We thank Deborah Frank for editing this manuscript and Jessica Chubiz for organizing the project. Funding: This work was supported by the March of Dimes Center Grant (22-FY14-486), by grants from NIH/National Institute of Child Health and Human Development (R01HD094381 to PIs Wang/Cahill; R01HD104822 to PIs Wang/Schwartz/Cahill), by grants from Burroughs Wellcome Fund Preterm Birth Initiative (NGP10119 to PI Wang), and by grants from the Bill and Melinda Gates Foundation (INV-005417, INV-035476, and INV-037302 to PI Wang).

All methods described here have been approved by the Washington University Institutional Review Board.
1. MRI-safe marker patches, electrode patches, and rulers (Figure 1)
<ol>
	<li>Print the MRI and electrode patch templates (Figure 1A) on paper.</li>
	<li>Cut clear vinyl and silicone rubber sheets (Table of Materials) into 22 (vinyl) and 44 (rubber) rectangular (120 mm x 60 mm), and 4 (vinyl) and 8 (silicone rubber) square (60 mm x 60 mm) patches.</li>
	<li>Make MRI-safe marker patches: Overlay a template with a clear vinyl patch and glue MRI-safe markers (vitamin D liquid softgels) to the vinyl patch at the centers of the circles, which represent the electrode holder cavities on the template (Figure 1B).</li>
	<li>Make electrode patches: Label the circle locations on the silicone rubber patches and punch holes at those locations using a punch set with a diameter of 8 mm.</li>
	<li>Attach electrode holders over each hole with double-sided adhesive collars (Table of Materials). Align the circumference of the electrode holder cavity with the circumference of the hole punched on the silicone sheet.</li>
	<li>Install the X-ring into the cavity on top of the electrode holder, cover the holder with the color-coded silicone sheet, and insert the pin-type active electrode through the X-ring into the holder. The electrode is centered in the cavity of the electrode holder. The electrode cables should go between the two layers of silicone sheets and in the middle of the two rows of holders along the long edge. Adjust the length of the electrode cable by twining it around the electrode holder if needed.The assembly of an electrode patch is concluded (Figure 1C).</li>
	<li>Apply three strips of medical-grade double-sided tape to the electrode patch between the rows of electrodes along the long edge of the patch.</li>
	<li>Cut six measuring tapes at their 30 cm marks. Retain the top section from 0 cm to 30 cm. To make a horizontal ruler, glue the edges at 0 cm of two measuring tapes to a long piece of vinyl strip with a gap in the width of the tape. Apply double-sided adhesive tape to each ruler.</li>
	<li>Store the patches and rulers in a closed-lid storage box.</li>
</ol>
2. MRI scan
NOTE: The MRI scan is scheduled at a gestational age (GA) of 36-40 weeks, prior to the mother&#39;s expected delivery date, determined based on the subject&#39;s schedule and her nurse&#39;s recommendation. The estimated time duration for this step is 2 h.
<ol>
	<li>After the subject signs the consent form, ask the subject to change out of her street clothing into the MR-safe pants and gown provided by the MRI technician. Place MR-safe marker patches (Figure 1B) on the body surface in the exam room.
	<ol>
		<li>Place patches on the back surface.
		<ol>
			<li>Instruct the subject to sit on a medical exam bed. Peel the liner off the double-sided tape and apply a vertical ruler along the subject&#39;s spine, with the end of the ruler at the buttock cleavage.</li>
			<li>Place a horizontal ruler at the level of the iliac crest, with the center crossing over the vertical ruler. Peel the liner off the double-sided tape on the patches.</li>
			<li>Apply two rectangular patches on the back, so that the long edges of the patches are next to the vertical ruler and the corners of the patches are at the intersection of the rulers.</li>
			<li>Place additional patches to the left and right of the first two patches so that the patches are bilaterally symmetric. For average-sized subjects, apply four rectangular patches at each side (Figure 1E).</li>
		</ol>
		</li>
		<li>Place patches on the abdominal surface.
		<ol>
			<li>Raise the head of the exam bed to around 40&#176; and guide the subject to lie down in Fowler&#39;s position. Place a vertical ruler along the midline of the abdomen, with the 3 cm mark near the fundus region determined by manual palpation.</li>
			<li>Apply a horizontal ruler so that its center is at the 6 cm mark of the vertical ruler and extends to the left and right lateral along the natural curvature of the abdomen.</li>
			<li>Place the first rectangular patch above the horizontal ruler and to the left of the vertical ruler, so that its long edge is parallel to the horizontal ruler and one corner of the patch is at the intersection of the two rulers.</li>
			<li>Place the second rectangular patch to the left of the first patch, with its long edge along the horizontal ruler. Place the third and fourth patches directly below the horizontal ruler and vertically aligned with the first and second patches.</li>
			<li>Place the fifth rectangular patch below the third patch, with its short edge along the vertical ruler. Place the sixth rectangular patch next to the fifth on the left side. Place the seventh patch below the fifth patch, with the short edge along the vertical ruler. Leave gaps of 2-3 cm between patches 3, 5, and 7 for the curvature of the abdomen.</li>
			<li>Place the two square patches (s1 and s2) below the sixth patch and seventh patch, vertically aligned with the sixth and seventh patch, respectively. Place patches on the right abdominal surface so they are bilaterally symmetric with those on the left (Figure 1F).</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Take photos and notes of the patch layout to record the positions of the rulers relative to each other and the subject&#39;s umbilicus.</li>
	<li>Have an MR technician screen the subject according to MRI safety rules and regulations at Zone II of the MRI facility. Then, guide the subject through Zone III to Zone IV, where a 3 T MR scanner resides.
	<ol>
		<li>Guide the patient to lie down on the MRI bed in a supine position and provide her with an MR-safe microphone, a headphone set, and a signaling squeeze ball. Cover the subject&#39;s lower abdomen with a 32-array MRI coil (Figure 2A). Start the MR scanning. 
		NOTE: A radial volume interpolated breath-hold examination fast T1-weighted sequence was used to perform MRI on the entire abdomen using either a 3 T Siemens Prisma or Vida scanner. The resulting MR images had a resolution of 1.56 mm x 1.56 mm and a slice thickness of 4 mm.</li>
	</ol>
	</li>
	<li>Use the localizer to adjust the field of view to cover the entire uterus and cervix. Then, perform an MRI scan with a T1-weighted sequence with the volume-interpolated breath-hold examination (repetition time [TR] = 4.07 ms, echo time [TE] = 1.78 ms, flip angle = 10&#176;) and multiplanar reconstruction of the data set (field of view [FOV] = 500 mm x 500 mm, matrix = 320 x 320, voxel size = 1.56 x 1.56 x 4 mm3).</li>
	<li>Store the data in digital imaging and communications in medicine (DICOM) format.</li>
	<li>Remove the MRI patches and rulers from the subject and clean the abdomen and back with baby wipes.</li>
	<li>Remove the double-sided tape from the patches, disinfect the patches with germicidal disposable wipes, and apply new double-sided tape for the next experiment.</li>
</ol>
3. Bioelectricity mapping and 3D optical scan
NOTE: Conduct bioelectricity mapping after the subject has been admitted to the labor and delivery unit, and her cervix has dilated to around 4 cm. The estimated time duration for this step is 2 h.
<ol>
	<li>Prepare the electrode patches: Fill conductive gel into a curved tip irrigation syringe. Add the gel into the electrode holder cavities on each electrode patch using the syringe. Remove the liners of the double-sided tapes.</li>
	<li>Apply the electrode patches according to the same procedures as described in step 2.1, following the placement layout described in the photos and notes taken in step 2.2.</li>
	<li>Connect the power and data cords of the 3D optical scanner. Open the 3D scanning software (Table of Materials). Hold the handheld optical scanner (Table of Materials) upright, with the flashing cameras facing the subject.
	<ol>
		<li>Press the Start button on the scanner to start the scanning, and press the Start button again to record the scanning. Move the scanner around the subject to take 3D optical scans to capture the electrode locations. 
		NOTE: Optical scans of the lower back surface are taken after placing electrode patches on the back surface. Optical scans of the abdominal surface are taken after placing electrode patches on the abdominal surface.</li>
		<li>Press the Stop button on the scanner to finish the 3D scanning.</li>
	</ol>
	</li>
	<li>Take photos and notes of the patch layout. Note the positions of the rulers relative to each other and the subject&#39;s navel.</li>
	<li>Place four grounding electrodes, with the &#34;LL&#34; electrode on the lower left abdomen,&#160;the &#34;LA&#34; electrode on the left upper chest, the &#34;RA&#34; electrode on the right upper chest, and the &#34;DRL&#34; electrode on the abdominal surface near the umbilicus or the lower right abdomen.</li>
	<li>Connect the components of the bioelectricity mapping hardware, including the laptop, analog to digital (AD) box, battery box, electrode patch, grounding electrode cables, optical fiber, and USB2 receiver (Figure 1D).</li>
	<li>Open the software Active View on the laptop and turn on the AD box. 
	NOTE: If the status light is yellow on the AD box, the grounding electrodes have poor contact with the skin. In this case, remove the grounding electrodes, add more gel, and place them back in their locations. Repeat until the status light turns blue.</li>
	<li>Check the Electrode offset module in Active View. If any electrodes have a large offset (over a quarter of the largest offset), improve their contact with the skin by securing them using medical paper tapes or by reinstalling (removing them, adding more gel, and placing them back in their locations).</li>
	<li>Click Start file &#62; Paused to save the bioelectricity signal data streams in real time. After a 900 s recording, click Pause Save &#62; Stop to finish the recording and store the multi-electrode measurement in a binary data file (BDF) file.</li>
	<li>Repeat step 3.9 four times after the research assistant has checked to ensure the subject is comfortable and willing to continue.</li>
	<li>After the last recording (usually four recordings in total), turn off the AD box and disconnect the electrode patches, grounding electrodes, optical fiber, and USB cable.</li>
	<li>Remove the electrode patches and grounding electrodes from the subject.</li>
	<li>Clean the subject&#39;s abdomen and lower back with a towel or baby wipes.</li>
	<li>Pack up all the equipment and store the electrode patches and grounding electrodes for cleaning.</li>
	<li>Clean the electrode patches and grounding electrodes in lukewarm water with dish soap in the cleaning room. Disinfect them with germicidal wipes.</li>
	<li>Air-dry the patches and apply double-sided mounting tape to the patches and rulers for the next experiment.</li>
</ol>
4. Generation of the body-uterus geometry
<ol>
	<li>Perform segmentation of the MRI data using a data analysis software application. 
	NOTE: Here, Amira software was used
	<ol>
		<li>Launch the data analysis software and load the MRI DICOM data. Go to the Segmentation module and click New to create a new label. Click Edit &#62; Adjust the range to &#62; Data histogram to change the image contrast.</li>
		<li>In Sagittal View, choose the Brush tool, label the uterus boundaries of the MR images, fill in the regions, and add to the label file. Repeat this step every three to five slices.</li>
		<li>Select the segmented regions and click Selection &#62; Interpolate &#62; + to interpolate the segmentation of all the slices. This completes the segmentation of the uterine surface.</li>
		<li>Click New to create a new label file. Choose the Magic wand tool, place the masking threshold at the initial local minimum of the data histogram, and adjust it gradually until the entire body is highlighted in blue.</li>
		<li>Choose All slices, click on any blue region, and then click + to add the segmentation into the label file. Click Segmentation &#62; Fill holes &#62; All slices &#62; + to fix the holes.</li>
		<li>Go to the Segmentation module and click New to create a new label for the uterus. Manually segment the uterus on the MR images. Use Interpolate if needed.</li>
		<li>In the Project module, generate the surface data from the label files of the uterus and body surface.</li>
		<li>Choose a surface file, reduce the number of faces in Simplification Editor &#62; Simplify by 50%, and click Simplify now. Choose the simplified surface file and right-click Smooth Surface (iteration = 20, lambda = 0.6) &#62; Apply. Then, choose the smoothed surface file and right-click Remesh Surface (% 100) &#62; Apply to re-mesh to each surface.</li>
		<li>Continue to perform step 4.1.7 until the body surface comprises approximately 18,000 faces and the uterine surface comprises roughly 640 faces.</li>
		<li>Click File &#62; Export Data As &#62; STL ascii to save the two surfaces in stereolithography (STL) format.</li>
	</ol>
	</li>
	<li>Perform post-processing of the optical 3D scan data.
	<ol>
		<li>Load the optical 3D scanning file of the abdominal surface into Artec studio 12 professional.</li>
		<li>Select the target optical scan and duplicate the scan.</li>
		<li>Click Autopilot to start processing the selected scan.</li>
		<li>In the Model creation module, choose the scan quality (geometry, texture), object size, hole-filling method (watertight), etc., and click Next.</li>
		<li>In the Editor module, choose Lasso selection and erase the redundant regions.</li>
		<li>Click Next to create an automatic refinement of the scan.</li>
		<li>Click Editor &#62; Lasso selection to remove unnecessary regions.</li>
		<li>Click File &#62; Export Meshes &#62; STL File Format to save the surface in STL format.</li>
	</ol>
	</li>
	<li>Align the optical 3D scan data to the MRI body surface and generate the body-uterus geometry with the tool command language (TCL) scripts in the data analysis software.
	<ol>
		<li>Load the STL format surfaces generated from steps 4.1 and 4.2 with pre-programmed data analysis software project.</li>
		<li>Run the prompt TCL command line to prepare data analysis software objects for rigid alignment for the abdominal surface.</li>
		<li>Click Two Viewers (horizontal) and display the optical scan torso surface in the left viewer and the MRI body surface in the right viewer.</li>
		<li>Place five or six landmarks on both surfaces and run the prompt TCL command line to apply the rigid alignment.</li>
		<li>Repeat steps 4.3.2-4.3.4 for the back surface.</li>
		<li>Click Single Viewer and display the rigid-aligned optical-scanned body surface in the viewer.</li>
		<li>Run the prompt TCL command line to prepare data analysis software objects for non-rigid alignment.</li>
		<li>Click Project &#62; Create Object &#62; Landmarks and add landmarks at the electrode locations on the optical scanned body surface.</li>
		<li>Click File &#62; Export Data As &#62; LandmarkSet Ascii to export the landmark files for non-rigid alignment.</li>
		<li>Run the Geometry module in the EMMI data processing pipeline to perform a non-rigid alignment.</li>
		<li>Execute the TCL command line prompt to import the automatically aligned electrode landmarks and improve the precision of the electrode landmarks in reference to the notes and photos described in steps 2.3 and 3.3.</li>
		<li>Click File &#62; Export Data As &#62; LandmarkSet Ascii to export landmark files for the electrode locations.</li>
		<li>Run the EMMI data processing pipeline-geometry module to load the STL files and LandmarkSet files, and generate the body-uterus geometry in MAT format.</li>
	</ol>
	</li>
</ol>
5. Electrical signal preprocessing
<ol>
	<li>Run the EMMI data processing pipeline-EMG preprocessing module to load the BDF file and process the raw electrical signal with a Butterworth filter with the frequency band 0.34-1 Hz.</li>
	<li>Run the EMMI data processing pipeline- artifacts detection module to automatically detect the local and global artifacts in the filtered signal.</li>
</ol>
6. Uterine electrical signal reconstruction and characterization
<ol>
	<li>Run the EMMI data processing pipeline-reconstruction module to load the body-uterus geometry and preprocessed electrical signal data and compute the electrical signals on the uterine surface.</li>
	<li>Run the EMMI data processing pipeline-EMG signal analysis module to automatically detect the onsets and offsets of each EMG burst on the uterine surface.</li>
	<li>Choose the observation window on the cluster figure overlay to compute the activation time at each uterine location for every observation window and create an isochrone for each observation window.</li>
</ol>

Visualizing Uterine Contractions by EMMI for Improved Labor Management

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G., Agostini, V., Knaflitz, M., Bonato, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Applications+of+EMG+in+clinical+and+sports+medicine.">Applications of EMG in clinical and sports medicine.</a> Intech Open. , 117-130 (2012).</li><li>Lange, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Velocity+and+directionality+of+the+electrohysterographic+signal+propagation.">Velocity and directionality of the electrohysterographic signal propagation.</a> PloS One. 9 (1), e86775 (2014).</li><li>Planes, J. G., Morucci, J. P., Grandjean, H., Favretto, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=External+recording+and+processing+of+fast+electrical+activity+of+the+uterus+in+human+parturition.">External recording and processing of fast electrical activity of the uterus in human parturition.</a> Medical &amp; Biological Engineering &amp; Computing. 22 (6), 585-591 (1984).</li><li>Mikkelsen, E., Johansen, P., Fuglsang-Frederiksen, A., Uldbjerg, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Electrohysterography+of+labor+contractions:+propagation+velocity+and+direction.">Electrohysterography of labor contractions: propagation velocity and direction.</a> Acta Obstetricia et Gynecologica Scandinavica. 92 (9), 1070-1078 (2013).</li><li>Young, R. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+uterine+pacemaker+of+labor.">The uterine pacemaker of labor.</a> Best Practice &amp; Research. Clinical Obstetrics &amp; Gynaecology. 52, 68-87 (2018).</li><li>Goldenberg, R. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+management+of+preterm+labor.">The management of preterm labor.</a> Obstetrics and Gynecology. 100 (5), 1020-1037 (2002).</li><li>Rubens, C. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prevention+of+preterm+birth:+harnessing+science+to+address+the+global+epidemic.">Prevention of preterm birth: harnessing science to address the global epidemic.</a> Science Translational Medicine. 6 (262), 5 (2014).</li><li>Shi, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Screen-printed+soft+capacitive+sensors+for+spatial+mapping+of+both+positive+and+negative+pressures.">Screen-printed soft capacitive sensors for spatial mapping of both positive and negative pressures.</a> Advanced Functional Materials. 29 (23), 1809116 (2019).</li><li>Lo, L. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+inkjet-printed+PEDOT:PSS-based+stretchable+conductor+for+wearable+health+monitoring+device+applications.">An inkjet-printed PEDOT:PSS-based stretchable conductor for wearable health monitoring device applications.</a> ACS Applied Materials and Interfaces. 13 (18), 21693-21702 (2021).</li><li>Lo, L. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stretchable+sponge+electrodes+for+long-term+and+motion-artifact-tolerant+recording+of+high-quality+electrophysiologic+signals.">Stretchable sponge electrodes for long-term and motion-artifact-tolerant recording of high-quality electrophysiologic signals.</a> ACS Nano. 16 (8), 11792-11801 (2022).</li></ol>

Y.W., A.G.C., P.C., and A.L.S. submitted US Provisional Application No. 62/642,389 titled "System and Method for Noninvasive Electromyometrial Imaging (EMMI)" for the EMMI technology described in this work. Y.W. serves as a scientific consultant for Medtronic and has NIH research funding.

Electromyography has indicated that the frequency and amplitude of uterine electrical signals alter during the gestational period2,16,25. Several studies have explored the uterine propagation patterns of uterine contractions in patients in active labor10,17,26,27,28. ...

Clinically, uterine contractions are measured either by using an intrauterine pressure catheter or by performing tocodynamometry1. In the research setting, uterine contractions can be measured by electromyography (EMG), in which electrodes are placed on the abdominal surface to measure the bioelectrical signals generated by the myometrium2,3,4,5,6,7. One can use the magnitude, frequency, and propagation features of electrical bursts8,9,10,11,12&#160;derived from EMG to predict the onset of labor in the preterm. However, in conventional EMG, the electrical activity of uterine contractions is measured from only a tiny region of the abdominal surface with a limited number of electrodes (two13 and four7,14,15,16 at the center of the abdominal surface, and 6417 at the lower abdominal surface). Furthermore, conventional EMG is limited in its ability to study the mechanisms of labor, as it reflects only the averaged electrical activities from the entire uterus and cannot detect the specific electrical initiation and activation patterns on the uterine surface during contractions.
A recent development called electromyometrial imaging (EMMI) has been introduced to overcome the shortcomings of conventional EMG. EMMI enables noninvasive imaging of the entire myometrium&#39;s electrical activation sequence during uterine contractions18,19,20,21. To acquire the body-uterus geometry, EMMI uses T1-weighted magnetic resonance imaging (MRI)22,23,24, which has been widely used for pregnant women during their second and third trimesters. Next, up to 192 pin-type electrodes placed on the body surface are used to collect electrical recordings from the myometrium. Finally, the EMMI data processing pipeline is performed to combine the body-uterus geometry with the electrical data to reconstruct and image electrical activities on the uterine surface21. EMMI can accurately locate the initiation of uterine contractions and image propagation patterns during uterine contractions in three dimensions. This article aims to present the EMMI procedures and demonstrate the representative results obtained from pregnant women.

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electromyometrial imaging of uterine contractions in pregnant women

During normal pregnancy, the uterine smooth muscle, the myometrium, begins to have weak, uncoordinated contractions at late gestation to help the cervix remodel. In labor, the myometrium has strong, coordinated contractions to deliver the fetus. Various methods have been developed to monitor uterine contraction patterns to predict labor onset. However, the current techniques have limited spatial coverage and specificity. We developed electromyometrial imaging (EMMI) to noninvasively map uterine electrical activity onto the three-dimensional uterine surface during contractions. The first step in EMMI is to use T1-weighted magnetic resonance imaging to acquire the subject-specific body-uterus geometry. Next, up to 192 pin-type electrodes placed on the body surface are used to collect electrical recordings from the myometrium. Finally, the EMMI data processing pipeline is performed to combine the body-uterus geometry with body surface electrical data to reconstruct and image uterine electrical activities on the uterine surface. EMMI can safely and noninvasively image, identify, and measure early activation regions and propagation patterns across the entire uterus in three dimensions.

Representative MRI-safe patches and electrode patches are shown in Figure 1B,C, created from the template shown in Figure 1A. The bioelectricity mapping hardware is shown in Figure 1C, with the connections of each component marked in detail. Figure 2 shows the entire EMMI procedure, including an MRI scan of the subject wearing MRI patches (Figure 2A), 3D op...

Watch this Scientific Journal Video about Advancing Labor Management Through Electromyometrial Imaging for Understanding Uterine Contractions at JoVE.com

Author Spotlight: Advancing Labor Management Through Electromyometrial Imaging for Understanding Uterine Contractions 

We present a protocol for conducting electromyometrial imaging (EMMI), including the following procedures: multiple electromyography electrode sensor recordings from the body surface, magnetic resonance imaging, and uterine electrical signal reconstruction.

Electromyometrial Imaging of Uterine Contractions in Pregnant Women

During normal pregnancy, the uterine smooth muscle, the myometrium, begins to have weak, uncoordinated contractions at late gestation to help the cervix ...

electromyometrial-imaging-of-uterine-contractions-in-pregnant-women

Research

JoVE Journal

Bioengineering

1.1K Views.  Washington University. Ons onderzoek is gericht op de ontwikkeling van een niet-invasieve beeldvormingstechnologie, elektromyometriale beeldvorming genaamd, om real-time 3D-beelden van samentrekkingen van de baarmoeder bij mensen te genereren. Ons werk zal een dieper begrip creëren van het mechanisme van samentrekkingen van de baarmoeder tijdens menselijke arbeid. We streven ernaar om belangrijke vragen te beantwoorden op het gebied van menselijk arbeidsbeheer en de voorspelling van vroeggeboorte en de arbeidsstop...

Video: Auteur in de schijnwerpers: het bevorderen van arbeidsbeheer door middel van elektromyometriale beeldvorming voor het begrijpen van samentrekkingen van de baarmoeder 

Three-dimensional Optical-resolution Photoacoustic Microscopy

Optical microscopy, providing valuable insights at the cellular and organelle levels, has been widely recognized as an enabling biomedical technology. As the mainstays of in vivo three-dimensional (3-D) optical microscopy, single-/multi-photon fluorescence microscopy and optical coherence tomography (OCT) have demonstrated their extraordinary sensitivities to fluorescence and optical scattering contrasts, respectively. However, the optical absorption contrast of biological tissues, which encodes essential physiological/pathological information, has not yet been assessable. 
The emergence of biomedical photoacoustics has led to a new branch of optical microscopy optical-resolution photoacoustic microscopy (OR-PAM)1, where the optical irradiation is focused to the diffraction limit to achieve cellular1 or even subcellular2 level lateral resolution. As a valuable complement to existing optical microscopy technologies, OR-PAM brings in at least two novelties. First and most importantly, OR-PAM detects optical absorption contrasts with extraordinary sensitivity (i.e., 100%). Combining OR-PAM with fluorescence microscopy3 or with optical-scattering-based OCT4 (or with both) provides comprehensive optical properties of biological tissues. Second, OR-PAM encodes optical absorption into acoustic waves, in contrast to the pure optical processes in fluorescence microscopy and OCT, and provides background-free detection. The acoustic detection in OR-PAM mitigates the impacts of optical scattering on signal degradation and naturally eliminates possible interferences (i.e., crosstalks) between excitation and detection, which is a common problem in fluorescence microscopy due to the overlap between the excitation and fluorescence spectra. 
Unique for optical absorption imaging, OR-PAM has demonstrated broad biomedical applications since its invention, including, but not limited to, neurology5, 6, ophthalmology7, 8, vascular biology9, and dermatology10. In this video, we teach the system configuration and alignment of OR-PAM as well as the experimental procedures for in vivo functional microvascular imaging.

Optical-resolution photoacoustic microscopy (OR-PAM) is an emerging technology capable of imaging optical absorption contrasts in vivo with cellular resolution and sensitivity. Here, we provide a visualized instruction on the experimental protocols of OR-PAM, including system configuration, system alignment, typical in vivo experimental procedures, and functional imaging schemes.

Optical microscopy, providing valuable insights at the cellular and organelle levels, has been widely recognized as an enabling biomedical technology. As ...

Murine Fetal Echocardiography

Transgenic mice displaying abnormalities in cardiac development and function represent a powerful tool for the understanding the molecular mechanisms underlying both normal cardiovascular function and the pathophysiological basis of human cardiovascular disease. Fetal and perinatal death is a common feature when studying genetic alterations affecting cardiac development 1-3. In order to study the role of genetic or pharmacologic alterations in the early development of cardiac function, ultrasound imaging of the live fetus has become an important tool for early recognition of abnormalities and longitudinal follow-up. Noninvasive ultrasound imaging is an ideal method for detecting and studying congenital malformations and the impact on cardiac function prior to death 4. It allows early recognition of abnormalities in the living fetus and the progression of disease can be followed in utero with longitudinal studies 5,6. Until recently, imaging of fetal mouse hearts frequently involved invasive methods. The fetus had to be sacrificed to perform magnetic resonance microscopy and electron microscopy or surgically delivered for transillumination microscopy. An application of high-frequency probes with conventional 2-D and pulsed-wave Doppler imaging has been shown to provide measurements of cardiac contraction and heart rates during embryonic development with databases of normal developmental changes now available 6-10. M-mode imaging further provides important functional data, although, the proper imaging planes are often difficult to obtain. High-frequency ultrasound imaging of the fetus has improved 2-D resolution and can provide excellent information on the early development of cardiac structures 11.

Fetal and perinatal death is a common feature when studying genetic alterations affecting cardiac development. High-frequency ultrasound imaging has improved 2-D resolution and can provide excellent information on early cardiac development and is an ideal method to detect the impact on cardiac structure and function prior to death.

Transgenic mice displaying abnormalities in  cardiac development and function represent a powerful tool for the understanding  the molecular mechanisms ...

Medicine

A Novel Use of Three-dimensional High-frequency Ultrasonography for Early Pregnancy Characterization in the Mouse

High-frequency ultrasonography (HFUS) is a common method to non-invasively monitor the real-time development of the human fetus in utero. The mouse is routinely used as an in vivo model to study embryo implantation and pregnancy progression. Unfortunately, such murine studies require pregnancy interruption to enable follow-up phenotypic analysis. To address this issue, we used three-dimensional (3-D) reconstruction of HFUS imaging data for early detection and characterization of murine embryo implantation sites and their individual developmental progression in utero. Combining HFUS imaging with 3-D reconstruction and modeling, we were able to accurately quantify embryo implantation site number as well as monitor developmental progression in pregnant C57BL6J/129S mice from 5.5 days post coitus (d.p.c.) through to 9.5 d.p.c. with the use of a transducer. Measurements included: number, location, and volume of implantation sites as well as inter-implantation site spacing; embryo viability was assessed by cardiac activity monitoring. In the immediate post-implantation period (5.5 to 8.5 d.p.c.), 3-D reconstruction of the gravid uterus in both mesh and solid overlay format enabled visual representation of the developing pregnancies within each uterine horn. As genetically engineered mice continue to be used to characterize female reproductive phenotypes derived from uterine dysfunction, this method offers a new approach to detect, quantify, and characterize early implantation events in vivo. This novel use of 3-D HFUS imaging demonstrates the ability to successfully detect, visualize, and characterize embryo-implantation sites during early murine pregnancy in a non-invasive manner. The technology offers a significant improvement over current methods, which rely on the interruption of pregnancies for gross tissue and histopathologic characterization. Here we use a video and text format to describe how to successfully perform ultrasounds of early murine pregnancy to generate reliable and reproducible data with reconstruction of the uterine form in mesh and solid 3-D images.

Mice are widely used to study gestational biology. However, pregnancy termination is required for such studies which precludes longitudinal investigations and necessitates the use of large numbers of animals. Therefore, we describe a non-invasive technique of high-frequency ultrasonography for early detection and monitoring of post-implantation events in the pregnant mouse.

High-frequency ultrasonography (HFUS) is a common method to non-invasively monitor the real-time development of the human fetus in utero. The mouse is ...

Developmental Biology

A Novel Application of Musculoskeletal Ultrasound Imaging

Ultrasound is an attractive modality for imaging muscle and tendon motion during dynamic tasks and can provide a complementary methodological approach for biomechanical studies in a clinical or laboratory setting. Towards this goal, methods for quantification of muscle kinematics from ultrasound imagery are being developed based on image processing. The temporal resolution of these methods is typically not sufficient for highly dynamic tasks, such as drop-landing. We propose a new approach that utilizes a Doppler method for quantifying muscle kinematics. We have developed a novel vector tissue Doppler imaging (vTDI) technique that can be used to measure musculoskeletal contraction velocity, strain and strain rate with sub-millisecond temporal resolution during dynamic activities using ultrasound. The goal of this preliminary study was to investigate the repeatability and potential applicability of the vTDI technique in measuring musculoskeletal velocities during a drop-landing task, in healthy subjects. The vTDI measurements can be performed concurrently with other biomechanical techniques, such as 3D motion capture for joint kinematics and kinetics, electromyography for timing of muscle activation and force plates for ground reaction force. Integration of these complementary techniques could lead to a better understanding of dynamic muscle function and dysfunction underlying the pathogenesis and pathophysiology of musculoskeletal disorders.

We describe a new ultrasound-based vector tissue Doppler imaging technique to measure muscle contraction velocity, strain and strain rate with sub-millisecond temporal resolution during dynamic activities. This approach provides complementary measurements of dynamic muscle function and could lead to a better understanding of mechanisms underlying musculoskeletal disorders.

Ultrasound is an attractive modality for imaging muscle and tendon  motion during dynamic tasks and can provide a complementary methodological  approach ...

In utero Measurement of Heart Rate in Mouse by Noninvasive M-mode Echocardiography

Congenital heart disease (CHD) is the most frequent noninfectious cause of death at birth. The incidence of CHD ranges from 4 to 50/1,000 births (Disease and injury regional estimates, World Health Organization, 2004). Surgeries that often compromise the quality of life are required to correct heart defects, reminding us of the importance of finding the causes of CHD. Mutant mouse models and live imaging technology have become essential tools to study the etiology of this disease. Although advanced methods allow live imaging of abnormal hearts in embryos, the physiological and hemodynamic states of the latter are often compromised due to surgical and/or lengthy procedures. Noninvasive ultrasound imaging, however, can be used without surgically exposing the embryos, thereby maintaining their physiology. Herein, we use simple M-mode ultrasound to assess heart rates of embryos at E18.5 in utero. The detection of abnormal heart rates is indeed a good indicator of dysfunction of the heart and thus constitutes a first step in the identification of developmental defects that may lead to heart failure.

In utero Measurement of Heart Rate in Mouse by Noninvasive M-mode Echocardiography

Ultra-high frequency ultrasound is a powerful live imaging tool to examine cardiac abnormalities in small animals. Its noninvasiveness allows maintaining the physiologic state of embryos. Herein, we show the use of M-mode ultrasound to measure the heart rates of embryos at E18.5 in utero.

Congenital heart disease (CHD) is the most frequent noninfectious cause of death at birth. The incidence of CHD ranges from 4 to 50/1,000 births (Disease ...

Is My Mouse Pregnant? High-Frequency Ultrasound Assessment

The mouse is the mammalian animal model of choice for many human diseases and biological processes. Developmental biology often requires staged-pregnant mice to determine evolving processes at various timepoints. Moreover, optimal and efficient breeding of model mice requires an assessment of timed pregnancies. Most commonly, mice are mated overnight, and the presence of a vaginal plug is determined; however, the positive predictive value of this technique is suboptimal, and one needs to wait to know if the mouse is truly pregnant. High-resolution ultrasound biomicroscopy is an effective and efficient tool for imaging: 1) Whether a mouse is pregnant; 2) What gestational stage the mouse has reached; and 3) Whether there are intrauterine losses. In addition to the embryos and fetuses, the investigator must also recognize common artifacts in the abdominal cavity so as not to mistake these for a gravid uterus. This article provides a protocol for imaging along with illustrative examples.

High-resolution ultrasound can help streamline experiments requiring timed-pregnant mice by determining the state of pregnancy, gestational age, and pregnancy losses. Presented here is a protocol to illustrate methods to assess mouse pregnancies as well as potential pitfalls (image artifacts) that may mimic pregnancy.

The mouse is the mammalian animal model of choice for many human diseases and biological processes. Developmental biology often requires staged-pregnant ...

Intrauterine Telemetry to Measure Mouse Contractile Pressure In Vivo

A complex integration of molecular and electrical signals is needed to transform a quiescent uterus into a contractile organ at the end of pregnancy. Despite the discovery of key regulators of uterine contractility, this process is still not fully understood. Transgenic mice provide an ideal model in which to study parturition. Previously, the only method to study uterine contractility in the mouse was ex vivo isometric tension recordings, which are suboptimal for several reasons. The uterus must be removed from its physiological environment, a limited time course of investigation is possible, and the mice must be sacrificed. The recent development of radiometric telemetry has allowed for longitudinal, real-time measurements of in vivo intrauterine pressure in mice. Here, the implantation of an intrauterine telemeter to measure pressure changes in the mouse uterus from mid-pregnancy until delivery is described. By comparing differences in pressures between wild type and transgenic mice, the physiological impact of a gene of interest can be elucidated. This technique should expedite the development of therapeutics used to treat myometrial disorders during pregnancy, including preterm labor.

Intrauterine Telemetry to Measure Mouse Contractile Pressure In Vivo

This manuscript provides a protocol for implanting telemeters in the mouse for the purpose of measuring intrauterine pressures during pregnancy.

A complex integration of molecular and electrical signals is needed to transform a quiescent uterus into a contractile organ at the end of pregnancy. ...

Contractility Measurements of Human Uterine Smooth Muscle to Aid Drug Development

Discovery and characterization of novel pharmaceutical compounds or biochemical probes rely on robust and physiologically relevant assay systems. We describe methods to measure ex vivo myometrium contractility. This assay can be used to investigate factors and molecules involved in the modulation of myometrial contraction and to determine their excitatory or inhibitory actions, and hence their therapeutic potential in vivo. Biopsies are obtained from women undergoing cesarean section delivery with informed consent. Fine strips of myometrium are dissected, clipped and attached to a force transducer within 1 mL organ baths superfused with physiological saline solution at 37 &#176;C. Strips develop spontaneous contractions within 2&#8211;3 h under set tension and remain stable for many hours (&#62;6 h). Strips can also be stimulated to contract such as by the endogenous hormones, oxytocin and vasopressin, which cause concentration-dependent modulation of contraction frequency, force and duration, to more closely resemble contractions in labor. Hence, the effect of known and novel drug leads can be tested on spontaneous and agonist-induced contractions.
This protocol specifically details how this assay can be used to determine the potency of known and novel agents by measuring their effects on various parameters of human myometrial contraction. We use the oxytocin- and V1a receptor antagonists, atosiban and SR49059 as examples of known compounds which inhibit oxytocin- and vasopressin-induced contractions, and demonstrate how this method can be used to complement and validate pharmacological data obtained from cell-based assays to aid drug development. The effects of novel agonists in comparison to oxytocin and vasopressin can also be characterized. Whilst we use the example of the oxytocin/ vasopressin system, this method can also be used to study other receptors and ion channels that play a role in uterine contraction and relaxation to advance the understanding of human uterine physiology and pathophysiology.

This article describes experimental protocols to study ex vivo contractions of human myometrium and their application in drug discovery. This technique is used to improve the understanding of myometrial physiology and pathophysiology as well as to validate pharmacological data from novel research probes or drug leads.

Discovery and characterization of novel pharmaceutical compounds or biochemical probes rely on robust and physiologically relevant assay systems. We ...

Ex Vivo Method for Assessing the Mouse Reproductive Tract Spontaneous Motility and a MATLAB-based Uterus Motion Tracking Algorithm for Data Analysis

Dysmenorrhea, or painful cramping, is the most common symptom associated with menses in females and its severity can hinder women&#39;s everyday lives. Here, we present an easy and inexpensive method that would be instrumental for testing new drugs decreasing uterine contractility. This method utilizes the unique ability of the entire mouse reproductive tract to exhibit spontaneous motility when maintained ex vivo in a Petri dish containing oxygenated Krebs buffer. This spontaneous motility resembles the wave-like myometrial activity of the human uterus, referred to as endometrial waves. To demonstrate the effectiveness of the method, we employed a well-known uterine relaxant drug, epinephrine. We demonstrate that the spontaneous motility of the entire mouse reproductive tract can be quickly and reversibly inhibited by 1 &#181;M epinephrine in this Petri dish model. Documenting the changes of uterine motility can be easily done using an ordinary smart phone or a sophisticated digital camera. We developed a MATLAB-based algorithm allowing motion tracking to quantify spontaneous uterine motility changes by measuring the rate of uterine horn movements. A major advantage of this ex vivo approach is that the reproductive tract remains intact throughout the entire experiment, preserving all intrinsic intrauterine cellular interactions. The major limitation of this approach is that up to 10-20% of uteri may exhibit no spontaneous motility. Thus far, this is the first quantitative ex vivo method for assessing spontaneous uterine motility in a Petri dish model.

Uterine contractions are important for the well-being of females. However, pathologically increased contractility may result in dysmenorrhea, especially in younger females. Here, we describe a simple ex vivo preparation allowing quick assessment of the efficacy of smooth muscle relaxants that may be used for treating dysmenorrhea.

Dysmenorrhea, or painful cramping, is the most common symptom associated with menses in females and its severity can hinder women&#39;s everyday lives. ...

Biology

High-frequency Ultrasonography Based Early Pregnancy Characterization: A Technique to Study Embryo Implantation and Pregnancy Progression in Pregnant Murine Model

Begin with preparing the ultrasound machine. Turn on the transducer and then attach the 3D motor stage to the transducer. Next, attach the probe to the transducer clamp. Now, position the mouse supine on the monitoring platform. Provide it anesthetic via nose cone and gently tape all of its paws to the heart rate monitoring pads on the platform.
Next, rub about 1 or 2 milliliters of ultrasound transmission gel onto the abdomen. Then, position the ultrasound probe on the lower abdomen using the manual motor stage. Using the ultrasound, locate the bladder, which should appear as a fluid-filled dark circle just cephalad to the vaginal opening.
Once the bladder is located, move the probe very slowly cephalad to visualize the pregnant uterus, which should appear as a cylindrical shape with round areas at pregnancy sites. This can be described as looking like pearls on a chain. Now, proceed with 2D imaging.
Once the pregnant uterus has been identified, begin at the pregnancy site closest to the bladder and slowly and sequentially move cephalad to determine location of all the pregnancy sites. Save the image. If the kidney, spleen, or liver can be seen, then the scan is too far cephalad. Reposition the probe closer to the bladder and save the image.
Next, image the contralateral uterine horn in the same manner. Freeze the image when the ultrasound frame is at the center of the pregnancy or implantation site and save the image for analysis. Now or later, use the saved images to measure implantation positions using the hyperechoic decidualization reaction as a marker.
Manually click on the &#34;measure&#34; tool and click on the location of an implantation site. Then, drag the cursor to the next implantation site and click again to draw a line. The software then reports the length of the line. After all the implantation sites are measured, use the same technique and proceed to measure the gestational sac size and the fetal pole size.

Electromyometrial Imaging of Uterine Contractions in Pregnant Women

Samenvatting

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