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Research Papers

Tensile Mechanical Properties and Dynamic Collagen Fiber Re-Alignment of the Murine Cervix Are Dramatically Altered Throughout Pregnancy OPEN ACCESS

[+] Author and Article Information
Carrie E. Barnum, Jennifer L. Fey, Stephanie N. Weiss, Snehal S. Shetye

McKay Orthopedic Research Laboratory,
University of Pennsylvania,
Philadelphia, PA 19104

Guillermo Barila, Amy G. Brown, Michal A. Elovitz

Maternal and Child Health Research Program,
Department of Obstetrics and Gynecology,
Perelman School of Medicine,
University of Pennsylvania,
Philadelphia, PA 19104

Brianne K. Connizzo

McKay Orthopedic Research Laboratory,
University of Pennsylvania,
Philadelphia, PA 19104;
Department of Biological Engineering,
Massachusetts Institute of Technology,
Cambridge, MA 02139

Louis J. Soslowsky

McKay Orthopedic Research Laboratory,
University of Pennsylvania,
Philadelphia, PA 19104
e-mail: soslowsk@upenn.edu

1Corresponding author.

Manuscript received July 27, 2016; final manuscript received April 6, 2017; published online April 27, 2017. Assoc. Editor: Steven D. Abramowitch.

J Biomech Eng 139(6), 061008 (Apr 27, 2017) (7 pages) Paper No: BIO-16-1319; doi: 10.1115/1.4036473 History: Received July 27, 2016; Revised April 06, 2017

The cervix is a unique organ able to dramatically change its shape and function by serving as a physical barrier for the growing fetus and then undergoing dramatic dilation allowing for delivery of a term infant. As a result, the cervix endures changing mechanical forces from the growing fetus. There is an emerging concept that the cervix may change or remodel “early” in many cases of spontaneous preterm birth (sPTB). However, the mechanical role of the cervix in both normal and preterm birth remains unclear. Therefore, the primary objective of this study was to determine the mechanical and structural responses of murine cervical tissue throughout a normal gestational time course. In this study, both tissue structural and material properties were determined via a quasi-static tensile load-to-failure test, while simultaneously obtaining dynamic collagen fiber re-alignment via cross-polarization imaging. This study demonstrated that the majority of the mechanical properties evaluated decreased at midgestation and not just at term, while collagen fiber re-alignment occurred earlier in the loading curve for cervices at term. This suggests that although structural changes in the cervix occur throughout gestation, the differences in material properties function in combination with collagen fiber re-alignment as mechanical precursors to regulate term gestation. This work lays a foundation for investigating cervical biomechanics and the role of the cervix in preterm birth.

FIGURES IN THIS ARTICLE
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Preterm birth (PTB) is one of the primary causes of infant morbidity and mortality in the U.S. affecting 11.2% of live births [1] and costing $26 billion per year. Moreover, preterm children have an inherently higher risk for future medical complications [2]. Many factors have been used to identify women with a higher risk for PTB including: multiple pregnancies, race, a prepregnancy body mass index less than 18, prior preterm birth, and drug use. However, these risk factors fail to identify the majority of the women who present with a spontaneous PTB [35]. The inability to accurately predict which women will have a spontaneous preterm birth (sPTB) lies in our lack of understanding of the precise pathogenesis by which this adverse event occurs.

Recent studies suggest that the cervix plays a critical role in both normal parturition and spontaneous PTB [68]. During pregnancy, the primary role of the cervix is to maintain the load of the growing fetus within the uterus. At parturition, the cervix radically switches its function, allowing delivery of the fetus via dilation [9,10]. Failure of the cervix to maintain its structure previously labeled as “cervical incompetence or insufficiency” is proposed to be the loss of mechanical integrity of the cervix and has been cited as one of the causes of PTB [1113]. Few studies have examined the changes of the human cervix during pregnancy, partially due to limitations in obtaining adequate samples [1417]. Previous research has examined gene expression pathways before and after spontaneous parturition and showed drastic changes in chemokines, cell adhesion, and extracellular matrix (ECM) proteins, as well as in other signaling pathways [15,16]. While another study demonstrated that a distinct micro ribonucleic acid (microRNA) profile in cervical cells was associated with eventual sPTB, suggesting a molecular change in the cervix during the second trimester of the pregnancy prior to any clinical signs or symptoms of PTB [8,17]. Despite these efforts, understanding of how the cervix drastically changes during normal gestation and how this is modified in sPTB during human pregnancy remains limited [18]. The current deficit of knowledge makes the use of animal models necessary [19].

Mouse studies have shown that multiple mechanisms contribute to the drastic physical changes the cervix undergoes during pregnancy [11,12,20]. The two most prominent theories postulate that cervical changes during gestation are triggered either by progesterone withdrawal or by an inflammatory response [2124]. Despite this previous research, the mechanisms of cervical change or remodeling during normal gestation and PTB do not adequately explain the complex structural response of the cervix during pregnancy [22]. Additional understanding of these mechanical adaptations, as well as how the cervical ECM affects these mechanical properties during gestation is warranted [16,25,26].

As a load bearing tissue [11], cervical strength and function are directly related to ECM, and one of its major components is collagen [9,20]. Fibrillar collagen is the main structural protein known to affect tensile properties of the cervix [27]. Changes in collagen have been shown to affect the normal function of many different organ systems [2831]. However, the role of collagen fibers within the cervix has only recently been investigated [3235]. In order to further understand the role of the cervix, it is imperative to study not only the molecular changes occurring during gestation and PTB, but also the biomechanical changes, and how components such as collagen fibers may alter the cervical function.

Multiple research groups have investigated the mechanical response of the cervix [22,27,36,37]. A classic study evaluated the tensile mechanical response of rat cervical tissue via a ring test, an approach which resolves the typical difficulties associated with the gripping biological tissue in a mechanical testing frame [38]. This testing methodology has been recently employed to investigate the mechanical properties of murine cervices [32,39]. However, a ring test makes calculating the true cross-sectional area (CSA) of the test sample difficult, and therefore, reporting material properties is not possible. Despite this, the previous work has showed important correlations between collagen crosslinks and both stiffness and ultimate strength [32]. Moreover, although most previous experimental studies have only reported structural properties such as load and stiffness, a recent study estimated material properties such as modulus through a mathematical model [39].

Investigating the intrinsic material properties of the cervix directly provides valuable information regarding cervical tissue adaptations during pregnancy. Given the significant role of collagen in the cervix to mechanical properties, characterization of the dynamic fiber re-alignment during cervical loading could provide crucial insights. The purpose of this study was to measure the biomechanical and dynamic collagen fiber re-alignment of the cervix throughout normal pregnancy as well as postpartum (PP) using a mouse model. Since a growing fetus causes increased loading and deformation of the cervix, we hypothesized that a pregnant cervix will have decreased stiffness, modulus, maximum load, and maximum stress as well as less collagen re-alignment.

Fine Dissection.

Nonpregnant (NP) and pregnant CD-1 mice at embryonic day (E) E10.5, E12.5, E14.5, E16.5, E18.5, and postpartum PP (PP, where samples were collected 24 h after delivery) (n = 10–16/group) were sacrificed and frozen until they were prepared for mechanical testing. The previous research has shown no effects of freezing on mechanical properties of the cervix [32,37,39]. At the time of testing, the reproductive tissue was carefully harvested (Fig. 1(a)), removing all musculature and surrounding soft tissue, and hydrated in phosphate-buffered saline (PBS) (Figs. 1(b) and 1(c)). During dissection, the vagina and cervix were cut open on the side opposite the bladder, and the bladder was removed. The cervix was dissected free of any extra soft tissue, and the uterus and vagina were carefully removed (Fig. 1(b′) and 1(c′)).

Mechanical Testing.

The cervix was laid flat to expose the lumen. The ends were affixed between two pieces of sandpaper for gripping, such that a uniaxial tensile load on the grips would simulate dilation of the cervical canal (loading occurred perpendicular to the proximal–distal direction). The prepared sample was continually immersed in PBS till the start of mechanical testing. A custom laser device was used to measure the cross-sectional area at a minimum of two locations, which took less than 60 s [40]. The approximate variability of tissue cross section was within 20% of the average area. The cervix was then placed in custom fixtures to grip it at both ends. The cervix was then tested in tension using an Instron 5848 testing system (Instron Corp., Norwood, MA) using a standard protocol consisting of a preload of 0.005 N followed by a hold of 5 min and then a ramp to failure at 1 mm/min. Representative force-elongation plots from mechanical testing for each gestational time point are shown in Fig. 2(d). The entire test was performed in a saline bath at room temperature. The location of failure was recorded for each sample. Samples were excluded from further analysis if failure did not occur within the midsubstance of the tissue.

Collagen Re-Alignment.

Collagen fiber alignment maps of the cervix were collected throughout the mechanical testing protocol using our established integrated cross-polarizer system, as described in Refs. [4143]. This custom system consists of a linear backlight (Dolan-Jenner, Boxborough, MA), rotating polarized sheets offset by 90 deg (Edmund Optics, Barrington, NJ), and a camera (Fig. 2(a)). Custom software (National Instruments LabVIEW, Austin, TX) synchronized with analog output signals from the Instron triggered alignment maps to image capture at 5 s intervals (for NP, E10.5, and E12.5) and at 7.5 s intervals (for E14.5, E16.5, and E18.5). Collagen alignment was measured at four points during the mechanical test: (1) start of the toe region, defined by the first map after the hold protocol, (2) at the end of the toe region, determined by the last map before the change of slope to the linear region, (3) at 45% of the maximum load, and (4) at 90% of the maximum load (Fig. 2(c)). Re-alignment was defined as a significant change in circular variance between two time points. Unfortunately, collagen fiber alignment was not analyzed reliably for PP samples, because they were substantially thicker than other samples, and the methodology relies on light passing through the sample.

Statistics.

One-way analysis of variance were used to compare between groups for mechanical parameters with Bonferroni-corrected post hoc tests when appropriate. Mann–Whitney U tests were used to evaluate differences in fiber re-alignment at each time point. The significance was set at p < 0.05 for all statistical comparisons, while p < 0.1 was defined as a trend.

Nonpregnant samples were significantly larger compared to other early gestational time points including E12.5 and E14.5. However, later gestational time points (E16.5 and E18.5) showed no significant differences in size when compared to NP samples (Fig. 3(a)). During gestation, cross-sectional area was initially reduced; E10.5 pregnant cervices were significantly smaller than both NP samples as well as later gestational time points (E14.5, E16.5, and E18.5). Interestingly, E12.5 cervices were significantly smaller only when compared to those later gestational time points (E16.5 and E18.5). There were no other differences in area found when comparing between the last three gestational ages (E14.5, E16.5, and E18.5). However, PP samples were significantly larger than all of the gestational time points tested as well as NP samples (Fig. 3(a)).

Tissue stiffness was decreased in all gestational samples (E12.5, E14.5, E16.5, and E18.5) compared to NP samples, with the exception of E10.5 samples. The E10.5 samples were also significantly stiffer compared to all other gestational ages (E12.5, E14.5, E16.5, and E18.5) and were no different when compared to NP samples (Fig. 4(a)). Interestingly, PP samples were also significantly stiffer than all other gestational ages except for E10.5.

Maximum load was significantly reduced in all gestational groups compared to NP samples (E10.5, E12.5, E14.5, E16.5, and E18.5). This was also observed in PP samples, which showed a significantly higher maximum load when compared to all the gestational samples, but was not significantly different when compared to NP samples (Fig. 4(b)). There were no differences found in maximum load between any of the gestational samples tested.

NP and E10.5 samples demonstrated significantly higher maximum stress when compared to all other gestational time points (E12.5, E14.5, E16.5, and E18.5) but were not statistically different from each other. However, E10.5 samples showed a significantly higher max stress when compared to PP samples that was not observed in NP samples. PP samples only showed a significantly higher max stress when compared to E18.5 samples (Fig. 4(c)). All other gestational time points did not show significant differences in maximum stress.

NP samples only showed a significantly higher modulus when compared to E18.5 samples. However, E10.5 samples showed a significantly higher modulus when compared to additional later time points (E14.5, E16.5, and E18.5). No significant differences were observed in tissue modulus between NP, E10.5, E12.5, and PP samples. Modulus of the other gestational time points after E10.5 were not significantly different when comparing between each other (E12.5, E14.5, E16.5, and E18.5) and were also not significantly different when compared to PP samples (Fig. 4(d)).

Re-alignment of collagen fibers was observed for all samples between the “toe” and “90% maximum load” time points, except for E12.5 samples (Fig. 5). In both early gestation (E10.5) and later gestation (E16.5), samples experienced a faster response to load, with re-alignment occurring earlier during mechanical testing (Toe-45% and ET-90%; Figs. 5(b) and 5(e)). However, E18.5 samples showed an immediate response to load with collagen fiber re-alignment during all time points examined (Toe-45, Toe-90, ET-45, ET-90, 45–90; Fig. 5(f)).

The primary objective of this study was to determine the biomechanical and dynamic collagen fiber structural response of cervical tissue throughout a normal gestational time course. To this end, tissue structural and material properties were determined via a quasi-static tensile load-to-failure test and dynamic collagen fiber re-alignment data were collected simultaneously. Overall, as hypothesized, a pregnant cervix demonstrated significantly reduced structural and material properties as compared to nonpregnant samples. Surprisingly, the majority of the mechanical properties of the cervix decreased at midgestation, while collagen fiber re-alignment occurred earlier in the loading curve for cervices at term. The previous research has proposed that the cervix gradually reaches its lowest tensile strength at term, and that this change is a necessary precursor for term delivery [24,44]; however, these data suggest that reduction in tensile strength alone might not be enough to ensure parturition. This work suggests that the cervix becomes “ready” to deliver, not exclusively because it is weaker, but also because it responds to load structurally via collagen fiber re-alignment.

Cervical cross-sectional area (CSA) data showed substantial structural rearrangement of the cervix with a significant reduction in area over the typical murine gestational time course. Interestingly, no differences in CSA were observed between the NP and E18.5 samples. However, a qualitative examination revealed an altered width to thickness ratio between the NP and E18.5 samples (Figs. 3(b) and 3(c)). Previous studies have shown that cervical tissue becomes significantly more hydrated as pregnancy progresses [21,22], which could partially contribute to the differences in CSA observed. However, hydration of PP samples was shown to decrease in 24 h [24,45,46], which does not explain the increase in CSA of PP samples found in the current study. Changes to the cervical ECM due to other compositional elements such as collagen, glycosaminoglycans (GAGs), and proteoglycans could partially explain the profound alterations in CSA observed. It has been suggested that differences in GAGs chain composition, length, and sulfation influences ECM and tissue structure via collagen packing; however, these factors have not yet been sufficiently studied, and further investigations are warranted [22,24,35,45,47].

Previous studies have typically employed an image-based protocol for measuring the cross-sectional area, which is highly sensitive to the location and orientation of the camera [23,24,32,35,37,39]. Further, the small size of the mouse cervix makes measuring the wall thickness difficult via this method [21,23,32,35,37,39]. The laser-based system employed in the current study [40] allowed for highly precise measurements of tissue thickness and width at multiple locations, providing a detailed examination of gross morphological changes. The drastic differences observed in CSA in this study highlight the interesting structural changes the cervical tissue undergoes during pregnancy. The dependence of structural properties such as maximum load and stiffness on CSA necessitates further research that investigates mechanisms that may cause these dramatic changes in cervical CSA.

A significant reduction in tissue stiffness was observed after the E10.5 time point. Similar observations have been made in previous studies where a significant drop of cervical tissue stiffness was observed after embryonic day 11 [22]. Interestingly, some of the values reported in this previous study were an order of magnitude lower than the current study [22], which could potentially be due to differences in mechanical testing protocols. Stiffness calculations can vary significantly based on the region selected in the force–displacement curve. Since the previous study reported much lower stiffness values, they might have been obtained from the toe region of the cervix tensile response curve. The maximum stress values in our study compare very well to the maximum stress values reported in another recently published study examining mechanical properties of the normal cervix during pregnancy [32]. In our study, the stiffness of PP samples was comparable to those of NP samples indicating a rapid return to baseline within 24 h after delivery. This outcome was not observed in a previous study, where significant differences in tissue stiffness were observed between PP and NP samples [32].

Our study indicated that the pregnant cervical tissue fails at a significantly lower maximum load when compared to NP or PP samples. This was partially expected, given the observed reductions in cervix CSA when compared to the PP samples. However, the result is not fully explained by area alone, since the NP samples and later gestational ages showed no differences in CSA. Overall, these structural data support the cervical-softening theory proposed in the early gestation. However, if the structural parameters measured are an indication of whether the cervix is “primed” for parturition, our studies suggest this occurs much earlier in gestation than proposed in previous mouse molecular studies [2124,35,48].

The chosen mechanical testing regime in the current study allowed for the evaluation of cervix material properties, specifically, Young's modulus and ultimate stress. The ultimate stress values generally followed similar trends as observed with the stiffness data. Interestingly, however, E10.5 samples had significantly higher ultimate stress than PP samples, which might indicate a protective mechanism during early gestation. Further, tissue modulus was only observed to change significantly at the E18.5 time point when compared to NP samples. This combination of structural and material property changes at the E18.5 point might be the necessary mechanical precursor to a timely term delivery.

Given the primary load bearing role of collagen fibers in biological tissue and specifically the cervix, collagen fiber re-alignment during tensile loading was examined for cervical tissue at all gestational time points (except PP). Some level of early re-alignment was observed at the E10.5 time point, which might be a precursor to the significant drop in mechanical properties observed at the E12.5 time point. Further, significant and early collagen fiber re-alignment was observed for the E16.5 and E18.5 samples, which might precede the cervix preparing to deliver. The lower levels of collagen fiber re-alignment at all other gestational time points correlate with the observed stabilization in the corresponding mechanical properties. It has been shown that collagen fibril density decreases during pregnancy, which would allow for easier and earlier realignment of the ECM [35]. In other tissues, it has been shown that increased or early collagen fiber re-alignment was associated with changes in the collagen structure and decreased tissue mechanics [49,50]. The previous work demonstrated that mature collagen crosslinks decrease during gestation and are correlated with tissue strength; since these crosslinks function to connect collagen fibers together, more of these crosslinks could decrease the ability of the collagen fibers to re-align [32]. Previous studies using both polarized light as well as second harmonic generation imaging have shown that the NP cervix without any load is already highly organized and more aligned when compared to pregnant samples [33,34]. This could also partially explain why some of the earlier gestational ages showed less collagen fiber re-alignment during loading [33,34]. The collagen fibers were noted to be much thicker and curved in pregnant cervix at term and late gestation. These physical changes in collagen fiber microstructure along with the loss of mature collagen crosslinks at later gestational ages [32] are in agreement with the increased dynamic collagen fiber realignment and concomitant reduction in cervix tissue stiffness observed here. In the future, quantification of density, porosity, and fibril size of collagen fibers from three-dimensional second harmonic generation (SHG) imaging of cervical tissue cervical tissue images will greatly assist in explaining the changes in tissue modulus and maximum stress.

Although measurement of cervix mechanical properties is inherently difficult in the human population, various in vivo techniques such as elastography and aspiration have been employed over the years. The observed reduction in stiffness at early gestation has been also documented recently in the human population via an aspiration test [51]. In contrast, studies using ultrasound elastography have found mixed results with weak to nonexistent correlations between gestational age and cervical stiffness [52,53].

Although this study provides structural and mechanical insights into the cervix during nonpregnant, pregnant, and postpartum states, it does have limitations. This study was performed in a mouse model. While the mouse has been used extensively in the past for similar studies, it should be noted there are differences in the mouse when compared to humans, and these differences might limit the implications of our findings. The mouse is not bipedal like humans, has two uterine horns, and carries many fetuses at a time. As such, possible loading differences during pregnancy (the uterus onto the cervix) must be appreciated. However, the cells and matrix that compose the mouse cervix are similar to human cervical tissue. Thus, mouse models have become a standard in this field and are very useful for the types of research questions posed here. Though the experimental methods for evaluating collagen re-alignment in this study were not feasible for PP samples due to their increased thickness, future studies could section the PP tissue to evaluate re-alignment in thinner samples. This study focused on collagen re-alignment under increasing load in the entire cervix, future studies may address these changes regionally, specifically to evaluate changes that might occur at the inner os versus the outer os. The uniaxial loading employed in this study does not exactly replicate the in vivo loading scenario. However, the current configuration was chosen to allow for accurate cross-sectional area measurement. It is possible that the deformations occurring during uniaxial loading in this study are ultra-physiological for the early gestational time points. However, these deformations are representative of the stretching of the cervix at delivery. It is possible that opening of the cervix tissue for uniaxial testing might have induced some nominal stresses causing the collagen fibers to realign. It has been previously shown that substantial realignment of collagen fibers can occur during preconditioning at low loads [42]. Finally, true stress and strain values were not evaluated in this study, and thus the changes in cross section dimensions were not accounted for.

The data presented in the current study are consistent with previous studies showing that the mouse cervix remodels structurally and mechanically during gestation [22,23,32,35]. However, this study showed that modulus changed significantly from the nonpregnant state just before delivery (E18.5). In contrast to the previous work, this study revealed a prompt recovery of most mechanical properties at the PP time point [32]. Understanding how the cervix “regains” function will be essential toward uncovering the processes that cause the cervix to “lose” function as is proposed to occur in spontaneous PTB. Knowledge of the regulation behind this phenomenon could improve potential therapeutic strategies of spontaneous PTB. This study demonstrated novel findings concerning the biomechanics of the pregnant cervix yet, further work is necessary to (1) correlate our findings of biomechanical changes with reported molecular changes that differentiate these time points during mouse gestation and (2) more thoroughly explain how the cervix maintains load during pregnancy. Further, correlation of these findings with human pregnancy will be necessary.

In conclusion, we demonstrated that the pregnant cervix has significantly reduced structural and material properties, which decreased at midgestation, as compared to nonpregnant samples, and not just at term. These decreased properties were accompanied by changes in collagen fiber re-alignment occurring earlier in the loading curve for cervices at term.

This work was supported in part by the March of Dimes Prematurity Research Center at the University of Pennsylvania and the Penn Center for Musculoskeletal Disorders at the University of Pennsylvania.

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Holt, R. , Timmons, B. C. , Akgul, Y. , Akins, M. L. , and Mahendroo, M. , 2011, “ The Molecular Mechanisms of Cervical Ripening Differ Between Term and Preterm Birth,” Endocrinology, 152(3), pp. 1036–1046. [CrossRef] [PubMed]
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Mahendroo, M. , 2012, “ Cervical Remodeling in Term and Preterm Birth: Insights From an Animal Model,” Reproduction, 143(4), pp. 429–438. [CrossRef] [PubMed]
Timmons, B. , Akins, M. , and Mahendroo, M. , 2010, “ Cervical Remodeling During Pregnancy and Parturition,” Trends Endocrinol. Metab., 21(6), pp. 353–361. [CrossRef] [PubMed]
Iams, J. D. , Goldenberg, R. L. , Meis, P. J. , Mercer, B. M. , Moawad, A. , Das, A. , Thom, E. , McNellis, D. , Copper, R. L. , Johnson, F. , and Roberts, J. M. , 1996, “ The Length of the Cervix and the Risk of Spontaneous Premature Delivery,” N. Engl. J. Med., 334(9), pp. 567–572. [CrossRef] [PubMed]
Fonseca, E. B. , Celik, E. , Parra, M. , Singh, M. , and Nicolaides, K. H. , 2007, “ Progesterone and the Risk of Preterm Birth Among Women With a Short Cervix,” N. Engl. J. Med., 357(5), pp. 462–469. [CrossRef] [PubMed]
Leppert, P. C. , and Yu, S. Y. , 1994, “ Apoptosis in the Cervix of Pregnant Rats in Association With Cervical Softening,” Gynecol. Obstet. Invest., 37(3), pp. 150–154. [CrossRef] [PubMed]
Andarawis-Puri, N. , Flatow, E. L. , and Soslowsky, L. J. , 2015, “ Tendon Basic Science: Development, Repair, Regeneration, and Healing,” J. Orthop. Res., 33(6), pp. 780–784. [CrossRef] [PubMed]
Screen, H. R. , Berk, D. E. , Kadler, K. E. , Ramirez, F. , and Young, M. F. , 2015, “ Tendon Functional Extracellular Matrix,” J. Orthop. Res., 33(6), pp. 793–799. [CrossRef] [PubMed]
Cooper, M. E. , 2004, “ Importance of Advanced Glycation End Products in Diabetes-Associated Cardiovascular and Renal Disease,” Am. J. Hypertens, 17(12 Pt. 2), pp. 31S–38S. [CrossRef] [PubMed]
Brownlee, M. , Cerami, A. , and Vlassara, H. , 1988, “ Advanced Glycosylation End Products in Tissue and the Biochemical Basis of Diabetic Complications,” N. Engl. J. Med., 318(20), pp. 1315–1321. [CrossRef] [PubMed]
Yoshida, K. , Jiang, H. , Kim, M. , Vink, J. , Cremers, S. , Paik, D. , Wapner, R. , Mahendroo, M. , and Myers, K. , 2014, “ Quantitative Evaluation of Collagen Crosslinks and Corresponding Tensile Mechanical Properties in Mouse Cervical Tissue During Normal Pregnancy,” PLoS One, 9(11), p. e112391. [CrossRef] [PubMed]
Yu, S. Y. , Tozzi, C. A. , Babiarz, J. , and Leppert, P. C. , 1995, “ Collagen Changes in Rat Cervix in Pregnancy—Polarized Light Microscopic and Electron Microscopic Studies,” Proc. Soc. Exp. Biol. Med., 209(4), pp. 360–368. [CrossRef] [PubMed]
Zhang, Y. , Akins, M. L. , Murari, K. , Xi, J. , Li, M. J. , Luby-Phelps, K. , Mahendroo, M. , and Li, X. , 2012, “ A Compact Fiber-Optic SHG Scanning Endomicroscope and Its Application to Visualize Cervical Remodeling During Pregnancy,” Proc. Natl. Acad. Sci. U.S.A., 109(32), pp. 12878–12883. [CrossRef] [PubMed]
Akins, M. L. , Luby-Phelps, K. , Bank, R. A. , and Mahendroo, M. , 2011, “ Cervical Softening During Pregnancy: Regulated Changes in Collagen Cross-Linking and Composition of Matricellular Proteins in the Mouse,” Biol. Reprod., 84(5), pp. 1053–1062. [CrossRef] [PubMed]
Myers, K. M. , Socrate, S. , Paskaleva, A. , and House, M. , 2010, “ A Study of the Anisotropy and Tension/Compression Behavior of Human Cervical Tissue,” ASME J. Biomech. Eng., 132(2), p. 021003. [CrossRef]
Timmons, B. C. , Reese, J. , Socrate, S. , Ehinger, N. , Paria, B. C. , Milne, G. L. , Akins, M. L. , Auchus, R. J. , McIntire, D. , House, M. , and Mahendroo, M. , 2014, “ Prostaglandins are Essential for Cervical Ripening in LPS-Mediated Preterm Birth But Not Term or Antiprogestin-Driven Preterm Ripening,” Endocrinology, 155(1), pp. 287–298. [CrossRef] [PubMed]
Harkness, M. L. R. , and Harkness, R. D. , 1959, “ Changes in the Physical Properties of the Uterine Cervix of the Rat During Pregnancy,” J. Physiol., 148(3), pp. 524–547. [CrossRef] [PubMed]
Yoshida, K. , Mahendroo, M. , Vink, J. , Wapner, R. , and Myers, K. , 2016, “ Material Properties of Mouse Cervical Tissue in Normal Gestation,” Acta Biomater., 36, pp. 195–209. [CrossRef] [PubMed]
Favata, M. , 2006, “ Scarless Healing in the Fetus: Implications and Strategies for Postnatal Tendon Repair,” Ph.D. Dissertation, University of Pennsylvania, Philadelphia, PA.
Dunkman, A. A. , Buckley, M. R. , Mienaltowski, M. J. , Adams, S. M. , Thomas, S. J. , Satchell, L. , Kumar, A. , Pathmanathan, L. , Beason, D. P. , Iozzo, R. V. , Birk, D. E. , and Soslowsky, L. J. , 2013, “ Decorin Expression is Important for Age-Related Changes in Tendon Structure and Mechanical Properties,” Matrix Biol., 32(1), pp. 3–13. [CrossRef] [PubMed]
Miller, K. S. , Edelstein, L. , Connizzo, B. K. , and Soslowsky, L. J. , 2012, “ Effect of Preconditioning and Stress Relaxation on Local Collagen Fiber Re-Alignment: Inhomogeneous Properties of Rat Supraspinatus Tendon,” ASME J. Biomech. Eng., 134(3), p. 031007. [CrossRef]
Freedman, B. R. , Sarver, J. J. , Buckley, M. R. , Voleti, P. B. , and Soslowsky, L. J. , 2014, “ Biomechanical and Structural Response of Healing Achilles Tendon to Fatigue Loading Following Acute Injury,” J. Biomech., 47(9), pp. 2028–2034. [CrossRef] [PubMed]
Drzewiecki, G. , Tozzi, C. , Yu, S. Y. , and Leppert, P. C. , 2005, “ A Dual Mechanism of Biomechanical Change in Rat Cervix in Gestation and Postpartum: Applied Vascular Mechanics,” Cardiovasc. Eng., 5(4), pp. 187–193. [CrossRef]
Anderson, J. , Brown, N. , Mahendroo, M. S. , and Reese, J. , 2006, “ Utilization of Different Aquaporin Water Channels in the Mouse Cervix During Pregnancy and Parturition and in Models of Preterm and Delayed Cervical Ripening,” Endocrinology, 147(1), pp. 130–140. [CrossRef] [PubMed]
Xu, X. , Akgul, Y. , Mahendroo, M. , and Jerschow, A. , 2010, “ Ex Vivo Assessment of Mouse Cervical Remodeling Through Pregnancy Via 23Na MRS,” NMR Biomed., 23(8), pp. 907–912. [CrossRef] [PubMed]
Ruscheinsky, M. , De la Motte, C. , and Mahendroo, M. , 2008, “ Hyaluronan and Its Binding Proteins During Cervical Ripening and Parturition: Dynamic Changes in Size, Distribution and Temporal Sequence,” Matrix Biol., 27(5), pp. 487–497. [CrossRef] [PubMed]
Timmons, B. C. , Mitchell, S. M. , Gilpin, C. , and Mahendroo, M. S. , 2007, “ Dynamic Changes in the Cervical Epithelial Tight Junction Complex and Differentiation Occur During Cervical Ripening and Parturition,” Endocrinology, 148(3), pp. 1278–1287. [CrossRef] [PubMed]
Connizzo, B. K. , Bhatt, P. R. , Liechty, K. W. , and Soslowsky, L. J. , 2014, “ Diabetes Alters Mechanical Properties and Collagen Fiber Re-Alignment in Multiple Mouse Tendons,” Ann. Biomed. Eng., 42(9), pp. 1880–1888. [CrossRef] [PubMed]
Connizzo, B. K. , Sarver, J. J. , Birk, D. E. , Soslowsky, L. J. , and Iozzo, R. V. , 2013, “ Effect of Age and Proteoglycan Deficiency on Collagen Fiber Re-Alignment and Mechanical Properties in Mouse Supraspinatus Tendon,” ASME J. Biomech. Eng., 135(2), p. 021019. [CrossRef]
Bauer, M. , Mazza, E. , Jabareen, M. , Sultan, L. , Bajka, M. , Lang, U. , Zimmermann, R. , and Holzapfel, G. A. , 2009, “ Assessment of the In Vivo Biomechanical Properties of the Human Uterine Cervix in Pregnancy Using the Aspiration Test: A Feasibility Study,” Eur. J. Obstet. Gynecol. Reprod. Biol., 144(Suppl. 1), pp. S77–S81. [CrossRef] [PubMed]
Hernandez-Andrade, E. , Hassan, S. S. , Ahn, H. , Korzeniewski, S. J. , Yeo, L. , Chaiworapongsa, T. , and Romero, R. , 2013, “ Evaluation of Cervical Stiffness During Pregnancy Using Semiquantitative Ultrasound Elastography,” Ultrasound Obstet. Gynecol., 41(2), pp. 152–161. [CrossRef] [PubMed]
Yamaguchi, S. , Kamei, Y. , Kozuma, S. , and Taketani, Y. , 2007, “ Tissue Elastography Imaging of the Uterine Cervix During Pregnancy,” J. Med. Ultrason., 34(4), pp. 209–210. [CrossRef]
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Eidem, H. R. , Ackerman, W. E. , McGary, K. L. , Abbot, P. , and Rokas, A. , 2015, “ Gestational Tissue Transcriptomics in Term and Preterm Human Pregnancies: A Systematic Review and Meta-Analysis,” BMC Med. Genomics, 8(1), p. 27. [CrossRef] [PubMed]
Elovitz, M. A. , and Mrinalini, C. , 2004, “ Animal Models of Preterm Birth,” Trends Endocrinol. Metab., 15(10), pp. 479–487. [CrossRef] [PubMed]
House, M. , Kaplan, D. L. , and Socrate, S. , 2009, “ Relationships Between Mechanical Properties and Extracellular Matrix Constituents of the Cervical Stroma During Pregnancy,” Semin. Perinatol., 33(5), pp. 300–307. [CrossRef] [PubMed]
Holt, R. , Timmons, B. C. , Akgul, Y. , Akins, M. L. , and Mahendroo, M. , 2011, “ The Molecular Mechanisms of Cervical Ripening Differ Between Term and Preterm Birth,” Endocrinology, 152(3), pp. 1036–1046. [CrossRef] [PubMed]
Read, C. P. , Word, R. A. , Ruscheinsky, M. A. , Timmons, B. C. , and Mahendroo, M. S. , 2007, “ Cervical Remodeling During Pregnancy and Parturition: Molecular Characterization of the Softening Phase in Mice,” Reproduction, 134(2), pp. 327–340. [CrossRef] [PubMed]
Mahendroo, M. , 2012, “ Cervical Remodeling in Term and Preterm Birth: Insights From an Animal Model,” Reproduction, 143(4), pp. 429–438. [CrossRef] [PubMed]
Timmons, B. , Akins, M. , and Mahendroo, M. , 2010, “ Cervical Remodeling During Pregnancy and Parturition,” Trends Endocrinol. Metab., 21(6), pp. 353–361. [CrossRef] [PubMed]
Iams, J. D. , Goldenberg, R. L. , Meis, P. J. , Mercer, B. M. , Moawad, A. , Das, A. , Thom, E. , McNellis, D. , Copper, R. L. , Johnson, F. , and Roberts, J. M. , 1996, “ The Length of the Cervix and the Risk of Spontaneous Premature Delivery,” N. Engl. J. Med., 334(9), pp. 567–572. [CrossRef] [PubMed]
Fonseca, E. B. , Celik, E. , Parra, M. , Singh, M. , and Nicolaides, K. H. , 2007, “ Progesterone and the Risk of Preterm Birth Among Women With a Short Cervix,” N. Engl. J. Med., 357(5), pp. 462–469. [CrossRef] [PubMed]
Leppert, P. C. , and Yu, S. Y. , 1994, “ Apoptosis in the Cervix of Pregnant Rats in Association With Cervical Softening,” Gynecol. Obstet. Invest., 37(3), pp. 150–154. [CrossRef] [PubMed]
Andarawis-Puri, N. , Flatow, E. L. , and Soslowsky, L. J. , 2015, “ Tendon Basic Science: Development, Repair, Regeneration, and Healing,” J. Orthop. Res., 33(6), pp. 780–784. [CrossRef] [PubMed]
Screen, H. R. , Berk, D. E. , Kadler, K. E. , Ramirez, F. , and Young, M. F. , 2015, “ Tendon Functional Extracellular Matrix,” J. Orthop. Res., 33(6), pp. 793–799. [CrossRef] [PubMed]
Cooper, M. E. , 2004, “ Importance of Advanced Glycation End Products in Diabetes-Associated Cardiovascular and Renal Disease,” Am. J. Hypertens, 17(12 Pt. 2), pp. 31S–38S. [CrossRef] [PubMed]
Brownlee, M. , Cerami, A. , and Vlassara, H. , 1988, “ Advanced Glycosylation End Products in Tissue and the Biochemical Basis of Diabetic Complications,” N. Engl. J. Med., 318(20), pp. 1315–1321. [CrossRef] [PubMed]
Yoshida, K. , Jiang, H. , Kim, M. , Vink, J. , Cremers, S. , Paik, D. , Wapner, R. , Mahendroo, M. , and Myers, K. , 2014, “ Quantitative Evaluation of Collagen Crosslinks and Corresponding Tensile Mechanical Properties in Mouse Cervical Tissue During Normal Pregnancy,” PLoS One, 9(11), p. e112391. [CrossRef] [PubMed]
Yu, S. Y. , Tozzi, C. A. , Babiarz, J. , and Leppert, P. C. , 1995, “ Collagen Changes in Rat Cervix in Pregnancy—Polarized Light Microscopic and Electron Microscopic Studies,” Proc. Soc. Exp. Biol. Med., 209(4), pp. 360–368. [CrossRef] [PubMed]
Zhang, Y. , Akins, M. L. , Murari, K. , Xi, J. , Li, M. J. , Luby-Phelps, K. , Mahendroo, M. , and Li, X. , 2012, “ A Compact Fiber-Optic SHG Scanning Endomicroscope and Its Application to Visualize Cervical Remodeling During Pregnancy,” Proc. Natl. Acad. Sci. U.S.A., 109(32), pp. 12878–12883. [CrossRef] [PubMed]
Akins, M. L. , Luby-Phelps, K. , Bank, R. A. , and Mahendroo, M. , 2011, “ Cervical Softening During Pregnancy: Regulated Changes in Collagen Cross-Linking and Composition of Matricellular Proteins in the Mouse,” Biol. Reprod., 84(5), pp. 1053–1062. [CrossRef] [PubMed]
Myers, K. M. , Socrate, S. , Paskaleva, A. , and House, M. , 2010, “ A Study of the Anisotropy and Tension/Compression Behavior of Human Cervical Tissue,” ASME J. Biomech. Eng., 132(2), p. 021003. [CrossRef]
Timmons, B. C. , Reese, J. , Socrate, S. , Ehinger, N. , Paria, B. C. , Milne, G. L. , Akins, M. L. , Auchus, R. J. , McIntire, D. , House, M. , and Mahendroo, M. , 2014, “ Prostaglandins are Essential for Cervical Ripening in LPS-Mediated Preterm Birth But Not Term or Antiprogestin-Driven Preterm Ripening,” Endocrinology, 155(1), pp. 287–298. [CrossRef] [PubMed]
Harkness, M. L. R. , and Harkness, R. D. , 1959, “ Changes in the Physical Properties of the Uterine Cervix of the Rat During Pregnancy,” J. Physiol., 148(3), pp. 524–547. [CrossRef] [PubMed]
Yoshida, K. , Mahendroo, M. , Vink, J. , Wapner, R. , and Myers, K. , 2016, “ Material Properties of Mouse Cervical Tissue in Normal Gestation,” Acta Biomater., 36, pp. 195–209. [CrossRef] [PubMed]
Favata, M. , 2006, “ Scarless Healing in the Fetus: Implications and Strategies for Postnatal Tendon Repair,” Ph.D. Dissertation, University of Pennsylvania, Philadelphia, PA.
Dunkman, A. A. , Buckley, M. R. , Mienaltowski, M. J. , Adams, S. M. , Thomas, S. J. , Satchell, L. , Kumar, A. , Pathmanathan, L. , Beason, D. P. , Iozzo, R. V. , Birk, D. E. , and Soslowsky, L. J. , 2013, “ Decorin Expression is Important for Age-Related Changes in Tendon Structure and Mechanical Properties,” Matrix Biol., 32(1), pp. 3–13. [CrossRef] [PubMed]
Miller, K. S. , Edelstein, L. , Connizzo, B. K. , and Soslowsky, L. J. , 2012, “ Effect of Preconditioning and Stress Relaxation on Local Collagen Fiber Re-Alignment: Inhomogeneous Properties of Rat Supraspinatus Tendon,” ASME J. Biomech. Eng., 134(3), p. 031007. [CrossRef]
Freedman, B. R. , Sarver, J. J. , Buckley, M. R. , Voleti, P. B. , and Soslowsky, L. J. , 2014, “ Biomechanical and Structural Response of Healing Achilles Tendon to Fatigue Loading Following Acute Injury,” J. Biomech., 47(9), pp. 2028–2034. [CrossRef] [PubMed]
Drzewiecki, G. , Tozzi, C. , Yu, S. Y. , and Leppert, P. C. , 2005, “ A Dual Mechanism of Biomechanical Change in Rat Cervix in Gestation and Postpartum: Applied Vascular Mechanics,” Cardiovasc. Eng., 5(4), pp. 187–193. [CrossRef]
Anderson, J. , Brown, N. , Mahendroo, M. S. , and Reese, J. , 2006, “ Utilization of Different Aquaporin Water Channels in the Mouse Cervix During Pregnancy and Parturition and in Models of Preterm and Delayed Cervical Ripening,” Endocrinology, 147(1), pp. 130–140. [CrossRef] [PubMed]
Xu, X. , Akgul, Y. , Mahendroo, M. , and Jerschow, A. , 2010, “ Ex Vivo Assessment of Mouse Cervical Remodeling Through Pregnancy Via 23Na MRS,” NMR Biomed., 23(8), pp. 907–912. [CrossRef] [PubMed]
Ruscheinsky, M. , De la Motte, C. , and Mahendroo, M. , 2008, “ Hyaluronan and Its Binding Proteins During Cervical Ripening and Parturition: Dynamic Changes in Size, Distribution and Temporal Sequence,” Matrix Biol., 27(5), pp. 487–497. [CrossRef] [PubMed]
Timmons, B. C. , Mitchell, S. M. , Gilpin, C. , and Mahendroo, M. S. , 2007, “ Dynamic Changes in the Cervical Epithelial Tight Junction Complex and Differentiation Occur During Cervical Ripening and Parturition,” Endocrinology, 148(3), pp. 1278–1287. [CrossRef] [PubMed]
Connizzo, B. K. , Bhatt, P. R. , Liechty, K. W. , and Soslowsky, L. J. , 2014, “ Diabetes Alters Mechanical Properties and Collagen Fiber Re-Alignment in Multiple Mouse Tendons,” Ann. Biomed. Eng., 42(9), pp. 1880–1888. [CrossRef] [PubMed]
Connizzo, B. K. , Sarver, J. J. , Birk, D. E. , Soslowsky, L. J. , and Iozzo, R. V. , 2013, “ Effect of Age and Proteoglycan Deficiency on Collagen Fiber Re-Alignment and Mechanical Properties in Mouse Supraspinatus Tendon,” ASME J. Biomech. Eng., 135(2), p. 021019. [CrossRef]
Bauer, M. , Mazza, E. , Jabareen, M. , Sultan, L. , Bajka, M. , Lang, U. , Zimmermann, R. , and Holzapfel, G. A. , 2009, “ Assessment of the In Vivo Biomechanical Properties of the Human Uterine Cervix in Pregnancy Using the Aspiration Test: A Feasibility Study,” Eur. J. Obstet. Gynecol. Reprod. Biol., 144(Suppl. 1), pp. S77–S81. [CrossRef] [PubMed]
Hernandez-Andrade, E. , Hassan, S. S. , Ahn, H. , Korzeniewski, S. J. , Yeo, L. , Chaiworapongsa, T. , and Romero, R. , 2013, “ Evaluation of Cervical Stiffness During Pregnancy Using Semiquantitative Ultrasound Elastography,” Ultrasound Obstet. Gynecol., 41(2), pp. 152–161. [CrossRef] [PubMed]
Yamaguchi, S. , Kamei, Y. , Kozuma, S. , and Taketani, Y. , 2007, “ Tissue Elastography Imaging of the Uterine Cervix During Pregnancy,” J. Med. Ultrason., 34(4), pp. 209–210. [CrossRef]

Figures

Grahic Jump Location
Fig. 2

(a) Custom testing setup to record collagen fiber re-alignment during the mechanical testing. (b) Close-up of the cervical tissue in grips during mechanical testing. (c) Schematic depicting typical force-displacement and stress-strain curves from a uniaxial test. Stiffness and maximum load were obtained from the force-displacement curve and Young's modulus and maximum stress were obtained from the stress-strain curve. Collagen fiber re-alignment was assessed at the beginning and end of the toe region, 45% of maximum load and 90% of maximum load. (d) Representative load-stretch plots for each gestational time point.

Grahic Jump Location
Fig. 3

Cross-sectional area of the cervix during gestation. (a) Cross-sectional area is shown for all gestational time points. The white bar on the left represents the NP and during gestation different time points are shown in increasing shades of grey. PP samples are represented on the far right with a checkered pattern. All of the data is presented as means with standard deviations, and significance noted at p < 0.05 with a line. Although no statistical differences were observed between the (b) NP and the (c) E18.5 samples, qualitative visual differences were observed.

Grahic Jump Location
Fig. 4

Cervix structural and material mechanical properties. (a) Stiffness, (b) Max Load, (c) Max Stress, and (d) Modulus for all samples. The white bar on the left represent the NP samples and during gestation different time points are shown in different shades of gray. PP samples are represented on the far right with a checkered pattern. All of the data is presented as means with standard deviations, and significance is noted at p < 0.05 with lines.

Grahic Jump Location
Fig. 1

Cervical mechanical testing dissection. (a) Schematic of cervix anatomy. (b) NP and (c) E18.5 cervices before and (b′) and (c′) after dissection. During dissection the cervix was cut open on the side opposite to the bladder and then the bladder was removed. The cervix was then laid flat to expose the lumen, and then rotated. The ends were affixed between two pieces of sandpaper for gripping so that when the cervix was pulled in tension, this represented circumferential loading.

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Fig. 5

Collagen fiber re-alignment through polarized light analysis of the cervix during mechanical testing. Representative plots of polarized light analyzed at toe, end of toe, 45% of maximum load, and 90% of maximum load. (a) NP, (b) E10.5, (c) E12.5, (d) E14.5, (e) E16.5, and (f) E18.5. Lines represent significance (p < 0.05) while dashed lines represent tends (p < 0.1).

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