Photoacoustic imaging of the uterine cervix to assess collagen and water content changes in murine pregnancy.

The uterine cervix plays a central role in the maintenance of pregnancy and in the process of parturition. Cervical remodeling involves dramatic changes in extracellular matrix composition and, in particular, of collagen and water content during cervical ripening (a term that describes the anatomical, biochemical, and physiologic changes in preparation for labor). Untimely cervical ripening in early gestation predisposes to preterm labor and delivery, the leading cause of infant death worldwide. Inadequate ripening of the cervix is associated with failure of induction or prolonged labor. The current approach to evaluate the state of the cervix relies on digital examination and sonographic examination. Herein, we present a novel imaging method that combines ultrasound (US) and photoacoustic (PA) techniques to evaluate cervical remodeling by assessing the relative collagen and water content of this organ. The method was tested in vitro in extracted collagen phantoms and ex vivo in murine cervical tissues that were collected in mid-pregnancy and at term. We report, for the first time, that our imaging approach provides information about the molecular changes in the cervix at different gestational ages. There was a strong correlation between the results of PA imaging and the histological assessment of the uterine cervix over the course of gestation. These findings suggest that PA imaging is a powerful method to assess the biochemical composition of the cervix and open avenues to non-invasively investigate the composition of this organ, which is essential for reproductive success.

[1]  Jonathan Bard,et al.  COLLAGEN SUBSTRATA FOR STUDIES ON CELL BEHAVIOR , 1972, The Journal of cell biology.

[2]  F. Glorieux,et al.  Collagen changes in the human uterine cervix at parturition. , 1978, American journal of obstetrics and gynecology.

[3]  N. Uldbjerg,et al.  Ripening of the human uterine cervix related to changes in collagen, glycosaminoglycans, and collagenolytic activity. , 1983, American journal of obstetrics and gynecology.

[4]  M. Rojkind,et al.  A simple micromethod for collagen and total protein determination in formalin-fixed paraffin-embedded sections. , 1985, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[5]  A Ishimaru,et al.  Diffusion of light in turbid material. , 1989, Applied optics.

[6]  L. Izquierdo,et al.  Vaginal ultrasonographic assessment of cervical length changes during normal pregnancy. , 1990, American journal of obstetrics and gynecology.

[7]  C. Rodeck,et al.  Preinduction cervical assessment by Bishop's score and transvaginal ultrasound. , 1991, European journal of obstetrics, gynecology, and reproductive biology.

[8]  D. Hassiakos,et al.  The role of steroid hormones in cervical ripening. , 1993, Clinical and experimental obstetrics & gynecology.

[9]  E. Thom,et al.  The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. , 1996, The New England journal of medicine.

[10]  K. Nicolaides,et al.  Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery , 1998, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[11]  W. Rath,et al.  pregnancy and parturition , 1999 .

[12]  H. Wolfe,et al.  Patients with an ultrasonographic cervical length < or =15 mm have nearly a 50% risk of early spontaneous preterm delivery. , 2000, American journal of obstetrics and gynecology.

[13]  P. Grigsby,et al.  Imaging in cervical cancer , 2003, Cancer.

[14]  R. Pitkin Commentary on "pelvic scoring for elective induction", 1964. , 2003 .

[15]  W. Grobman,et al.  When Has an Induction Failed? , 2005, Obstetrics and gynecology.

[16]  R. Brentani,et al.  Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections , 1979, The Histochemical Journal.

[17]  S. Yellon,et al.  Increased Innervation and Ripening of the Prepartum Murine Cervix , 2005, The Journal of the Society for Gynecologic Investigation: JSGI.

[18]  Vincent C Hascall,et al.  Regulation of hyaluronan expression during cervical ripening. , 2004, Glycobiology.

[19]  Lihong V. Wang,et al.  Photoacoustic imaging in biomedicine , 2006 .

[20]  Jeff Reese,et al.  Utilization of different aquaporin water channels in the mouse cervix during pregnancy and parturition and in models of preterm and delayed cervical ripening. , 2006, Endocrinology.

[21]  Geng Ku,et al.  Noninvasive imaging of hemoglobin concentration and oxygenation in the rat brain using high-resolution photoacoustic tomography. , 2006, Journal of biomedical optics.

[22]  Progesterone and the risk of preterm birth among women with a short cervix. , 2007, The New England journal of medicine.

[23]  R. Word,et al.  Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice. , 2007, Reproduction.

[24]  Shannon M. Mitchell,et al.  Dynamic changes in the cervical epithelial tight junction complex and differentiation occur during cervical ripening and parturition. , 2007, Endocrinology.

[25]  K. Nicolaides,et al.  Cervical length at mid-pregnancy and the risk of primary cesarean delivery. , 2008, The New England journal of medicine.

[26]  C. A. de la Motte,et al.  Hyaluronan and its binding proteins during cervical ripening and parturition: dynamic changes in size, distribution and temporal sequence. , 2008, Matrix biology : journal of the International Society for Matrix Biology.

[27]  S. Socrate,et al.  Mechanical and biochemical properties of human cervical tissue. , 2008, Acta biomaterialia.

[28]  Michael House,et al.  Relationships between mechanical properties and extracellular matrix constituents of the cervical stroma during pregnancy. , 2009, Seminars in perinatology.

[29]  Pai-Chi Li,et al.  Photoacoustics for molecular imaging and therapy. , 2009, Physics today.

[30]  Michael House,et al.  Changes in the biochemical constituents and morphologic appearance of the human cervical stroma during pregnancy. , 2009, European journal of obstetrics, gynecology, and reproductive biology.

[31]  N. Uldbjerg,et al.  Collagen concentration and biomechanical properties of samples from the lower uterine cervix in relation to age and parity in non-pregnant women , 2010, Reproductive biology and endocrinology : RB&E.

[32]  Meredith Akins,et al.  Cervical remodeling during pregnancy and parturition , 2010, Trends in Endocrinology & Metabolism.

[33]  R. Romero,et al.  Clinical significance of early (< 20 weeks) vs. late (20–24 weeks) detection of sonographic short cervix in asymptomatic women in the mid‐trimester , 2010, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[34]  L. Sullivan,et al.  Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double‐blind, placebo‐controlled trial , 2011, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[35]  Katherine Luby-Phelps,et al.  Cervical Softening During Pregnancy: Regulated Changes in Collagen Cross-Linking and Composition of Matricellular Proteins in the Mouse1 , 2011, Biology of reproduction.

[36]  Christof Sohn,et al.  A novel optical method to assess cervical changes during pregnancy and use to evaluate the effects of progestins on term and preterm labor. , 2009, American journal of obstetrics and gynecology.

[37]  Rami Nachabé,et al.  Diagnosis of breast cancer using diffuse optical spectroscopy from 500 to 1600 nm: comparison of classification methods. , 2011, Journal of biomedical optics.

[38]  R. Romero,et al.  Cervical Remodeling/Ripening at Term and Preterm Delivery: The Same Mechanism Initiated by Different Mediators and Different Effector Cells , 2011, PloS one.

[39]  A. Word,et al.  Dynamic changes in cervical glycosaminoglycan composition during normal pregnancy and preterm birth. , 2012, Endocrinology.

[40]  R. Romero,et al.  The new American Journal of Obstetrics and Gynecology, 5 years later: looking back and moving forward. , 2012, American journal of obstetrics and gynecology.

[41]  Lihong V. Wang,et al.  Photoacoustic Tomography: In Vivo Imaging from Organelles to Organs , 2012, Science.

[42]  Anita Mahadevan-Jansen,et al.  Detecting Biochemical Changes in the Rodent Cervix During Pregnancy Using Raman Spectroscopy , 2012, Annals of Biomedical Engineering.

[43]  S. Emelianov,et al.  Photoacoustic Imaging for Cancer Detection and Staging. , 2013, Current molecular imaging.

[44]  S. Hassan,et al.  Evaluation of cervical stiffness during pregnancy using semiquantitative ultrasound elastography , 2013, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[45]  R. Romero,et al.  A blueprint for the prevention of preterm birth: vaginal progesterone in women with a short cervix , 2013, Journal of perinatal medicine.

[46]  R. Schmitz,et al.  Quantitative Elastography for Cervical Stiffness Assessment during Pregnancy , 2014, BioMed research international.

[47]  S. Fisher,et al.  Preterm labor: One syndrome, many causes , 2014, Science.

[48]  R. Romero,et al.  Cervical strain determined by ultrasound elastography and its association with spontaneous preterm delivery , 2014, Journal of perinatal medicine.

[49]  R. Romero,et al.  Effect of depth on shear-wave elastography estimated in the internal and external cervical os during pregnancy , 2014, Journal of perinatal medicine.

[50]  T. Hall,et al.  Estimation of shear wave speed in the human uterine cervix , 2014, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[51]  Roberto Romero,et al.  Vaginal progesterone, but not 17α-hydroxyprogesterone caproate, has antiinflammatory effects at the murine maternal-fetal interface. , 2015, American journal of obstetrics and gynecology.

[52]  G. Rus,et al.  Mechanical assessment of cervical remodelling in pregnancy: insight from a synthetic model. , 2015, Journal of biomechanics.

[53]  K. Nicolaides,et al.  Vaginal progesterone decreases preterm birth ≤ 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta‐analysis including data from the OPPTIMUM study , 2016, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[54]  Yu Gan,et al.  Collagen Fiber Orientation and Dispersion in the Upper Cervix of Non-Pregnant and Pregnant Women , 2016, PloS one.

[55]  S. Yellon,et al.  Progesterone Receptor–Mediated Actions Regulate Remodeling of the Cervix in Preparation for Preterm Parturition , 2016, Reproductive Sciences.

[56]  M. Mahendroo,et al.  Distinct reorganization of collagen architecture in lipopolysaccharide-mediated premature cervical remodeling † , 2017, Biology of Reproduction.

[57]  Guillermo Rus,et al.  Transient Elastography to Assess the Cervical Ripening during Pregnancy: A Preliminary Study , 2015, Ultraschall in der Medizin - European Journal of Ultrasound.

[58]  T. Hall,et al.  Assessment of Structural Heterogeneity and Viscosity in the Cervix Using Shear Wave Elasticity Imaging: Initial Results from a Rhesus Macaque Model. , 2017, Ultrasound in medicine & biology.

[59]  Paola Taroni,et al.  Diffuse optical characterization of collagen absorption from 500 to 1700 nm , 2017, Journal of biomedical optics.

[60]  Nađa Aračić,et al.  The value of ultrasound measurement of cervical length and parity in prediction of cesarean section risk in term premature rupture of membranes and unfavorable cervix , 2017, Journal of perinatal medicine.

[61]  O. Christiansen,et al.  Recurrence rates after abdominal and vaginal cerclages in women with cervical insufficiency: a validated cohort study , 2017, Archives of Gynecology and Obstetrics.

[62]  N. Freedman,et al.  Infant and Youth Mortality Trends by Race/Ethnicity and Cause of Death in the United States , 2018, JAMA pediatrics.

[63]  Yuan Qu,et al.  Transvaginal fast-scanning optical-resolution photoacoustic endoscopy , 2018, Journal of biomedical optics.

[64]  R. Romero,et al.  A soft cervix, categorized by shear-wave elastography, in women with short or with normal cervical length at 18–24 weeks is associated with a higher prevalence of spontaneous preterm delivery , 2018, Journal of perinatal medicine.

[65]  Roberto Romero,et al.  Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta‐analysis of individual patient data , 2017, American journal of obstetrics and gynecology.

[66]  David R. Kaeli,et al.  Scalable and massively parallel Monte Carlo photon transport simulations for heterogeneous computing platforms , 2017, Journal of biomedical optics.

[67]  Yan Yan,et al.  Photoacoustic imaging of the uterine cervix: a novel method to characterize tissue composition: 17 , 2019, American Journal of Obstetrics and Gynecology.