. Once there, it comes in contact with its specific R and causes changes in the protein structure of the uterus that induce their way through the cytoplasm to reach the nucleus. During this first phase, the R is called the hormone-cytoplasmic receptor (HRc) complex. This inactivated complex starts its way to the cell nucleus through a movement called translocation (Ortega et al., 1991; Kadanali et al., 2001; Kleszczewski et al., 2003; Savaris & Chies, 2003; Karasahin et al., 2011). While approaching the nucleus, the complex undergoes a transmutation called transformation to bind to the nuclear chromatin and modify in an active complex, the so-called nuclear hormone-receptor complex (HRn; Figure 11; De Castro, 1993). Once the active complex is located inside the cell nucleus, an action is produced on the DNA, which entails the appearance of an mRNA to carry the information of the specialized work of the cytoplasmic ribosomes and to regulate the intracellular protein synthesis. Once the function of the active complex has been completed, it passes back to the cytoplasm, deactivating and undergoing a recycling process to start the whole process again.
Recycling reproductive process mechanism. H, hormone; HR, hormone-receptor complex; HRc, hormone-cytoplasmic receptor complex; HRn, nuclear hormone-receptor complex; mRNA, RNA (carrier of genetic codes); R, receptor.
7 Conclusion and recommendations
Chemical analyses (ICP-OES, ICP-MS, FAAS, and AAS), absorbance measurements, and electrochemical methods are adequate for the quantification of the copper release process of a Cu-IUD in an SUS environment. The SUS described in the literature are suitable to perform in in vitro experiments on the copper release of a Cu-IUD.
Burst release phenomenon taking place in the first 3 weeks of Cu-IUD insertion in the uterus cavity (copper release of 5–10 μg/day followed by a low steady-state dissolution process with ~0.5 μg/day), producing bleeding and pain, needs to be avoided or minimized, so the phenomenon needs a in-depth investigation. Results reported in the literature using corrosion inhibitors as pretreatment of SUS are hopeful and need to be studied in detail.
Microbial biofilms can coexist on the Cu-IUD surfaces due to the porous structure formed with the extracellular polymeric matrix. The interaction between these microbial growths and the copper ions released does not affect the efficacy of the contraceptive function of the device.
Studies are required to understand the mechanism of action of a Cu-IUD. For instance, (1) the copper dissolution rate of 2 μg/day for a Cu-IUD with indomethacin after a long time of insertion in the uterus and (2) the released cupric ions in the uterine solution that need to be higher than 10−6 mol/l are important findings that require to be studied in depth. Another example is that the minimum copper release rate necessary for a Cu-IUD to be efficient is not known.
About the authors
David M. Bastidas is an associate professor of corrosion engineering at The University of Akron. He received his PhD in materials science and engineering and BSc in chemistry from the University of Barcelona (Spain). His research focuses on the corrosion of steel in concrete, inhibition, and Cu-IUD corrosion. He is a member of research and infrastructure committees of NACE and the vice chairman of corrosion of steel in concrete WP of EFC.
Benjamin Valdez is a professor at the Institute of Engineering, UABC and was the Institute’s director from 2006 to 2013. He has PhD and MSc in chemistry and BSc in chemical engineering. He was appointed a member of the Mexican Academy of Science and the National System of Researchers in Mexico. He was a guest editor of Corrosion Reviews. His activities include corrosion research, consultancy, and control in industrial plants and environments.
Michael Schorr is a professor (Dr. honoris causa) at the Institute of Engineering, UABC. He received his PhD in materials engineering and BSc in chemistry from the Technion-Israel Institute of Technology. He was an editor of Corrosion Reviews (1986–2004). His research focuses on volatile corrosion inhibitors in industrial environments. He is a corrosion consultant and a professor in Israel, United States, Latin America, and Europe.
Jose M. Bastidas is a full professor at the CENIM, CSIC. He received his PhD in chemistry from Complutense University of Madrid, Spain. He was a postdoctoral Ramsey fellow at the University of Manchester (UK). His research focuses on corrosion and inhibition mechanisms, protection methods and numerical modeling in biomedical materials, chemical industry, heritage science, construction, and transportation.
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Funding: D.M. Bastidas acknowledges funding from The University of Akron.
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© 2019 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- In this issue
- Reviews
- Corrosion performance of cold deformed austenitic stainless steels for biomedical applications
- Corrosion of copper intrauterine devices: review and recent developments
- Chromate-free chemical conversion coatings for aluminum alloys
- A review on graphene-based polymer composite coatings for the corrosion protection of metals
Articles in the same Issue
- Frontmatter
- In this issue
- Reviews
- Corrosion performance of cold deformed austenitic stainless steels for biomedical applications
- Corrosion of copper intrauterine devices: review and recent developments
- Chromate-free chemical conversion coatings for aluminum alloys
- A review on graphene-based polymer composite coatings for the corrosion protection of metals
