Engineering and women's health: a slow start, but gaining momentum

Abstract

While biomedical engineers have participated in research studies that focus on understanding aspects particular to women's health since the 1950s, the depth and breadth of the research have increased significantly in the last 15–20 years. It has been increasingly clear that engineers can lend important knowledge and analysis to address questions that are key to understanding physiology and pathophysiology related to women's health. This historical survey identifies some of the earliest contributions of engineers to exploring aspects of women's health, from the behaviour of key tissues, to issues of reproduction and breast cancer. In addition, some of the more recent work in each area is identified and areas deserving additional attention are described. The interdisciplinary nature of this area of engineering, along with the growing interest within the field of biomedical engineering, promise to bring exciting new discoveries and expand knowledge that will positively impact women's health in the near future.

1. Introduction

Gynaecology has been identified as a subarea of medicine at least as far back as 1800 BC, when it was the topic of discussion in an ancient Egyptian papyrus [1]. Empirical observation and the art of medicine by necessity dealt with diseases, conditions and maladies that were specific to women—including pregnancy and fertility. For centuries, however, this portion of medicine was the domain of midwives and medicine women—and the mysteries of women's health were often wrapped up in suspicion. While there has been significant progress in bringing women's health out of the shadows, some vestiges remain. Some of these—referring to a due date as an ‘estimated date of confinement’, for example—are generally harmless references to days gone by. Others, however—such as the continuing practice within regions of Nepal of banishing women to period huts based on the belief, known as chaupadi, that menstruation makes a woman impure—not only significantly reinforce discrimination and disadvantage women, but have also resulted in deaths of women and children [2].

Thus, it may or may not come as a surprise that women's health and the effect of gender-based differences on physiology and pathophysiology have only recently been given equal consideration within the biomedical research community. It was not until 1994 that the National Institutes of Health required that women be included in all clinical studies in order to understand the differences between men and women when it comes to disease diagnosis, progression and treatment. And while the Eunice Kennedy Shriver National Institute for Child Health and Human Development was founded in 1962, for the first 50 years its focus on women's health was primarily on reproduction as it impacted child development. In 2012, the Gynecologic Health and Disease Branch was finally established to more broadly study the science behind gynaecological disorders—although the Branch's mission still points to the effect on reproductive health, and the age groups of interest only include those between puberty and menopause [3].

Through this lens, biomedical engineers have initiated their focus on women's health at a much quicker rate than biomedical science in general. The progression of medicine to include women's health as a distinct science took almost 4000 years (1800 BC to 1962/2012). If the work by Y.C. Fung in the 1960s is considered the starting point for the application of engineering to understand basic physiology and pathophysiology (as compared to understanding injury or designing medical devices), then the inclusion of a session on reproductive biomechanics at the 2008 World Congress of Biomechanics less than 50 years later occurred at a lightning pace. And by 2016, there were four sessions with a focus on women's health and reproductive biomechanics at the same conference. In the last 50 years, engineers have expanded their focus on women's health from the development of diagnostic and treatment regimens for diseases or conditions found primarily in women (e.g. pregnancy, breast cancer and osteoporosis) to the understanding of the mechanisms of pathophysiological processes, disorders and injuries that are specific to women.

With that history as a backdrop, the following review takes a look at the early development of engineering applied to women's health in a number of key areas. It is not an exhaustive review—that would require several textbooks—but represents an attempt to find the earliest published work by engineers in each area. While significant work is now being done to advance diagnostic techniques, especially in the area of breast cancer, this review focuses on the use of biomedical engineering to understand the physiology and pathophysiology of women's health rather than the design and development of diagnostic or treatment technologies. Each history is followed by examples of some of the more recent research and a brief discussion of the gaps that may still deserve attention from the biomedical engineering community.

2. Tissue biomechanics and mechanobiology

The first indication that gender-based differences were being considered by biomedical engineers in understanding physiology or pathophysiology came in the area of tissue biomechanics. Even in the 1970s, it was well recognized that the biomechanical properties of tissues varied between individuals as well as over time within a single individual. Early researchers in this area looked to answer fairly straightforward questions regarding how properties changed as a result of normal physiological changes, but without addressing the mechanism of such changes.

2.1. Effect of gender-based physiology

Researchers such as John Currey, who had begun to characterize the properties of bone, were curious about the effect of normal physiological processes for women—including pregnancy and lactation—on the strength of whole bones [4]. The interest on this particular link stemmed from the observation that ‘during lactation, rats and women lose calcium from their skeleton’ [4]—not a broader understanding of the complex hormonal changes that can also affect tissue properties. In testing the properties of whole femora in rats, he found that pregnancy and lactation did affect some (though not all) of the properties of the long bone and deduced that this was influenced by a combination of ash content (mineralization), geometric changes and a number of unknown factors that had yet to be determined. This work by Currey laid the foundation for the study of changes in bone's structural and material properties in osteoporosis, which is known to be exacerbated by hormonal changes post-menopause. The study of osteoporotic bone changes was initiated in the 1990s [5,6] and continues today, with an increasing focus on mechanobiology to truly understand the mechanism behind changes in tissue properties as a result of changes in the greater systemic physiology.

On the opposite end of the tissue spectrum from bone, but with initial interest occurring around the same time, a single article from 1977 points to a study on the biomechanics of healing skin during pregnancy [7]. This work by a Scandinavian group investigated the stiffness of the healing tissue following an incision created at the beginning or end of the gestational period in rats, with mechanical tests conducted 10 and 20 days post-injury. They found that at 20 days post-incision, the tissue was stiffer when the healing took place during the pregnancy, with the stiffening appearing to occur in the latter half of the pregnancy. They pointed to hormonal changes as the likely cause of this change, based on parallel research conducted on hormonal levels. However, there was no direct mechanism investigated for this change in properties and, unlike for bone tissue, the research did not spark further investigation.

The vast majority of tissue biomechanics research has not included gender-based differences as a parameter. As it is now widely understood that many diseases common to both genders, such as cardiovascular disease, vary in their progression and are impacted by the differences in the hormonal environment, the comparison of the mechanobiology of the involved tissues and gender-based differences in the tissue response to loading may lend additional insight into both the pathologies and potential therapies.

2.2. Tissues of the female reproductive tract

The biomechanical properties of reproductive tissues are of paramount importance to understanding the physiology and pathophysiology of reproductive processes in women. Most of the work has focused on the properties of these tissues during pregnancy and parturition, which is discussed later on in this paper. A much smaller amount of engineering research has addressed the properties or behaviour of these tissues outside of their role in pregnancy. In 2016, de Vita's research group provided a comprehensive analysis of the state of the knowledge—or lack thereof—with respect to complete mechanical characterization of the female reproductive organs and supporting pelvic ligaments [8]. They concluded that there was a need for consistency in testing methods as well as the validation of animal models as true mimics for human tissue.

2.2.1. Cervix

In 1872 and then in 1974, obstetricians tried to evaluate the mechanical response of the cervix [9,10]. While it might be encouraging that the importance of the biomechanics of the cervix was understood even in the nineteenth century, the analysis conducted did not provide results in any form that could be used quantitatively to assess the tissue. In 1975, an engineering–clinical collaboration calculated the mechanical properties of the cervix post-hysterectomy using dilation measurements and estimating the cervix as a thick-walled cylinder [11]. All of the subjects had previous deliveries and were between 30 and 50 years of age. The calculations assumed that the tissue was elastic, isotropic, homogeneous and incompressible—though it did take into account the nonlinear behaviour expected for soft tissues. Unfortunately, the results were reported only as ‘typical examples’ rather than with statistical analysis of the measured properties, which again limited their use by other researchers. Interestingly, they saw rupture of several of the specimens at between 9 and 11 cm dilation, which corresponds to the normal physiological dilation that occurs during labour. This finding supported future investigation of how the cervix remodels during pregnancy to minimize the chance of tissue failure during delivery.

There do not appear to be further studies on the non-pregnant cervix from an engineering standpoint through 2010. Tissue engineering has been proposed as a means by which an in vitro system can be developed and validated to study cervical tissue remodelling in a more controlled fashion than can occur with in vivo studies [12], and initial studies using this system have been published. Most recently, Myer's work on modelling of the mechanical response of the cervix includes the properties of non-pregnant tissue [13]. As that work focused substantially on the changes that occur between the non-pregnant and pregnant cervix, the results are discussed in a later section of this paper.

The non-pregnant cervix deserves to be more completely understood, both as a starting point for the remodelling process that occurs during and after pregnancy and based on its general role in reproductive health, including fertility and contraception. Through a combination of tissue engineering, mechanobiology and mechanics principles, the understanding of this important structure can be greatly increased.

2.2.2. Vagina

There is no indication that the biomechanical properties of the vagina were on anyone's radar screen through most of the twentieth century. The first publication that even touched on this topic came in 1998, but the properties obtained for the vaginal tissue (in patients who had experienced vaginal prolapse) were used simply for validation of a new measurement technique and were not compared to any other tissue properties or tissue characteristics [14].

In the late 2000s and throughout the 2010s, a number of different research groups started to investigate the mechanical properties of the vagina—in particular as it pertains to pelvic organ prolapse. Using excised human tissue taken at the time of proplapse repair surgery [15,16], mouse models [17,18] and swine models for larger tissue sample analysis [19], researchers have been working to more completely characterize the tissue mechanics. Due to the interest in making non-destructive and minimally destructive tests on human tissue samples, procedures have also been developed based on rheological assessment of biopsy samples [20] and in vivo aspiration/suction tests that can be made in volunteers not undergoing surgery [21].

As vaginal reconstruction post-prolapse has been occurring with increasing frequency, there has also been some interest in how the vaginal tissue remodels when an artificial mesh is implanted. As should not be surprising to anyone familiar with tissues' response to changes in mechanical loading, a study looking at various stiffnesses of mesh found that the tissue stiffness was reduced after three months with all of the implant systems (which are stiffer than the natural tissue), and the greatest decrease occurred with the stiffest mesh [22].

As is the case in many mechanically important tissues, researchers have started to assess the mechanobiology of the cells that make up the vaginal tissue [23]. This is a very young area of research, but one that can be expected to have significant impact—along with a more complete mechanical characterization of normal and pathological tissue—on understanding pathologies such as pelvic organ prolapse as well as the development of reconstructive systems for congenital abnormalities and post-injury repair.

2.3. Maternal tissues key to fetal development

Three specific tissues that fit this category have been the subject of engineering investigation: fetal membranes (amniotic sac), the umbilical cord and the placenta.

2.3.1. Fetal membranes

It appears that the fetal membranes were the first reproductive tissue that drew significant attention from engineers. In 1953, a collaboration between obstetricians at Northwestern University and an engineer at the Office of Naval Research published results of bursting tension measurements made on human fetal membranes obtained immediately post-partum [24]. This work actually sparked some controversy, as a subsequent publication by a lone researcher, an obstetrician [25], called into question the mathematics that Danforth's team used when his own results were off by a factor of 2 and the units used were not what he expected. The dispute was addressed in an interesting way, as Danforth asked an independent engineering expert to review the methods and calculations used by his team and provide a report, which was then published within the clinical literature [26]. The conclusion of this independent assessment was that both papers were apparently correct mathematically (although the expert did not have Embrey's data to directly assess it), and that the difference in the properties may have been the result of differences in which side of the tissue (amnion or chorion) was exposed to the increasing gas pressure or to one of the other independent variables that the researchers were actually trying to identify as reasons for the natural variation in properties.

Twenty years later, in 1976, a team of clinical and engineering researchers at Case Western for the first time identified specific parameters of the fetal membranes that appeared to vary between patients who had sustained premature rupture of membranes and those who had not [27]. But it was only the thickness at the point of rupture and Young's modulus of the tissue adjacent to the placenta that were found to vary significantly between the two populations. One of the primary differences between this later study and the earlier ones was the use of more traditional tensile testing techniques rather than burst tests, which allowed for the characterization of a broader range of properties.

Through the 1990s and 2000s, a significant amount of work was conducted to better understand the mechanical properties of the fetal membranes, including of the independent layers that make up the tissue [28]. This work transitioned to focus on more advanced mechanics, including the sub-fracture behaviour [29] and fracture behaviour [30]. The mechanobiology of the fetal membranes related to membrane rupture and the onset of labour has also been a focus of research since the 1990s [31,32]. Combining increased knowledge of the mechanobiology with advances in the mechanics of this key tissue, researchers hope to identify biomarkers and imaging techniques that may allow for more accurate prediction of premature rupture of membranes and, hopefully, reduce the occurrence of preterm births. Despite the attention paid to this issue over the past decade, many questions still exist that warrant an interdisciplinary approach.

2.3.2. Umbilical cord

Studies on the biomechanics of the umbilical cord also were initiated in the 1960s and 1970s. The initial work did not have a clinical application, but was instead interested in the properties as a factor in forensic investigations [33]. However, soon afterwards, the research shifted to being of interest to clinicians as they attempted to minimize the occurrence of cord rupture during the delivery process [34].

Very little attention was paid to the mechanical properties of the umbilical cord for almost 30 years, when it finally came to the attention of an engineer and was characterized more completely [35]. He found that excessive elongation of the cord due to fetal activity, which could subsequently negatively impact blood flow and fetal circulation, was apparently prevented by the anisotropy of the umbilical cord properties. More recently, the complex biofluid and biosolid behaviour of the umbilical cord has been identified as an area of interest [36], pointing to the interaction of the various tissue constituents, the mechanoreceptors of the various cells and the blood flow through the umbilical artery and vein in both normal fetal development as well as in various maternal and fetal complications during pregnancy. Based on the importance of umbilical cord physiology to proper fetal development, applying modern techniques to fully elucidate its function appears to be an appropriate focus for research.

2.3.3. Placenta

Due to the complex fluid flow and transport phenomena that take place within the placenta, it would seem to be a prime target for engineering analysis to better understand both normal placental physiology and abnormalities that can affect fetal development. Initial work on modelling transport of oxygen [37,38] and carbon dioxide [39] focused on simple, two compartment models that did not take into account variations in maternal blood flow and relied on basic, one-dimensional concepts of diffusion.

The advent of finite-element modelling and computational fluid dynamics has more recently resulted in more complex model developments that include variations in blood flow within specified volume elements (placentones) of the structure [40]. In 2013, a review by Lewis pointed to the need for the development of models of placental transport for larger, undissolved structures such as amino acids—the active transport of which is key to overall nutrient transfer and placental function [41]. Some initial work in this complex model development has been done in the last few years by a multi-institutional, multidisciplinary group in the UK, combining molecular modelling with basic transport modelling [42]. However, there are numerous questions that still beg to be addressed to better understand the physiology and pathophysiology of the placenta.

3. Biomedical engineering and reproduction

While it may be easy to assume that the work of biomedical engineers related to reproduction would focus on medical device development for contraception or assisted reproduction, there has been a substantial amount of engineering work directed at understanding the fundamental physiology and pathophysiology of human reproduction.

3.1. Fertility

3.1.1. Embryo transport for implantation

The first engineers to address the issue of fertility from a physiological perspective were in David Elad's group in Israel. In 1999, they published the first numerical analysis of intrauterine fluid motion due to the peristaltic contractions that occur normally outside of pregnancy [43]. Their goal was to understand the forces through which an embryo may be successfully transported from the junction of the uterus and fallopian tube to an appropriate site for implantation. By representing the uterus as a two-dimensional channel whose walls oscillate either symmetrically or asymmetrically, they provided the first analysis indicating which biomechanical factors may drive appropriate (or inappropriate) implantation locations for embryos. However, they admitted that there was a lack of clinical data to validate the model. Ten years later, the model was updated to investigate the uterine fluid flow in a two-dimensional channel with one end (representing the fundus) closed [44], and it has also been used to model the movement of an embryo towards implantation following in vitro fertilization and embryo transfer [45]. However, comparison with precise in vivo measurements is still not possible. In a 2013 review, Chen and colleagues called for additional computational and experimental work to be conducted by teams of clinicians, reproductive scientists, bioengineers and computational experts to fully understand the intrauterine environment [46].

3.1.2. Ovum production

Engineering research into the earlier physiological stages that are key to fertility—namely the production of gametes—is much younger by comparison, even to many other areas of women's health. It is only within the last 5–6 years that biomedical engineers have teamed up with clinicians and biologists to develop systems that support increased understanding of the physiology of ovum production.

Successful reproduction is initiated with ovum release, which requires a well-regulated menstrual cycle. That cycle involves multiple anatomical structures as well as significant interaction with broader physiological systems, especially the endocrine system. In 2013, a perspective article called for the development of a microfluidic system to mimic the complex physiology of the female reproductive tract [47]. Within 4 years, a collaborative team had developed such an engineered tool (containing connected organ modules of the ovary, fallopian tube, uterus, cervix and liver) and demonstrated that it could replicate the hormone profile of the human 28-day menstrual cycle [48]. This study only reported on the validation of the model and pointed to its use in drug and toxicity studies moving forward. However, development of such complex microfluidic systems can also be used to answer questions regarding physiology and pathophysiology.

In parallel with the development of biomimetic models of the reproductive system, biomedical engineers have been working on tissue engineering approaches to address infertility. A review published in 2014 outlined the necessary design principles for a tissue engineered system that would support follicle maturation and allow for the generation of mature oocytes through either in vitro culture or transplantation [49]. Biomaterials and cellular engineering research has emphasized the mechanical heterogeneity required for follicle development and ovulation in engineered ovarian microtissue [50]. The futuristic view of artificial ovaries to address both fertility [51] and hormonal replacement due to menopause [52] have both recently been proposed. As one of the newest areas of reproductive science to be approached through engineering, there are many questions that are still to be answered in both basic science and translational applications.

3.2. Pregnancy

The engineering analysis of pregnancy has primarily focused on questions related to maintaining pregnancy and minimizing the occurrence of premature birth or miscarriage.

3.2.1. Uterus

Most of the engineering research on the uterus has focused on its role during normal labour and delivery, and even that is fairly limited. Much less attention has been paid to uterine biomechanics during normal gestation. In 1965, the resting tension of strips of the uterine wall was measured following hysterectomy (non-gravid and 12–16 weeks gestation) or cesarean section (29–40 weeks gestation) [53]. Wood found that resting tension increased during pregnancy and pointed to this as one of the factors that influences cervical dilation during labour.

In 1967, an analysis by biophysicists produced the first theoretical relationship between amniotic fluid pressure and myometrial tension in the pregnant uterus, based on basic fluid mechanics principles [54]. They found that the relationship was significantly dependent on uterine size, and so had to be adjusted throughout pregnancy. This was deemed to be very important if amniotic fluid pressure, which can be measured clinically, was going to be used to estimate myometrial tension mid-pregnancy. In 2010, the early work of Anderson's team to model uterine tension was expanded upon using numerical analysis of an ellipsoid model of the uterus as well as measurements of uterine geometry throughout pregnancy taken from a large sample of women [55]. This team determined that there was no statistical difference in the uterine wall tension between singleton and twin births and found a decrease in uterine tension, hypothesized to be due to an inflammatory process, in preterm singleton deliveries that occurred between 31 and 36 weeks. These data contradicted the hypothesis that increased uterine wall tension was a factor in preterm deliveries for both twin and singleton births, and identified additional questions that deserve be addressed. As discussed by Myers and Elad in a substantive review of the mechanics of the uterus [56], including during pregnancy, foundational questions still exist regarding the biomechanics and mechanobiology of the uterine myometrium that must be answered to fully understand the conditions that trigger labour, both prematurely and at term.

3.2.2. Cervix

In addition to the tremendous changes that the uterus undergoes during pregnancy, the cervix remodels substantially during the gestation period in order to prepare for the dilation necessary for a successful delivery—including changes in the extracellular matrix. Most of the studies on the cervix to date have focused on the biology, with little attention paid to the influence of the biomechanics or the mechanical environment. The first engineering studies on the cervix during pregnancy occurred in 1958, when a physicist teamed with obstetricians to measure the amount of force needed to dilate the cervix in patients that had experienced a miscarriage [57]. Unfortunately, similar to much of the early work done to characterize the non-pregnant cervix, the results that were presented were not standard mechanical properties—in this case, it was a unitless quantity that represented dilatability as the ratio of dilation divided by force. Thus, these values are not ones that can be translated to more standard engineering analysis.

Using standard engineering techniques, the mechanical properties of the pregnant cervix were first studied in sheep in a paper that was published in 1991 [58]. Much of the initial work was done in large animals—due to the importance of understanding the reproductive process for animal husbandry in agriculture, rather than as a surrogate for human tissues. This team tested the tensile modulus of excised cervical tissue at various stages of pregnancy and found that only minimal softening occurred compared to pre-pregnancy properties—up until the time immediately before delivery, when there was a rapid and significant decrease in modulus. The authors pointed to changes in collagen content or intermolecular binding as the cause for the change, assuming that the cervix was a predominantly collagenous structure. Interestingly, an article published 8 years previously by other veterinary researchers had indicated for the first time that the cervix actually demonstrated myoelectric activity that dropped significantly during the hours immediately preceding labour [59]. Even today, there are continuing questions about the role of the cervical smooth muscle in maintaining the mechanical integrity of the cervix during pregnancy [60].

In the late 2000s, attention returned to measuring cervical biomechanics in vivo—including in human patients—as an indicator of cervical insufficiency and risk of preterm labour [61]. However, such tests are unable to accomplish as rigorous an assessment of the biomechanical response as those on excised tissue due to the need for non-destructive and non-damaging methods for in vivo tests. Thus, multiple approaches are indicated as a better understanding of this tissue is developed.

In the current decade, engineering analysis of the cervix has taken two different directions—a rigorous focus on the underlying material structures that make up the cervix or a focus on the cellular response to environmental (e.g. hormonal) changes that affect the tissue remodelling. The first area has been approached both computationally and experimentally. In 2015, Myers and her team developed a fibre composite model with a continuously distributed fibre network that matched experimental behaviour in both non-pregnant and pregnant cervical tissue [62]. This change in behaviour was attributed not only to increased dispersion of the collagen fibre angles, but primarily to a two-orders-of-magnitude reduction in collagen fibre stiffness, believed to be due to a reduction in collagen cross-linking. The development of such a model can work in tandem with experimental tests on rare tissue samples to better understand the complex remodelling and mechanical response that this tissue undergoes. In 2017, Barnum related the softening of the cervix during pregnancy to directly measured changes in collagen fibre alignment [63]. Although this was in a murine model, the finding that the change in properties occurred starting at midgestation will support a greater understanding of the changes that may occur in the human cervix and can hopefully be verified through more limited testing on human samples.

From the cellular point of view, Shukla's work on the effect of various hormones and cytokines on the biomechanics of cervical fibroblasts, as well as on the interactions between the cells and the extracellular matrix, shows how such studies can add to the understanding of these complex phenomena [64]. Using traction force microscopy and various cellular assays, they demonstrated that progesterone was not protective of the reduction in cellular adhesion and tension that resulted from exposure to an inflammatory cytokine. However, progesterone did increase cellular to extracellular matrix adhesion, which led the researchers to hypothesize that it may reduce the effect of loading of the cervix by the growing fetus.

Thus, it can be expected to be a complex interaction between the dynamic cellular and structural activity within the cervix during pregnancy that supports a pregnancy continuing to term—and continued research will benefit from a multifaceted, multidisciplinary effort to advance our understanding.

3.3. Labour and delivery

The parturition process has been recognized for several centuries as being a mechanical process. The increased adoption of obstetrical forceps in the eighteenth century [65] had the specific goal of applying additional force to advance the child through the maternal pelvis and birth canal. In 1869, a physician at the Hospital for Women in London recognized the necessary activity of the abdominal muscles for successful delivery of a fetus and proposed a ‘pelvic band’ with springs and pads to mimic and add to the abdominal forces of the mother [66]. However, these developments were based on empirical observation rather than a true engineering analysis.

In 1973, an obstetrician who was also an engineer published a summary of an address in which he described parturition as a biomechanical process [67]. Most of this address focused on the position of the mother to assist with the natural biomechanics of birth; however, an engineering study was introduced at the end that used a physical model of the fetus to examine how increases in intrauterine pressure before and after rupture of the amniotic membranes influenced fetal circulation. With this, he argued against premature, artificial rupture of membranes as it resulted in reduced blood volume within the fetus (as blood was transferred to the placenta) and fetal tachycardia during contractions.

In the modern era, Ashton-Miller's group was the first to develop computational models of vaginal birth—with an emphasis on understanding how the pelvic floor muscles stretched during the second stage of labour. The first model predicted that the medial pubococcygeus muscle of the levator ani reached a stretch ratio of 3.26, with the amount of stretch in each of the muscles proportional to the size of the fetal head [68]. A review article that discussed the state of the literature with regard to modelling the mechanisms of labour [69] called for improvement in the modelling of the boundary conditions, including a deformable fetal skull and more biofidelic properties for the pelvic tissues. Six years later, a similar review [70] found that while advances had been made, particularly with respect to including nonlinear properties of tissues and fetal head moulding, there are still significant questions to be answered based on naturally constrained fetal movement through the pelvis and the assessment of population-based variations in anatomy. Combining traditional mechanical modelling with mechanobiology regarding the cellular and tissue response of the reproductive tissues will be an important next step in this understanding.

In addition to the engineering work discussed above, there has been research into the biomechanical effects of labour and delivery on the neonate—in particular, skull moulding, brain injury and brachial plexus injury. As that work falls more within the scope of pediatric injury biomechanics than women's health, it will not be included in this review.

4. Breast physiology and pathophysiology

As the breast is not generally thought of as a tissue or structure that is loaded mechanically, it may not be an obvious candidate for biomechanical or mechanobiological investigation. However, both the physiological process of lactation and the pathophysiology of breast cancer have been the focus of study by engineers.

4.1. Breast feeding

Research from the late 1800s through the 1950s, including imaging studies with barium labelled milk, had not answered the question of whether sucking (e.g. inducing subatmospheric pressures) or mouthing (deforming the nipple) caused the milk to advance from the breast to the infant's mouth [71]. Due to instrumentation limitations, this research generally used an artificial reservoir for the milk, either an instrumented bottle or a more complicated system to provide constant supply [72]. In 1971, Kron (a psychiatrist) teamed up with Litt (a chemical engineer) to do an engineering analysis of the system that he had introduced into research 8 years earlier. This analysis allowed for the linking of the energy expenditure of the infant to the nutrient benefit of feeding and demonstrated that newborns became more efficient and optimized the suction-based feeding process over the first few days of life [71].

The next time that an engineering approach to this question is presented in the literature is 1997, when a computer model of both sucking and peristaltic motion caused by the infant's mouth was compared to the pure sucking force of a breast pump [73]. By modelling the nipple as a poroelastic structure, it was demonstrated that there was an optimum combination of the suction and peristaltic motion to increase milk flow. While this model was the first to include the maternal tissue, it only cracked the surface of the maternal aspect of this physiological process. The most recent work by an international team distributed between Texas and Australia has expanded the computational fluid dynamics research to the milk transfer from the alveolar sacs through to the mammary ducts and the nipple [74]. The focus of most of this research has been on the prediction of infant milk intake or to support the improvement of breast pump design. The mechanobiology of milk production appears to be an area that has yet to be researched and may provide the next link in the understanding of the biomechanical processes associated with breastfeeding.

4.2. Breast cancer

The application of engineering to understand the progression of breast cancer is one of the newest areas of women's health that has seen the benefit of an engineering approach. The biology and biochemistry of breast cancer cells have been the topic of study for decades, especially the response of the cells to the hormonal environment. Research to understand the effect of the mechanical environment and the mechanical response of breast cancer cells is much more recent. The first paper to systematically quantify the adhesion force in breast cancer cells appears to have been published in 2008 [75]. Palmer's study demonstrated that metastatic potential of breast cancer cells was inversely related to their adhesion force. In 2010, it was identified that the mechanical properties of the extracellular matrix interacted with the transformative potential of breast cancer cells to determine the intracellular mechanical state, as measured rheologically [76]. Since these early studies, significant work has been conducted to investigate the molecular mechanisms that drive the mechanical environment's control of proliferation and migration for breast tumour cells. And using microfluidics (e.g. [77]), organoids (e.g. [78]) and more traditional tissue engineering (e.g. [79]), biomedical engineers have joined cancer biologists and clinicians to develop systems that will allow improved, controlled studies to better understand breast cancer—which will hopefully support the development of improved therapies in the future.

5. Conclusion

As is illustrated by the articles of this issue, the advances in engineering to understand women's health have been substantial. From those initial steps to explore the basic biomechanical performance of the fetal membranes in the 1950s to the most recent work combining mechanobiology and classic mechanics to understand the complex processes affecting the onset of preterm labour at a multiscale level, the engineers who have joined and now lead research teams have contributed critical knowledge and analytical techniques to significantly expand scientific knowledge.

Approaching questions regarding women's health from an engineering perspective is important not only to fully understand the physiology and pathophysiology, but also to develop design criteria for any engineered model or tissue replacement systems. Without the analysis that an engineer can bring to the process, many attempts at developing mimicking or replacement systems have been done through trial and error rather than systematic optimization.

All of the advances in engineering related to women's health build on the previous clinical and basic science work conducted by our colleagues. In fact, the greatest advancements have generally involved teams of engineers working with scientists and/or clinicians to identify the key questions as well as to ensure that developed models—whether they are computational or in vitro—best mimic the natural physiological environment.

The expansion in the number of biomedical engineering research groups who are exploring topics key to women's health is encouraging, as is the work that is starting to occur through collaborations between institutions. Reproductive biomechanics and tissue engineering or mechanobiology studies related to breast cancer are no longer odd balls at conferences or within funding agencies. As has been the case with more traditional systems studied by biomedical engineers—such as the musculoskeletal and cardiovascular systems—the broadening of interest into these areas will be a great opportunity to drive the science forward—with the eventual goal of improving women's health.

Data accessibility

This article has no additional data.

Competing interests

I declare I have no competing interests.

Funding

I received no funding for this study.