Download PDF Engineering for Women's Health April 25, 2022 Volume 52 Issue 1 The articles in this issue describe the latest technologies for detection of breast and other cancers, approaches to reduce the incidence of premature births, and remote monitoring for pregnancy, a development of particular interest as the pandemic discouraged many people from going to a doctor’s office or hospital. Investigating Reproductive Biomechanics Using Physical Models Tuesday, March 29, 2022 Author: Alexa Baumer, Alexis Gimovsky, Michael Gallagher, and Megan C. Leftwich Engineering models can enhance understanding of reproductive biomechanics and improve the care provided to pregnant women. Most research into pregnancy and childbirth has historically been done through a clinical framework, relying on large-scale statistical studies. This process makes developments in standard practices and new technologies slow to implement. To find better solutions to current challenges, an engineering framework grounded in understanding fundamental biomechanics can serve as a complementary approach. The reproductive biomechanics field is broad, involving every aspect from implantation through delivery. The focus of the work in our laboratory is mid- to late-stage pregnancy and birth. It is difficult and invasive to research reproductive mechanics in vivo with usual methods. Therefore, we approach the biomechanics questions with an engineering modeling perspective to add to the base of knowledge and, hopefully, the scientific foundation for women’s health. Introduction The cervix, at the base of the uterus, is a region of dense connective tissue between the uterus and vagina (figure 1). It has a generally cylindrical shape, with a diameter around 2.5 cm and a length between 2 and 4 cm. At each end of the cervix is an opening, referred to as the internal and external orifice (or os). Between these two openings is the endocervical canal, a narrow passageway between the uterus and vagina. FIGURE 1 Schematic of the human female reproductive system. The cervix is dynamic—its mechanical properties change throughout pregnancy. In the initial part of pregnancy, the cervix remains long and closed while the fetus develops. Toward the end of pregnancy, the cervix shortens and dilates to allow for a successful delivery. In addition, the cervical tissue softens throughout this remodeling process. The exact timing and rate at which the cervical tissue softens has been difficult to quantify. However, it is generally thought that if the tissue softens too quickly, it can lead to preterm birth. Preterm Births Complications can arise at any point during a pregnancy and may result in preterm birth (before 37 weeks gestation). Worldwide, it is estimated that 9 to 12 percent of births are classified as preterm (Beck et al. 2010; Blencowe et al. 2013). Preterm deliveries can result in neonatal complications as well as prolonged hospital stays (Ward and Beacy 2003). To minimize the rate of incidence, understanding the causes of preterm birth is vital. In cases of preterm birth due to premature cervical remodeling, the cervix is unable to retain the pregnancy, absent the signs and symptoms of clinical contractions, or labor, or both during the second trimester (ACOG 2014). The diagnosis is typically made between 18 and 22 weeks gestation through a combination of transvaginal ultrasound, clinical examination, and patient history (Ciavattini et al. 2016). Lack of treatment often leads to a miscarriage, but there is no cure for the condition. In managing it, the priority is to prolong the pregnancy as much as possible. A typical treatment plan is to give a progesterone supplement and to perform a cervical cerclage, a treatment protocol that yields varying results. Cervical cerclage involves stitching the cervix closed with a strong suture. When it succeeds, the pregnancy is prolonged and the risk of miscarriage is lessened. Results vary on the success rate of the procedure; a 47 percent success rate has been reported for emergency cerclage (Gupta et al 2010), but the efficacy of the procedure is the subject of ongoing debate (Namouz et al. 2013; Naqvi and Barth 2016). Determining why the procedure works in some patients and not in others is critically important to clinical decision making and improved overall care. This makes cerclage a great example of a standard practice that could benefit from examination with a mechanics framework. Because typical mechanics tools cannot be used to study the real, physiological system, we created a synthetic model of the cervix and a platform to investigate various aspects of cerclage and its mechanical performance. With this engineering approach, we gain information that cannot be achieved through patient studies. In this article we describe the methodology and discuss how this technique can be applied to enhance understanding of women’s health. Engineering Methods The two primary considerations when creating a synthetic analog of the cervix are material and geometry. We had to mimic the material properties of a pregnant cervix, but it is difficult to successfully quantify the properties of most soft tissues. Tissue Properties and Material Selection There are limited methods to measure properties such as stiffness under physiological loading. Excising tissues and testing them is an approach to generate information, but it is limited because of mechanical behavior changes in tissues once they are outside the body. The cervix is no exception to this multifaceted challenge. To further complicate things, the nonpregnant cervix is significantly different from the pregnant cervix and, because of the cervix’s dynamic nature, measurements taken throughout pregnancy will yield distinct values. So researchers have to be thoughtful and innovative with their methods. Studies to quantify cervical tissue have used animal models, taken samples from hysterectomies for testing, and made measurements in vivo. Investigations of remodeling in mice cervices have revealed that collagen fiber stiffness and ground substance elastic modulus decrease throughout gestation (Yoshida et al. 2016). Human cervical tissue samples (obtained during hysterectomies) from nonpregnant patients are significantly stiffer than those from pregnant patients (Myers et al. 2008). Another approach to quantifying the stiffness of the cervical tissue has been done in vivo by aspirating the ectocervix and measuring the closure pressure (Badir et al. 2013). In this work, measurements of cervical tissue were done before, during the pregnancy, and postpartum. The results revealed an initial period of cervical softening (approximately a 50 percent decrease from the first to second trimester) earlier in pregnancy than previously thought, followed by a stabilization and gradual decrease in softening between the second and third trimesters. All these methods have expanded knowledge of this complex tissue and provided valuable insight into ways to create a synthetic tissue to mimic the softening cervix. Cervical softness throughout pregnancy is typically determined by physical exam. This qualitative assessment involves the physician palpating the patient’s cervix and assigning it a value of “soft, medium, or hard.” Because there are minimal data on the material properties that correspond to those terms, we decided to apply this physician method in creating our synthetic tissue. FIGURE 2 The process for choosing silicone mixtures used as cervical tissue analogs. First, we created a large array of samples (left) for physicians to feel. They determined which sample best represented the three clinical descriptors of cervical tissue: soft (designated in lavender), medium (green), and hard (yellow). The other colors denote different degrees of elasticity. We created ten different samples of silicone to find three matching the physicians’ assessment (figure 2). Silicone is a widespread choice for mimicking properties of biological tissue; it is highly versatile and cost effective, it can produce a range of elastic moduli, and it preserves well in laboratory settings. Once we had our ten specimens of silicone fabricated, our three physician collaborators felt each sample and determined, to the best of their ability, which sample most effectively represented each clinical group. Based on their assessments, we determined material properties for the synthetic tissues (figure 2, center and right panels). Geometry and Physical Models To determine cervical shape and design, we acquired transvaginal ultrasound images from routine 20-week pregnancy scans at the George Washington University Hospital. These image sets were used to extract relevant geometry, such as cervical length, tissue thickness, and whether the cervix exhibited any funneling or dilation. FIGURE 3 Fabrication process for our synthetic cervix model. First panel on the left: 3D-printed components fully assembled. Second panel: Interior piece, representing the cervical canal, attached to the base plate. These models are highly configurable, with many options for the cervical length and canal shape. Third panel: Silicone cervix before cerclage. Fourth panel: Cerclage placed in the synthetic cervix (using 5 mm Mersilene tape), ready for the experiment. Patient-specific features of each cervix were generalized into a cylinder (figure 3), at the top of which the model fans out to represent the lower portion of the uterus. For experiments, the model was 3D printed in three components: the base plate, and the exterior and interior of the model. The interior represents the cervical canal. The synthetic cervices were cast with the silicone mixtures mimicking the cervical tissue as determined by the physicians. Cerclage Testing The synthetic cervices created in our lab were stitched using materials and methods similar to those in the clinic (with a McDonald cerclage using 5 mm Mersilene tape on a tapered needle). The suture was placed at the highest point possible along the cervix, close to the section of the model that fans out. The needle moved in and out of the cervix circumferentially beginning and ending at the 12 o’clock position. The two ends of the tape were pulled tight and knotted 7 or 8 times. FIGURE 4 Two examples of data obtained in our cerclage experiments. Left: Individual experimental runs with a soft, medium, and hard cervix. The force on the cerclage is plotted as a function of extension into the material and the rupture point is indicated with a black dot. Right: The average rupture force for each cervical stiffness plotted against the elastic moduli (measured in megapascals). In the material testing facility, an aluminum insert with a conical head was designed to fit on an MTS machine and apply force to the cerclage (the cervices were constrained in a 3D-printed capsule to minimize motion). The failure criterion was determined to be when the suture began to rip through the synthetic tissue, resulting in a drop in recorded force values from the load cell. Data are illustrated in figure 4. Selection of Parameters The parameter space of this problem is wide, with the geometry considerations and changing material properties. In the initial experiments, we focused solely on cervical softness (Baumer et al. 2019). We found that stiffer tissues were able to maintain the cerclage at higher forces before rupturing. In experiments since then we have tested different cervical lengths (patients experiencing premature cervical remodeling often have a shorter cervix length), cervical canal shapes (figure 5), and cerclage suture materials. FIGURE 5 Modifications to the model cervix. (A) Three cervical lengths: 15 mm, 25 mm, and 35 mm. (B) Schematics of three cervical canal shapes: Y, V, and open. In focusing on the parameters separately, we can investigate the importance of each independent of the others. But there are still more parameters to examine. For example, there are other types of cerclage technique (e.g., the Shirodkar), which could be compared in further experiments. And parameters can be combined for a deeper understanding of the cervical physiology. While our model cervix has been used primarily to test cerclage, it could also be used in testing protocols for future experiments with emerging technology. Another application with the simple, low-cost model could be as a training tool for medical students and residents. As the knowledge base surrounding the cervix grows, new devices and methods will be developed to treat premature cervical remodeling. Lessons Learned and Limitations The protocol described here to develop synthetic cervical tissue is a viable first step toward providing material information useful in other physical and computational models. For our study, we recognize that creating synthetic tissues with limited physiological data and a reliance on physician training has limitations. The qualitative, “by feel” assessment can yield different results among doctors (Badir et al. 2020), and this may affect clinical decisions. We attempted to mitigate discrepancies by using multiple physicians. The synthetic cervix developed for our experimental testing nonetheless has several limitations. The first, and possibly most important, is that in simplifying a complex, heterogeneous tissue to a homogeneous silicone, we fail to capture certain material behavior under physiological loading. Another limitation is the boundary conditions placed on the model. In the body, the cervix is surrounded by ligaments and tissues that transfer internal forces. By eliminating these elements and instead using solid walls, the stress distribution in the model is not analogous to the physiological reality. Finally, soft tissues, such as the cervix, display nonlinear responses, becoming more compliant through subsequent loading cycles (Myers et al. 2015). In the synthetic cervix model, the loading on the cerclage was a single cycle with a direct force increasing in magnitude within a relatively short amount of time. Future models can be modified to capture these mechanics more fully. Conclusion The method described above provides a framework to study reproductive biomechanics. While, like all models, it requires some simplification of a very complex problem, it can be used when in situ experiments are not possible. We have presented one example where a model of a cervix was designed and built to study a specific condition, the relationship between cervical softening and potential cerclage success. We also discuss modifications—lengthening the mold, changing the geometry of the cervical canal and suture material—to increase the usefulness of this model. This type of engineering model can, and should, be used to gain fundamental insight into other aspects of reproductive biomechanics. Similar models can be constructed to explore labor and delivery: the role of maternal pelvic shape, fetal presentation, or geometry. Such models are inexpensive to produce and easily modifiable. They can be an extremely useful complement to animal models, computational work, and clinical studies to enhance understanding of reproductive biomechanics and improve the care provided to pregnant women. References ACOG [American College of Obstetricians and Gynecologists]. 2014. Practice Bulletin No. 142: Cerclage for the management of cervical insufficiency. Obstetrics and Gynecology 123:372–79. Badir S, Mazza E, Zimmerman R, Bajka M. 2013. Cervical softening occurs early in pregnancy: Characterization of cervical stiffness in 100 healthy women using the aspiration technique. Prenatal Diagnosis 33(8):737–41. Badir S, Bernardi L, Delgado FF, Loetscher KQ, Hebisch G, Hoesli I. 2020. Aspiration technique-based device is more reliable in cervical stiffness assessment than digital palpation. BMC Pregnancy and Childbirth 20(1):1–9. Baumer A, Gimovsky AC, Gallagher M, Leftwich MC. 2019. A synthetic cervix model and the impact of softness on cerclage integrity. Interface Focus 9:20190009. Beck S, Wojdyla D, Say L, Betran AP, Merialdi M, Requejo JH, Rubens C, Menon R, Van Look PFA. 2010. The worldwide incidence of preterm birth: A systematic review of maternal mortality and morbidity. Bulletin of the World Health Organization 88:31–38. Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller A, Narwal R, Adler A, Garcia CV, Rohde S, Say L, Lawn JE. 2012. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: A systematic analysis and implications. The Lancet 379(9832):2162–72. Ciavattini A, Carpini GD, Boscarato V, Febi T, Giuseppe JD, Landi B. 2016. Effectiveness of emergency cerclage in cervical insufficiency. Journal of Maternal-Fetal Neonatal Medicine 29(13):2088–92. Gupta M, Emary K, Impey L. 2010. Emergency cervical cerclage: Predictors of success. Journal of Maternal-Fetal and Neonatal Medicine 23(7):670–74. Myers KM, Paskaleva AP, House M, Socrate S. 2008. Mechanical and biochemical properties of human cervical tissue. Acta Biomaterialia 4(1):104–16. Myers KM, Feltovich H, Mazza E, Vink J, Bajka M, Wapner R, Hall T, House M. 2015. The mechanical role of the cervix in pregnancy. Journal of Biomechanics 48(9):1511–23. Namouz S, Porat S, Okun N, Windrim R, Farine D. 2013. Emergency cerclage: Literature review. Obstetrical & Gynecological Survey 68(5):379–88. Naqvi M, Barth WH. 2016. Emergency cerclage: Outcomes, patient selection, and operative considerations. Clinical Obstetrics and Gynecology 59(2):286–94. Ward RM, Beacy JC. 2003. Neonatal complications following preterm birth. BJOG 110:8–16. About the Author:Alexa Baumer is a research assistant in the School of Engineering and Applied Science at George Washington University (GW). Alexis Gimovsky is a maternal-fetal medicine specialist at Women and Infants Hospital in Providence. Michael Gallagher is a clinical associate professor at the GW School of Medicine and Health Sciences, and Megan Leftwich is an associate professor in the GW Department of Mechanical and Aerospace Engineering.