Cupric Ion Release Research Articles

A Double Network Composite Hydrogel with Self-Regulating Cu2+/Luteolin Release and Mechanical Modulation for Enhanced Wound Healing.

Designing adaptive and smart hydrogel wound dressings to meet specific needs across different stages of wound healing is crucial. Here, we present a composite hydrogel, GSC/PBE@Lut, that offers self-regulating release of cupric ions and luteolin and modulates mechanical properties to promote chronic wound healing. The double network hydrogel, GSC, is fabricated through photo-cross-linking of gelatin methacrylate, followed by Cu2+-alginate coordination cross-linking. On one hand, GSC allows for rapid Cu2+ release to eliminate bacteria in the acidic pH environment during inflammation and reduces the hydrogel's mechanical strength to minimize tissue trauma during early dressing changes. On the other hand, GSC enables slow Cu2+ release during the proliferation stage, promoting angiogenesis and biocompatibility. Furthermore, the inclusion of pH- and reactive oxygen species (ROS)-responsive luteolin nanoparticles (PBE@Lut) in the hydrogel matrix allows for controlled release of luteolin, offering antioxidant and anti-inflammatory effects and promoting anti-inflammatory macrophage polarization. In a murine model of Staphylococcus aureus infected wounds, GSC/PBE@Lut demonstrates exceptional therapeutic benefits in antibacterial, anti-inflammatory, angiogenic, and tissue regeneration. Overall, our results suggest that smart hydrogels with controlled bioactive agent release and mechanical modulation present a promising solution for treating chronic wounds.

A Stimulus-Responsive Ternary Heterojunction Boosting Oxidative Stress, Cuproptosis for Melanoma Therapy.

Cuproptosis, a recently discovered copper-dependent cell death, presents significant potential for the development of copper-based nanoparticles to induce cuproptosis in cancer therapy. Herein, a unique ternary heterojunction, denoted as HACT, composed of core-shell Au@Cu2O nanocubes with surface-deposited Titanium Dioxide quantum dots and modified with hyaluronic acid is introduced. Compared to core-shell AC NCs, the TiO2/Au@Cu2O exhibits improved energy structure optimization, successfully separating electron-hole pairs for redox use. This optimization results in a more rapid generation of singlet oxygen and hydroxyl radicals triggering oxidative stress under ultrasound radiation. Furthermore, the HACT NCs initiate cuproptosis by Fenton-like reaction and acidic environment, leading to the sequential release of cupric and cuprous ions. This accumulation of copper induces the aggregation of lipoylated proteins and reduces iron-sulfur proteins, ultimately initiating cuproptosis. More importantly, HACT NCs show a tendency to selectively target cancer cells, thereby granting them a degree of biosecurity. This report introduces a ternary heterojunction capable of triggering both cuproptosis and oxidative stress-related combination therapy in a stimulus-responsive manner. It can energize efforts to develop effective melanoma treatment strategies using Cu-based nanoparticles through rational design.

Feasibility evaluation of a Zn-Cu alloy for intrauterine devices: In vitro and in vivo studies

The comprehensively adopted copper-containing intrauterine devices (Cu-IUDs) present typical adverse effects such as bleeding and pain at the initial stage of post-implantation. The replacement of Cu material is demanded. Zinc and its alloys, the emerging biodegradable materials, exhibited contraceptive effects since 1969. In this work, we evaluated the feasibility of bulk Zn alloys as IUD active material. Using pure Cu and pure Zn as control groups, we investigated the contraceptive performance of Zn-0.5Cu and Zn-1Cu alloys via in vitro and in vivo tests. The results showed that the main corrosion product of Zn-Cu alloys is ZnO from both in vitro and in vivo studies. CaZn2(PO4)2·2H2O is formed atop after long-term immersion in simulated uterine fluid, whereas CaCO3 is generally formed atop after implantation in the rat uterine environment. The cytocompatibility of the Zn-1Cu alloy was significantly higher than that of the pure Zn and pure Cu to the human endometrial epithelial cell lines. Furthermore, the in vivo results showed that the Zn-1Cu alloy presented much improved histocompatibility, least damage and the fastest recovery on endometrium structure in comparison to pure Zn, Zn-0.5Cu and pure Cu. The systematic and comparing studies suggest that Zn-1Cu alloy can be considered as a possible candidate for IUD with great biochemical and biocompatible properties as well as high contraceptive effectiveness. Statement of significanceThe existing adverse effects with the intrinsic properties of copper materials for copper-containing intrauterine devices (Cu-IUD) are of concerns in their employment. Such as burst release of cupric ions (Cu2+) at the initial stage of the Cu-IUD. Zinc and its alloys which have been emerging as a potential biodegradable material exhibited contraceptive effects since 1969. In this study, Zn-1Cu alloys displayed significantly improved biocompatibility with human uterus cells and a decreased inflammatory response within the uterus. Therefore, high antifertility efficacy of the Zn-1Cu alloy was well maintained, while the adverse effects are significantly eased, suggesting that the Zn-1Cu alloy is promising for IUD.

Feasibility evaluation of a Cu-38 Zn alloy for intrauterine devices: In vitro and in vivo studies

The existing adverse effects of copper in copper-containing intrauterine devices (Cu-IUDs) have raised concerns regarding their use. These adverse effects include burst release of cupric ions (Cu2+) at the initial stage and an increasingly rough surface of the Cu-IUDs. In this study, we investigated the use of two copper alloys, Cu-38 Zn and H62 as the new upgrading or alternative material for IUDs. Their corrosive properties were studied in simulated uterine fluid (SUF) by using electrochemical methods, with pure Cu as a control. We studied the in vitro long-term corrosion behaviors in SUF, cytotoxicity to uterine cells (human endometrial epithelial cells and human endometrial stromal cells), in vivo biocompatibility and contraceptive efficacy of pure Cu, H62, and Cu-38 Zn. In the first month, the burst release rate of Cu2+ in the Cu-38 Zn group was significantly lower than those in the pure Cu and H62 groups. The in vitro cytocompatibility Cu-38 Zn was better than that of pure Cu and H62. Moreover, Cu-38 Zn showed improved tissue biocompatibility in vivo experiments. Therefore, the contraceptive efficacy of the Cu-38 Zn is still maintained as high as the pure Cu while the adverse effects are significantly eased, suggesting that Cu-38 Zn can be a suitable potential candidate material for IUDs. Statement of significanceThe existing adverse effects associated with the intrinsic properties of copper materials for copper-containing intrauterine devices (Cu-IUD) are of concern in their employment. Such as, burst release of cupric ions (Cu2+) at the initial stage and an increasingly rough surface of the Cu-IUD. In this work, Cu alloyed with a high amount of bioactive Zn was used for a Cu-IUD. The Cu-38 Zn alloy exhibited reduced burst release of Cu2+ within the first month compared with the pure Cu and H62. Furthermore, the Cu-38 Zn alloy displayed significantly improved biocompatibility and a much smoother surface. Therefore, high antifertility efficacy of the Cu-38 Zn alloy was well maintained, while the adverse effects are significantly eased, suggesting that the Cu-38 Zn alloy is promising for a Cu-IUD.

Antimicrobial Property of Polypropylene Composites and Functionalized Copper Nanoparticles.

Copper nanoparticles (CuNPs) functionalized with polyethyleneimine (PEI) and 4-aminobutyric acid (GABA) were used to obtain composites with isotactic polypropylene (iPP). The iPP/CuNPs composites were prepared at copper concentrations of 0.25–5.0 wt % by melt mixing, no evidence of oxidation of the CuNP was observed. Furthermore, the release of copper ions from iPP/CuNPs composites in an aqueous medium was studied. The release of cupric ions was higher in the composites with 2.5 and 5.0 wt %. These composites showed excellent antibacterial activity (AA) toward Pseudomona aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus). The incorporation of CuNP into the iPP polymeric matrix slightly decreased the thermal stability of the composite material but improved the crystallinity and the storage modulus. This evidence suggests that CuNPs could work as nucleating agents in the iPP crystallization process. The iPP/CuNPs composites presented better AA properties compared to similar composites reported previously. This behavior indicates that the new materials have great potential to be used in various applications that can be explored in the future.

Cu2+-loaded cellulose micro-beads applied to the direct patterning of metallic surfaces using a fast and convenient process

In this paper, we propose both a new application for cellulose micro-beads and a new concept in colloidal lithography to directly deposit and template a metal from ions transported by the organized colloidal particles, using the colloidal particles themselves. To do so, 5 μm-sized cellulose micro-beads (CμBs) were first surface-functionalized by trimellitic anhydride to introduce carboxylate ligands before decorating them with Cu2+ ions by complexation of the carboxylate groups with a CuCl2 solution. The Cu2+-loaded CμBs, dispersed in an aqueous phase, were organized in compact monolayer at the vicinity of a planar electrode. The release of cupric ions and subsequent copper deposition were triggered by an electric field delivered by a tension generator. 2D non-close-packing arrays of copper dots assemblies displaying hexagonal symmetry were generated below or around the micro-beads – depending on the ions concentration in the aqueous phase – leading respectively to copper dots deposited circularly or concentrated in rings. The Cu2+-loaded cellulose beads allowed the covering of 2 cm²-surfaces by copper patterns in less than 45 min, using an easy and cheap process.

The effect of wetting property on anti-fouling/foul-release performance under quasi-static/hydrodynamic conditions

In this study, we synthesized hydrophilic and hydrophobic polyacrylate resin using free-radical polymerization and embedded cupric ion source (Cu2O) into the as-prepared resins to fabricate antifouling coatings, such of that the coatings combine the concept of “antifouling” and “fouling release” properties. In particular, the effect of hydrophobicity/hydrophilicity on anti-biofouling was investigated. The physicochemical properties of the coatings were characterized by infrared spectroscopy, atomic absorption spectroscopy, and contact angle measurements. Biofouling assays for the settlement and release of the diatom Navicula sp. and green alga Dunaliella tertiolecta were carried out under quasi-static and hydrodynamic condition. To prove the chemical stability and broad-spectrum antifouling characteristics of these coatings, the field tests were implemented in the South China Sea. Both results show that hydrophilic coating exhibits superior foul-resistance behavior to the hydrophobic coatings probably because of larger cupric ion release rate and the inhibition of hydrophobic interaction on hydrophilic coating.

Nano-Cu/Low-Density Polyethylene Composites: Structure and Control Release of Cupric Ions

In recent years a new type of intrauterine device (nanoCu/LDPE composites) has been concerned by a lot of scholars for its short release time, high bioavailability and good biocompatibility. In this study nanoCu/low-density polyethylene composites were prepared by extruding mixtures of pure LDPE and nanoCu using melt-blending method, the release rate of cupric ions (Cu2+) was measured in simulated uterine fluid. The non-isothermal crystallization behavior and thermal stability of the composites before and after immersion were studied by differential scanning calorimetry (DSC) and thermogravimetric analyzer (TG). The results showed that Composites effectively shorten the time of the copper ion "burst release" , the burst release phenomenon of Cu2+ occurred during the first five days after immersion , and then tend to stable . By immersion the crystallinity of composites increased, and the thermal stability decreased.

Do CVD grown graphene films have antibacterial activity on metallic substrates?

Accurate assessment of the antibacterial activity of graphene requires consideration of both the graphene fabrication method and, for supported films, the properties of the substrate. Large-area graphene films produced by chemical vapor deposition were grown directly on copper substrates or transferred on a gold substrate and their effect on the viability and proliferation of the Gram-positive bacteria Staphylococcus aureus and the Gram-negative bacteria Escherichia coli were assessed. The viability and the proliferation of both bacterial species were not affected when they were grown on a graphene film entirely covering the gold substrate, indicating that conductivity plays no role on bacterial viability and graphene has no antibacterial activity against S. aureus and E. coli. On the other hand, antibacterial activity was observed when graphene coated the copper substrates, resulting from the release of bactericidal cupric ions in inverse proportion to the graphene surface coverage.

Study on antibacterial activity and cytocompatibility of Ti–6Al–4V–5Cu alloy

A new biomedical Ti–6Al–4V–5Cu alloy with antibacterial function was developed by proper addition of copper (Cu) into Ti based alloy in this study. The microstructure, antibacterial activity and cytotoxicity of this Cu bearing titanium alloy were studied. It was found that the microstructure of Ti–6Al–4V–5Cu alloy consisted of α phase, β phase and Ti2Cu intermetallic compound, which could obtain a considerable antibacterial ability and inhibit the formation of bacterial biofilm through trace release of cupric ions from its surface. The cytotoxicity evaluation demonstrated that Ti–6Al–4V alloy played no toxic effect on the viability of MC3T3-E1 cells, showing a satisfied biocompatibility.

Anti-aging properties of the Cu/LDPE composite for intrauterine contraceptive devices

Abstract Copper/low-density polyethylene (Cu/LDPE) composite is a novel copper intrauterine devices (Cu-IUDs) material; the aim of this study is to report its anti-aging properties. After the prepared composite samples were treated with an aging-box at a temperature of 60 °C and a humidity of 90% under one atmospheric pressure for various days, the structures and properties of these experimental samples and the original composite samples were studied systematically. The results show that aging has some influences on the structures and properties of these aged samples. Compared with the structure of original composite samples, although no changes of the phases, functional groups, molecular weights and molecular weight distributions have been found among these aged samples, the crystallinity degrees of these aged samples are different and they increase slightly with the increasing of aging time. Additionally, Cu(II) species have been formed in the surface and subsurface of the experimental composite samples, and their concentrations increase with the increasing of accelerated aging time. Compared with the properties of original composite samples, with the increasing of aging time, their tensile strengths and their elastic moduli increase initially and then level off, their glass-transition temperatures increase and elongations at break decrease slightly, and their cupric ion release rates decrease slightly. These results are very important for us to design both storage time and lifespan of the Cu/LDPE composite Cu-IUDs for the future clinical use.

A novel copper/polydimethiylsiloxane nanocomposite for copper‐containing intrauterine contraceptive devices

In this article, a novel composite of copper (Cu) nanoparticles and polydimethiylsiloxane (PDMS) has been prepared and investigated for the potential application in Cu-containing intrauterine device. The Cu/PDMS composite with various mass fraction of Cu nanoparticles was fabricated via the hot vulcanizing process. The chemical structures and surface morphologies of the Cu/PDMS composites were characterized confirming the physical interaction between Cu nanoparticles and PDMS. The surface morphology observation using scanning electron microscope and atomic force microscope showed the agglomeration of Cu nanoparticles in PDMS matrix and the distribution of the agglomerations was more uniform with increased amount of Cu nanoparticles. The cupric ion release behaviors of the Cu/PDMS composites with different amounts of Cu nanoparticles were investigated in simulated uterine fluid at 37°C for 150 days. The corrosion morphologies of the Cu/PDMS composites were also characterized. Both the burst release rate of the cupric ion in the first few days and the steady release rate after 30-day immersion were improved. The cytotoxicity test has been done for the Cu/PDMS composites.

Preparation and cupric ion release behavior of Cu/LDPE porous composites with tunable pore morphology for intrauterine devices

Copper/low-density polyethylene (Cu/LDPE) porous composites are novel materials for copper-containing intrauterine devices (Cu-IUDs). Here we report a method, i.e., by changing the mass ratio of two kinds of porogens that have different melting points through the combined techniques of injection molding and particulate leaching, to prepare the Cu/LDPE porous composites with tunable pore morphology. After these Cu/LDPE porous composites with different pore morphologies were obtained, the influences of pore morphologies on their cupric ion release behaviors were studied. The results show that the pore morphology has great influence on the cupric ion release behavior of Cu/LDPE porous composites. This phenomenon is caused by the different influences of different pore morphologies on the effective porosity and the surface hydrophilicity. And those results can be applied to guide the fabrication of Cu/LDPE porous composite Cu-IUDs with minimal weight at an appropriate cupric ion release rate.

Improvement of the Hydrophilicity of Cu/LDPE Composite and its Influence on the Release of Cupric Ions

t is of great importance to improve the hydrophilicity of Cu/LDPE composite, a material for a new type of IUDs (Intrauterine Devices). The aim of the study is not only satisfying the biocompatibility of medical devices implanted in human bodies, but also improving the releasing rate of cupric ions. In this study, various hydrophilic materials (sodium chloride, anhydrous glucose and soluble starch) were added respectively, in order to improve the hydrophilicity of Cu/LDPE composite. The microstructure of Cu/LDPE composite was characterized, moreover, the influence of the addition of these hydrophilic materials on the surface hydrophilicity and the releasing rate of cupric ions of Cu/LDPE composite was studied. The compatibility between three hydrophilic materials and the matrix of LDPE is rather different, which can affect the dispersible uniformity of these additives in Cu/LDPE composite, and the dispersible uniformity of NaCl is the worst among these three hydrophilic materials. The addition of three hydrophilic materials was all beneficial to the improvement of the hydrophilicity of Cu/LDPE composite. Connected holes were formed in Cu/LDPE composite, which provided channels for the infiltration of solution and the diffusion of cupric ions, and improved the releasing rate of cupric ions in the Cu/LDPE composite IUDs.

Decrease in Cytotoxicity of Copper-Based Intrauterine Devices (IUD) Pretreated with 6-Mercaptopurine and Pterin as Biocompatible Corrosion Inhibitors

The copper intrauterine device (IUD) based its contraceptive action on the release of cupric ions from a copper wire. Immediately after the insertion, a burst release of copper ions occurs, which may be associated to a variety of side effects. 6-Mercaptopurine (6-MP) and pterin (PT) have been proposed as corrosion inhibitors to reduce this harmful release. Pretreatments with 1 × 10(-4) M 6-MP and 1 × 10(-4) M PT solutions with 1h and 3h immersion times were tested. Conventional electrochemical techniques, EDX and XPS analysis, and cytotoxicity assays with HeLa cell line were employed to investigate the corrosion behavior and biocompatibility of copper with and without treatments. Results showed that copper samples treated with PT and 6-MP solutions for 3 and 1 h, respectively, are more biocompatible than those without treatment. Besides, the treatment reduces the burst release effect of copper in simulated uterine solutions during the first week after the insertion. It was concluded that PT and 6-MP treatments are promising strategies able to reduce the side effects related to the "burst release" of copper-based IUD without altering the contraceptive action.

The antifertility effectiveness of a novel copper-containing composite used in intrauterine contraceptive devices and the releasing behavior of cupric ions contained in the composite in rats

BackgroundThis study was conducted to investigate the antifertility effectiveness of a novel copper-containing composite used in intrauterine contraceptive devices (IUDs) that contain cupric chloride/silicon dioxide/poly(vinyl alcohol) (CuCl2/SiO2/PVA) and the releasing behavior of cupric ions in the composite into the serum and uterine fluid in rats. Study DesignTwo hundred and forty sexually mature female Sprague–Dawley rats were randomly divided into six groups: sham-operated control group (n=20), bulk copper group (Cu group, n=40), SiO2/PVA group (n=40), CuCl2/SiO2/PVA groups I (n=40, copper ion was released from IUD at a rate of 5–10 mcg/220 mm2 per day) and II (n=40, copper ion was released from IUD at a rate of 10–20 mcg/220 mm2 per day), and normal control group (n=20). IUD was inserted into the uterus of rats after acclimatization of 1 week .At different time points after implantation of the IUDs, cupric ion concentrations were measured in the serum and local uterine fluid in each group by flame atomic absorption, respectively. After 30 days of insertion, half of the rats in each group were mated with fertile male rats, and the antifertility rates were observed at 14 days of pregnancy. After the IUDs were removed, the remaining rats in each group were mated again to determine their fertility. ResultsAntifertility rates in the Cu group and CuCl2/SiO2/PVA groups I and II were 100%, and each of these rates was significantly higher than that in the other groups (p<.05). There were no differences in fertility restoration rates after the IUD was removed among the Cu group and the CuCl2/SiO2/PVA group (p>.05). No significant change in time dependence was found for the serum cupric ion concentrations in each group (p>.05), while the local uterine fluid cupric ion concentrations in the other groups were significantly lower than those in the Cu group (p<.05) and without a burst release of cupric ions in the initial days of application. ConclusionsThe novel copper-containing composite used in intrauterine contraceptive devices (CuCl2/SiO2/PVA composite IUD) had a low pregnancy rate and high contraceptive efficacy without a burst release of cupric ions in the initial days of application.

Indomethacin/Cu/LDPE porous composite for medicated copper intrauterine devices with controlled release performances

A novel functional material, indomethacin/copper/low density polyethylene (IDM/Cu/LDPE) porous composite, has been developed for medicated copper intrauterine devices (Cu-IUDs). The aim of this study was to report its preparation, structure and release performances. Samples of the IDM/Cu/LDPE porous composite were prepared by a combined technique involved in injection molding, particulate leaching, IDM solution incubating, and solvent vacuum drawing. Results of structure characterizations of these prepared samples show that the IDM/Cu/LDPE porous composite is obtained successfully and it is only a simple hybrid of IDM, copper particles and LDPE, and both the IDM and the copper particles are generally distributed homogeneously in its porous LDPE matrix. Results of IDM-loaded and release properties characterizations of these prepared samples show that the amount of loaded-IDM increases with the increasing of introduced porosity, and the release rates of both IDM and cupric ions increase with the increasing of porosity for these prepared samples with the same 25 wt.% of copper particles. It indicates that this novel porous composite not only can control its release of IDM, but also can control its release of cupric ions, its release properties can be regulated easily by controlling its amount of introduced porosity.

Effective inhibition of the early copper ion burst release with ultra-fine grained copper and single crystal copper for intrauterine device application

To solve the main problems of existing coarse grained copper (CG Cu) intrauterine devices (IUD)—namely burst release and a low transfer efficiency of the cupric ions during usage—ultra-fine grained copper (UFG Cu) and single crystal copper (SC Cu) have been investigated as potential substitutes. Their corrosion properties with CG Cu as a control have been studied in simulated uterine fluid (SUF) under different conditions using electrochemical measurement methods. Long-term immersion of UFG Cu, SC Cu and CG Cu samples in SUF at 37 °C have been studied for 300 days. A lower copper ion burst release and a higher efficiency release of cupric ions were observed for UFG Cu and SC Cu compared with CG Cu in the first month of immersion and 2 months later. The respective corrosion mechanisms for UFG Cu, SC Cu and CG Cu in SUF are proposed. In vitro biocompatibility tests show a better cellular response to UFG Cu and SC Cu than CG Cu. In terms of instantaneous corrosion behavior, long-term corrosion performance and in vitro biocompatibility, the three pure copper materials follow the order: UFG Cu > SC Cu > CG Cu, which indicates that UFG Cu could be the most suitable candidate material for intrauterine devices.

A porous Cu/LDPE composite for copper-containing intrauterine contraceptive devices

To improve the rates of both cupric ion release and the utilization of copper in non-porous copper/low-density polyethylene (Cu/LDPE) composite, a porous Cu/LDPE composite is proposed and developed in the present work. Here 2,5-di-tert-butylhydroquinone was chosen as the porogen, ethyl acetate was chosen as the solvent for extraction, and the porous Cu/LDPE composite was obtained by using injection molding and the particulate leaching method. After any residual ethyl acetate remaining inside the porous Cu/LDPE composite had been removed by vacuum drying, the composite was characterized by X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, gas chromatography–mass spectrometry and absorption measurement. For comparison, a non-porous Cu/LDPE composite was also characterized in the same way. The results show that the porous structure was successfully introduced into the polymeric base of the non-porous Cu/LDPE composite, and the porous Cu/LDPE composite is a simple hybrid of copper particles and porous LDPE. The results also show that the introduction of a porous structure can improve the cupric ion release rate of the non-porous Cu/LDPE composite with a certain content of copper particles, indicating that the utilization rate of copper can be improved either the introduction of a porous structure, and that the porous Cu/LDPE composite is another promising material for copper-containing intrauterine devices.

Release of copper and indomethacin from intrauterine devices immersed in simulated uterine fluid

Objectives To study the release of cupric ions and indomethacin from copper-bearing intrauterine devices (Cu-IUDs) and to assess the influence of their surface area of copper and the pH of the test medium on the release of cupric ions.Methods Cu-IUDs were incubated in simulated uterine fluid (SUF). The in vitro release of cupric ions and indomethacin was determined by means of a flame atomic absorption spectrometer and a UV 752 spectrophotometer, respectively, over a period of 220 days. The effect of indomethacin on the pH of the SUF was monitored during the cupric ions release study.Results The Cu-IUDs released cupric ions in vitro according to a biphasic pattern. After an initial burst release, the rate slowed down and then became steady. The release of indomethacin from two medicated Cu-IUDs was biphasic and, in both cases, in accordance with the in vitro dissolution model of the drug. The surface area of copper of Cu-IUDs and the pH change induced by indomethacin incorporated in their frame affected the release rate of copper (p < 0.05).Conclusion The surface area of the copper and the pH of the test medium modulate the in vitro release of cupric ions from Cu-IUDs.