Intrauterine Devices An interactive learning module

1. Intrauterine DevicesAn interactive learning module Julia Chapman, Hattie Cutcliffe, Mansi Ganatra BME 215: Biomaterials, Fall 2010 Department of Biomedical Engineering, Duke University Click to begin!

2. Getting Started HOME • This presentation is intended as an interactive overview of intrauterine devices. • It is recommended that users view presentation in SLIDE SHOW mode. • To enter Slide Show: Click the icon at the bottom left (Mac) or bottom right (PC) corner of Powerpoint (shown here): • To move between slides, click the links at the top of each slide, or click the buttons shown below. • To return to the HOME Menu, or other submenus click the links found at the top left corner of each slide. • A stop sign signifies the end of a section: STOP Click me to start presentation!

3. Home Return to this page by clicking HOME on any slide. HOME Click the blue buttons to learn more! Disease State STOP Implantation Sterilization & Insertion Intro to IUDs Design Performance

4. Return to this page by clicking “Intro to IUDs” Intro to IUDs HOME Intro to IUDs Biological Context IUD Overview Disease State STOP Implantation Overview of Uterine Functions Embryo Development Why choose an IUD? How do IUDs function? Location & Anatomy Fertilization Menstrual Cycle What is an IUD?

5. What is an IUD? HOME Intro to IUDs What is an IUD? • Intrauterine Devices (IUDs) are a form of contraception that involve the placement of an object in the uterus to prevent fertilization, inhibit tubular transport of the fertilized egg, or destroy the embryo post-fertilization. • The two IUDs shown above are the only two designs currently available in the United States. These two IUDs will be the focus of this presentation. Paragard Copper IUD Mirena Hormonal IUD Continue to Why Choose an IUD?

6. Why choose an IUD? Why choose an IUD? HOME Intro to IUDs • IUD’s are used by 150 MILLION women worldwide! • 2nd only to Female Sterilization as most common female contraceptive (does not include male contraceptives such as condoms). Continue to How do IUDs Function? Learn more about Female Sterilization

7. Female Sterilization Why choose an IUD? Female Sterilization HOME Intro to IUDs • Female sterilization is a surgical procedure that involves tying off or blocking the fallopian tubes, so as to prevent mature eggs from traveling from the ovary to the uterus. In this manner, it is a method of contraception. • It is essentially a permanent procedure. • Its contraceptive effects take place immediately. • Worldwide, female sterilization is used by 33% of married women. 10 • Unfortunately, sometimes female sterilization is not the woman’s choice, and she is coerced into being sterilized either for the purpose of population control or eugenics. • Often, the woman is jailed or detained in a hospital until she agrees to undergo sterilization. • Countries in which this has been documented include: the United States, Canada, Mexico, Honduras, the Dominican Republic, Brazil, Peru, the United Kingdom, Switzerland, Norway, Finland, Sweden, Germany, the Czech Republic, Nigeria, Tibet, Vietnam, Bangladesh, Indonesia, India, Japan, China, and Australia. Continue to How do IUDs Function?

8. How do IUDs function? HOME Intro to IUDs How do IUD’s function? End of section. • IUDs prevent fertilization by killing sperm, inhibiting sperm motility, and reducing frequency of ovulation. • Although fertilization is rare, IUDs prevent embryo development upon fertilization. http://www.scientificamerican.com/blog/post.cfm?id=sperm-cells-swimming-secrets-reveal-2010-02-04 Next Section: Biological Overview Return to Intro to IUDs Menu

9. Location & Anatomy of the Uterus HOME Intro to IUDs Location & Anatomy of the Uterus The uterus is a pear-shaped, muscular sex organ of the female reproductive tract that houses the developing fetus during gestation. • Location: • Behind bladder • In front of bowel • Continuous with cervix and vagina on one end. • Other end opens into fallopian tubes. • Dimensions: • 7.5 cm long • 5 cm wide • 2.5 cm thick http://en.wikipedia.org/wiki/File:Gray38.png Continue to Overview of Uterine Functions

10. Overview of Uterine Functions HOME Intro to IUDs Overview of Uterine Functions Structural Support Uterus provides support to the bladder, bowels, and pelvis. Sexual Response The uterus directs blood flow to the pelvis and genitalia; the uterus is responsible for uterine orgasm. Reproduction The uterus houses the developing fetus. Uterus provides support to the bladder, bowels, and pelvis. Continue to Menstrual Cycle

11. Menstrual Cycle HOME Intro to IUDs The Menstrual Cycle The menstrual cycle is a series of physiological changes that can occur in a female in response to regulation by the endocrine system. The menstrual cycle is responsible for a female’s reproductive abilities. Control of the menstrual cycle with hormonal contraceptives can interrupt or prevent reproductive capabilities. Continue to Fertilization Learn more about the Menstrual Cycle!

12. Menstrual Cycle HOME Intro to IUDs The Menstrual Cycle Time Span: Starts on first day of bleeding and lasts approximately 28 days. Phases: 1) Follicular: – estrogen levels increase – uterine walls thicken – increased hormone levels promote follicle development 2) Ovulation: – single follicle released as ovum – occurs mid-cycle in response to LH spike 3) Luteal: – follicular remains become corpus luteum – progesterone release causes thickening of endometrium http://en.wikipedia.org/wiki/Menstrual_cycle If fertilization and implantation do not occur within two weeks, the corpus luteum disappears and the body’s progesterone and estrogen levels drop sharply. The uterus sheds the egg and endometrium through menstrual bleeding. Continue to Fertilization

13. Fertilization HOME Intro to IUDs Fertilization • Fertilization is the union of the ovum and sperm, and usually occurs in the fallopian tubes. • Once fertilization has occurred, IUDs can prevent implantation of the fertilized egg on uterine wall. • Embryos that are not implanted within two weeks are shed during menses. http://en.wikipedia.org/wiki/Human_fertilization Continue to Embryo Development

14. Embryo Development HOME Intro to IUDs Embryo Development End of section. The uterus accepts a fertilized ovum from one of the fallopian tubes. The ovum develops into an embryo in the uterus, attaches to the wall, and develops in the uterus as a fetus, until childbirth. Prevention of embryo development is one contraceptive mechanism of IUDs. Continue to IUD Design Menu Return to HOME Menu

15. IUD Design Menu HOME Design Specifications Materials Fabrication Return to HOME menu

16. Materials HOME Design Materials Click the boxes to learn more about individual materials. + Polyethylene Barium Sulfate PDMS Levonorgestrel Copper Return to IUD Design Menu Next Section: Specifications

17. Copper Copper HOME Design Materials Copper’s Biocompatibility, constant release rate, and contraceptive effects make it desirable for use in IUDs. http://commons.wikimedia.org/wiki/ File:Electron_shell_029_Copper.svg http://green.autoblog.com/2006/12/27/oshkosk-using-copper-motor-rotor-technology-for-military/ Contraceptive Effects Biocompatibility Corrosion Complications Return to Materials Menu

18. Copper Corrosion Copper HOME Design Materials Copper Corrosion Corrosion: Copper corrodes in the uterine fluid, generating soluble ions (Cu2+) in solution and Cu2O films on the metal surface. • Within days post implantation, copper has extremely high corrosive rate and many cupric ions are released.4 This is called the“burst release” of cupric ions.4After the burst release, copper exhibits near zero-order (approximately constant) release rates of 0.01-0.37 mg per day.4 Burst release Constant release Note: Graph is also from reference 4. Learn more about Corrosion Mechanisms! Return to Copper Menu

19. Corrosion Mechanisms Copper HOME Design Materials Corrosion Mechanisms • Corrosion reaction: Copper corrodes from bulk copper (Cu) to cupric ions (Cu2+) in one of two ways: Cu + H+ + O2  Cu2+ + H2O Mechanism 1: 8 Cu + O2 + 2 H2O  4 Cu2O + 4 H+ + 4 e- Cu2O + 2 H2O + 2 e-  2 Cu2+ + H2O + 2 e- Mechanism 2: 2 Cu + 4 H+ + O2  2 Cu2+ + 2 H2O Mechanisms 1 & 2 can happen simultaneously in the uterine environment. Continue to Biocompatibility

20. Biocompatibility Copper HOME Design Materials Biocompatibility • Intrauterine copper ions do not disrupt the menstrual cycle and ovulation still occurs each month. No systemic effects have been found other than a small increase in the levels of some antibodies. Thus, the recommended duration of copper IUD use is 3 to 10 years. http://dickinsonn.ism-online.org/tag/antibody/ http://www.girlshealth.gov/parents/parentsbody/pcos_educators.cfm Continue to Contraceptive Effects

21. Contraceptive Effects Copper Contraceptive Effects HOME Design Materials Cupric ions enhance the effects of the foreign body reaction by creating local inflammatory reactions in the uterus. • Cupric ions are toxic to sperm and egg cells. egg sperm Learn more about the Foreign Body Reaction! Skip to more Contraceptive Effects

22. Contraceptive Effects Copper Contraceptive Effects HOME Design Materials Foreign body reaction: The presence of a foreign body within the uterus prompts a cytotoxic inflammatory reaction that is spermicidal. • Specifically, the endometrium releases leukocytes, prostaglandins, and macrophages, which are hostile to both sperm and egg cells and promote their degradation. • Once the IUD is removed, the inflammatory reaction stops, and the contraceptive effects vanish. Inflammatory reaction Continue learning about the FBR! Skip to more Contraceptive Effects uterus image: http://bloominbabies.blogspot.com/2009/11/we-have-plan-and-answers.html

23. Foreign Body Reaction Copper Contraceptive Effects HOME Design Materials • The foreign body reaction is the response of biological tissue to any foreign material that is placed within the tissue. • It begins as inflammation (recruitment of macrophages), but the continued presence of an implant or other particulate inhibits full healing. • The foreign body reaction is characterized by the formation of foreign body giant cells (see photo), encapsulation of the foreign object, and chronic inflammation. • Foreign body giant cells are are the products of macrophage fusion and are created when macrophages encounter an object too large to be degraded by phagocytosis. • Encapsulation refers to the creation of a firm, avascular collagen shell deposited around a foreign body, effectively isolating it form the host tissues. Foreign Body Giant cell http://www.breastpathology.info/BMS%20Trimming.html Continue to copper-specific Contraceptive Effects

24. Contraceptive Effects Contraceptive Effects Copper HOME Design Materials • Copper ions increase the viscosity of the cervical mucus. • Increased mucus viscosity reduces sperm motility and inhibits fertilization. http://www.scientificamerican.com/blog/post.cfm?id=sperm-cells-swimming-secrets-reveal-2010-02-04 Continue to Complications Return to Copper Menu

25. Complications Copper HOME Design Materials Complications The burst release of cupric ions has negative local effects, including increased bleeding and pelvic pain. ouch! uterus image: http://bloominbabies.blogspot.com/2009/11/we-have-plan-and-answers.html Continue to more Complications

26. Complications Copper HOME Design Materials Complications End of section. • Copper IUDs increase the risk of Pelvic Inflammatory Disease (PID). • PID refers to any infection in the uterus or fallopian tubes. • Can lead to ectopic pregnancy, infertility, sepsis, and in rare cases death. http://www.mdguidelines.com/pelvic-inflammatory-disease Return to Materials Menu Next Material: Polyethylene

27. Polyethylene Polyethylene HOME Design Materials Polyethylene is a polymer used in IUD frames & strings because of its biocompatability, mechanical properties, and contraceptive effects. Mechanical Properties http://en.wikipedia.org/wiki/File:Polyethylene-repeat-2D.png Contraceptive Effects http://en.wikipedia.org/wiki/File:Polyethylene-3D-vdW.png Biocompatibility Return to Materials Menu

28. Biocompatibility Polyethylene Biocompatibility HOME Design Materials • Polyethylene is biologically and chemically inert. • Polymer does NOT degrade. • Polymer does not release toxins into the uterine environment. • Lasts for 5-10 years. • Capable of being sterilized. Year 1 Over time, no degradation! Year 10 Continue to Mechanical Properties

29. Mechanical Properties Polyethylene Mechanical Properties HOME Design Materials The strength, elasticity, and hydrophobicity of polyethylene make it an ideal material for the frame and removal strings of IUDs. Hydrophobicity Polyethylene http://en.wikipedia.org/wiki/File:Polyethylene-3D-vdW.png Strength Elasticity Skip to Contraceptive Effects

30. Strength Polyethylene Mechanical Properties HOME Design Materials • Tensile strength between 6 and 9 MPa. 25 • Yield strength between 6 and 7 MPa. 25 Polyethylene has a preferred molecular orientation along its fiber axis, increasing its strength and elasticity. Preferred Orientation Both the T frame and strings are strong enough to resist breaking upon IUD removal. However, the strings are made of HDPE (high density polyethylene—stronger than low density polyethylene), so that they don’t break when pulled on during removal. http://neon.mems.cmu.edu/cramb/27-100/lab/S00_lab2/lab2.html Continue to Elasticity

31. Elasticity Polyethylene Mechanical Properties HOME Design Materials • Elastic modulus between 38 and 48 MPa. 28 • Due to the polymer’s elasticity and flexibility, the T arms are able to fold inward during implantation and unfold afterwards. Both the T frame and strings are elastic enough to fit comfortably within the uterus. However, the T frame is made of LDPE (low density polyethylene—more elastic than high density polyethylene), so that it is flexible enough to bend and fold during implantation and removal. Continue to Hydrophobicity

32. Hydrophobicity Polyethylene Mechanical Properties HOME Design Materials • Nonpolar and has a low surface energy. The nonpolar nature of the polymer discourages water molecules from adhering to the polyethylene molecule. Hydrophilic (polar) surface Polyethylene Hydrophobic (nonpolar) surface Continue to Contraceptive Effects Return to Mechanical Properties

33. Contraceptive Effects Polyethylene Contraceptive Effects HOME Design Materials STOP Foreign body reaction: The presence of a foreign body within the uterus prompts a cytotoxic inflammatory reaction that is spermicidal. • Specifically, the endometrium releases leukocytes, prostaglandins, and macrophages, which are hostile to both sperm and egg cells and promote their degradation. • Once the IUD is removed, the inflammatory reaction stops, and the contraceptive effects vanish. Inflammatory reaction uterus image: http://bloominbabies.blogspot.com/2009/11/we-have-plan-and-answers.html Next Material: Barium Sulfate Return to Materials Menu Learn more about the Foreign Body Reaction!

34. Foreign Body Reaction Polyethylene Contraceptive Effects HOME Design Materials STOP • The foreign body reaction is the response of biological tissue to any foreign material that is placed within the tissue. • It begins as inflammation (recruitment of macrophages), but the continued presence of an implant or other particulate inhibits full healing. • The foreign body reaction is characterized by the formation of foreign body giant cells (see photo), encapsulation of the foreign object, and chronic inflammation. • Foreign body giant cells are are the products of macrophage fusion and are created when macrophages encounter an object too large to be degraded by phagocytosis. • Encapsulation refers to the creation of a firm, avascular collagen shell deposited around a foreign body, effectively isolating it form the host tissues. Giant cell Foreign Body http://www.breastpathology.info/BMS%20Trimming.html Next Material: Barium Sulfate Return to Materials Menu

35. Barium Sulfate HOME Design Materials Barium Sulfate STOP Barium Sulfate is a nontoxic, radiopaque agent used in IUD frames. Barium Sulfate can be absorbed by the body. • Barium sulfate is a nontoxic, radiopaque contrast agent used in IUD frames. • This is an example of an x-ray, showing a misplaced IUD. The IUD is circled. http://commons.wikimedia.org/wiki/File:Barium-sulfate-2D.png • It blocks the transmission of x-rays. • Therefore, it is used to coat the T frame so that the IUD shows up in an x-ray image. • Barium sulfate can be absorbed by the body. http://en.allexperts.com/q/Contraception-VD-997/2008/9/Mirena-IUD-lost-abdomen.htm Return to Materials Menu Next Material: Levonorgestrel

36. Levonorgestrel HOME Design Materials Levonorgestrel A hormone used in IUD reservoirs to provide contraceptive effects is levonorgestrel: • Molecular formula: • C21H28O2 Contraceptive Effects http://en.wikipedia.org/wiki/Levonorgestrel Return to Materials Menu Bioactivity Release Profile Complications

37. Bioactivity HOME Design Materials Levonorgestrel Bioactivity Why Levonorgestrel? Levonorgestrel is a synthetic progesterone. Progesterone is a steroid hormone involved in ovulation and does not contain estrogen. Thus, levonorgestrel is an organic compound that is tolerated by the body and is nontoxic. • Levonorgestrel’s effects are local; illustrated by its high concentration in endometrial tissue but low concentration in surrounding tissues. • Its local effects include irregular bleeding and an absence of menstruation (amenorrhea). • In the blood, levonorgestrel is usually bound to sex hormone binding globulin (SHBG). Endometrium High concentration Low concentration http://www.health.com/health/library/mdp/0,,tp12652,00.html

38. Why Levonorgestrel? HOME Design Materials Levonorgestrel Bioactivity • Other hormones that could possibly be used in IUDs include d-norgestrel, norethindrone, progesterone, and estradiol. • D-norgestrel and norethindrone are synthetic progestins whereas progesterone is the natural progestin excreted by the body. • Estradiol is also a natural hormone excreted by the body but it is an estrogen, not a progestin. • The main difference between estrogens and progestins are the number of carbons in their molecular backbone; estrogens have 18 while progestins have 21. • Levonorgestrel is optimal because it provides effective contraception at minimal dosage. • Doesn’t prevent ovulation. • Doesn’t cause excessive bleeding. • Limits the amount of hormone introduced to the body. Continue to Contraceptive Effects

39. Contraceptive Effects HOME Design Materials Levonorgestrel Contraceptive Effects • Levonorgestrel reduces the frequency of ovulation. • Fewer eggs are released, leading to fewer possibilities of embryo formation. http://www.health.com/health/library/mdp/0,,tp12652,00.html • Once the IUD is removed, or once the hormone concentration falls below 20 μg/day, the contraceptive effects vanish as well. Continue to more Contraceptive Effects Skip to Complications

40. Contraceptive Effects HOME Design Materials Levonorgestrel Contraceptive Effects • Levonorgestrel thins the endometrium, hindering embryo implantation and survival. Endometrium http://www.health.com/health/library/mdp/0,,tp12652,00.html • Once the IUD is removed, or once the hormone concentration falls below 20 μg/day, the contraceptive effects vanish as well. Continue to more Contraceptive Effects Skip to Complications

41. Contraceptive Effects HOME Design Materials Levonorgestrel Contraceptive Effects • Levonorgestrel increases the viscosity of the cervical mucus, reducing sperm motility. http://www.scientificamerican.com/blog/post.cfm?id=sperm-cells-swimming-secrets-reveal-2010-02-04 http://www.health.com/health/library/mdp/0,,tp12652,00.html • Once the IUD is removed, or once the hormone concentration falls below 20 μg/day, the contraceptive effects vanish as well. Continue to Complications

42. Complications HOME Design Materials Levonorgestrel Complications SHBG-bound levonorgestrel can be passed to nursing infants. Thus, nursing mothers should not use hormonal IUDs. Levonorgestrel is found in nursing infants at 7% of the concentration in their mother.3 Levonorgestrel is suspected of increasing the risk of breast cancer in patients with a history of breast cancer. 3 Breast cancer tumors are sensitive to progestin hormones. However, there is no evidence of an increased risk of breast cancer due to progestin use in patients without a history of the disease. http://www.dailyclipart.net/clipart/baby-bottle-clip-art-2/ Levonorgestrel can cause cysts (large follicles) to develop on the uterus or ovaries. 3 Cysts occur in 12% of women using levonorgestrel.3 They are usually benign and resolve themselves, but they may be painful and require surgical treatment. http://nbcam.org/ Normal ovary Ovary with cysts http://ovariancystpictures.com/ovarian-cyst-diagram-overview/ Continue to Release Profile

43. Release Profile HOME Design Materials Levonorgestrel Release Profile STOP Levonorgestrel is a released by diffusion at an approximately constant rate.Initially, it is released at about 20 μg/day. Over 5 years, release decreases to 10 μg/day, and drug loses contraceptive effects. Thus, this contraceptive drug can be used for 5 years. Levonorgestrel Released (μg/day) 20μg/day 10μg/day Time (years) 5 years Learn more about Release Profile! Next Material: PDMS

44. Release Profile HOME Design Materials Levonorgestrel Release Profile STOP • Levonorgestrel is a released from the PDMS by diffusion. • Diffusion is driven by the concentration gradient: the higher relative amount of drug inside the polymer than outside the polymer: • The drug reservoir is encapsulated by the PDMS membrane. • Because the IUD is within the uterus, the PDMS membrane is saturated with fluid and the transport of the levonorgestrel molecules across the membrane is essentially constant. http://missbakersbiologyclasswiki.wikispaces.com/Test+Study+Guide Return to Materials Menu Next Material: PDMS

45. HOME Design Materials PDMS PDMS The polymer used in hormone IUD reservoirs is polydimethylsiloxane (PDMS): Biocompatibility Mechanical Properties http://en.wikipedia.org/wiki/File:Pdms.png Return to Materials Menu

46. Biocompatibility PDMS Biocompatibility HOME Design Materials • Like polyethylene, PDMS is biologically and chemically inert. • Polymer does NOT degrade. • Polymer does not release toxins into the uterine environment. • Lasts for 5-10 years. • Capable of being sterilized. Year 1 Over time, no degradation! Year 10 Continue to Mechanical Properties

47. PDMS: Mechanical Properties HOME Design Materials PDMS Mechanical Properties PDMS has a number of qualities that make it suitable for use in IUDs: Hydrophobicity http://www.wou.edu/las/physci/ch462/BouncingPutty.htm Elasticity Porosity Skip ahead to Specifications Menu Return to Materials Menu

48. Elasticity HOME Design Materials PDMS Mechanical Properties • Elastic modulus between 38 and 48 MPa. 28 • Due to the polymer’s elasticity and flexibility, the T arms are able to fold inward during implantation and unfold afterwards. Continue to Hydrophobicity

49. Hydrophobicity HOME Design Materials PDMS Mechanical Properties • Nonpolar and has a low surface energy The nonpolar nature of the polymer discourages water molecules from adhering to the polyethylene molecule. Hydrophilic (polar) surface PDMS Hydrophobic (nonpolar) surface Continue to Porosity

50. Porosity HOME Design Materials PDMS Mechanical Properties STOP • PDMS reservoir matrix is porous Continue to Specifications • This porosity is due to crosslinked networks of PDMS molecules. • These holes allow for a • near-constant release of hormone. Example of a porous polymer matrix. http://www.sheffield.ac.uk/northcampus/research/softnano Return to Materials Menu