Development and growth of fasciae in and around the esophageal hiatus: a histological study using human fetuses

Development and growth of fasciae in and around the esophageal hiatus: a histological study using human fetuses | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Development and growth of fasciae in and around the esophageal hiatus: a histological study using human fetuses Ai Hirano-Kawamoto, Yohei Honkura, Gen Murakami, Shin-ichi Abe, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4540171/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Dec, 2024 Read the published version in Surgical and Radiologic Anatomy → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose An entire fascial configuration at the esophageal hiatus might not be demonstrated histologically. According to observations of human fetus histology, the aim of this study was to consider which factor is likely to make the individual variation in adults. Methods We observed frontal histological sections containing the esophageal hiatus from 12 midterm fetuses at 12–16 weeks (crown-rump length:CRL, 85–137 mm) and 10 near-term fetuses at 26–30 weeks (CRL, 214–250 mm). Results At midterm, the inferior fascia of diaphragm turned upward to join the adventitia of the esophagus, but the superior fascia was underdeveloped. At near-term, both the inferior and superior fasciae often joined the adventitia in the left side but not in the right side. Fascial development advanced in the left side of the hiatus. The pleural recess as well as the upward protruding right crus of diaphragm was likely to disturb the fascial connection especially in the superior side. The foregut-midgut junction, suggested with cytokeratin 5/6 immunostaining, was located in the hiatus. Conclusion The phreno-esophageal membrane, interposed between the superior and inferior fasciae of diaphragm and the adventitia of esophagus, seemed to be established first in the left side at near-term. The delayed growth in the right side might connect to individual differences in adults. Esophageal hiatus diaphragm fascia phreno-esophageal membrane human fetus Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction A structure of the esophageal hiatus is critically important for surgery of gastroesophageal reflux disease and severe hiatal hernia. The hiatus is lined by the phreno-esophageal membrane or ligament (PEM) according to the macroscopic observation [ 1 – 8 ], but lots of variations were reported in the fascial configuration (Fig. 1 ): in short, the superior and inferior fasciae of diaphragm continued to the upper and lower leaves of PEM, respectively, and these leaves joined the adventitia of esophagus. Most of previous histological studies of the PEM focused on striated muscle and elastic fibers in normal development [ 9 ] and hiatal hernia [ 8 ]. Daniels [ 10 ] and Botros et al. [ 11 ] seemed to be 2 limited studies showing histology of a junction between the inferior fascia of diaphragm and the adventitia of esophagus. However, Daniels used tissue materials after bad fixation and Botros et al. demonstrated a very small area at the diaphragmatic edge at the hiatus. Fasciae around viscera are more clearly identified in histology of fetuses than adults because of no inflammation and degeneration [ 12 – 14 ]. Consequently, to consider which factor is likely to make the individual variation, we aimed to demonstrate the entire structure of the PEM in mid- and late-stage human fetuses. In addition, whether an esophageal epithelium in the hiatus is derived from the foregut or midgut was also our interest. Small molecule cytokeratin is known to be a marker of the foregut-derived structures [ 15 , 16 ]. Materials and Methods The study was performed in accordance with the provisions of the Declaration of Helsinki 1995 (as revised in 2013). We observed histological sections from 12 midterm at 12–16 weeks of GA (crown-rump length or CRL, 85–137 mm) and 10 near-term fetuses at 26–30 weeks of GA (CRL, 214–250 mm). These paraffin-embedded sections were part of the large collection kept at the Department of Anatomy of the Universidad Complutense, Madrid, and the resulting embryos were obtained from miscarriages and ectopic pregnancies from the Department of Obstetrics of the University. The sectional planes were all frontal. Almost all sections were stained with hematoxylin and eosin (HE), azan or elastica-Masson (a variation of Masson-Goldner staining) and a few were applied to immunohistochemistry using monoclonal anti-human cytokeratin 5/6 (Dako, Glostrup, Denmark). This study was approved by the Ethics Committees of Complutense University (B08/374) and Tokyo Dental College (No. 932). Most photographs of histology were taken with a Nikon Eclipse 80, while some photos were prepared using a high-quality trans-illumination scanner Epson GTX970 at a magnification under x0.5 objective. Results Topographical anatomy in the present frontal sections Figure 2 demonstrate four sections from two specimens at the ultra-low magnification. Sections of midterm specimens contain almost entire thoracoabdominal region, whereas near-term sections missed the anterior or posterior half because the trunk is too thick to attach the microtome. The liver extended in the left and right sides of the esophagus. To reduce the size of paraffin block at near-term, lateral tissues including the spleen were usually removed. We identified the left-right orientation according to the stomach. In all seven figures, the left-hand side of each panel corresponds to the left side of the body. Observations of midterm specimens At and near the hiatus, the adventitia of the esophagus was identified as a thick membrane along the circular muscle layer of the esophagus since the longitudinal muscle layer was still underdeveloped (Figs. 3 and 4 ). Development of fascial structures appeared to advance in the left side. The left side morphology was characterized by 1) the inferior fascia turning upward to extend along the margin of diaphragm (Fig. 4 B); 2) the inferior fascia bundled with the adventitia of the esophagus at the next step (Fig. 3BE). Notably, these fasciae were usually underdeveloped in the right side (10 of the 12 specimens; Figs. 3CF and 4CF). A foregut-midgut junction, suggested by cytokeratin 5/6 immunoreactivity (Fig. 5 E), was located at the upper half of the hiatus. Observations of near-term specimens Both the inferior and superior fasciae of diaphragm often joined the adventitia of the esophagus in the left side of the hiatus (6 of the 10 specimens; Figs. 5 C and 6 C). In the residual 4 specimens, the left superior fascia was unclear (Fig. 7 B). In the right side, we almost always found the connection between the inferior fascia and adventitia (Figs. 5 D and 6 D), but the right superior facia rarely met the adventitia (Fig. 7 C). Fragmented striated muscle fibers of diaphragm were sometimes seen at and near hiatus (Fig. 6 D insert). Distrurbing factors of the developing fascial structure At midterm as well as near-term, the right fascial connection between the esophagus and diaphragm was delayed and disturbed by 1) a transient pleural recess (Figs. 4 C, 5 A and 7 C) and 2) up-standing muscle fibers at the right edge or crus of diaphragm (Figs. 4 F, 5 D, 6 D and 7 C). The right crus of diaphragm, that was pushed upward by the growing liver and right adrenal, is emphasized in a schematic representation of the present observations (Fig. 6 D). Discussion The present study might be the first photographic demonstration of the entire fascial configuration at and around the esophageal hiatus. Even at near-tern, the PEM still corresponded to a growing complex of junctions between the esophageal adventitia and the fasciae of diaphragm. The inferior fascia developed earlier than the superior one (Fig. 6 D): this was different from Botros et al. [ 11 ]. Notably, the development and growth of fasciae advanced in the left side of the hiatus (Fig. 6 D). The present configuration in the left side was consistent with Botha who emphasized a simple configuration of the infants’ hiatus [ 17 ]. In the abdominal approach in infants, surgeons might find an easy and clear separation of the esophagus from the diaphragm after a cutting of the fascial junction between the inferior fascia and adventitia. In the right side of the hiatus, the transient pleural recess as well as the upstanding muscle fibers of the right diaphragmatic crus seemed to disturb, break or modify a connection between the superior fascia and adventitia. Therefore, variations might occur especially in the right side: this was contrast to Kremer et al [ 5 ]. (Fig. 1 ) who considered a fascial variation occurring symmetrically. The pleural recess was likely to originate from irregular protrusions during the cavitation process [ 18 ]. Botros et al. reported that, possibly due to muscle fiber degeneration, the diaphragm becomes separated from the esophagus at and until 20 weeks [ 11 ]. We also found fragmented muscle fibers. We speculated that the regression of diaphragm is synchronized with a migration of a foregut-midgut junction. Further study is necessary to evaluate the migration. Conclusion The phreno-esophageal membrane, interposed between the superior and inferior fasciae of diaphragm and the adventitia of esophagus, seemed to be established first in the left side at near-term. The delayed growth in the right side might connect to individual differences in adults. Declarations Author contributions AHK: Staining of specimens, Manuscript writing, YH: Preparing the figures, GM: Project development, Observation of specimens, Manuscript writing, SA: Observation of specimens, manuscript editing, JFR: Preparing of specimens, YK: Staining of specimens, Manuscript editing. Funding No funding was received to assist with the preparation of this manuscript. Conflict of Interest All authors declare that they have no conflict of interest. Ethical approval The study was performed in accordance with the provisions of the Declaration of Helsinki 1995 (as revised in 2013). Approval was granted by the Ethics Committees of Complutense University (B08/374) and Tokyo Dental College (No. 932). References Bombeck CT, Dillard DH, Nyhus LM (1966) Muscular anatomy of the gastroesophageal junction and role of phrenoesophageal ligament; autopsy study of sphincter mechanism. Ann Surg 164:643–654 Strasberg SM, Silver MD (1968) The phrenoesophageal membranne. Surg Forum 19:294–296 Liebermann-Meffert D (1981) [Surgical anatomy of the esophagogastric junction]. Helv Chir Acta 47:667–677 Groszek I, Matysiak WJ (1985) [Morphology of the phrenoesophageal membrane]. Gegenbaurs Morphol Jahrb 131:1–18 Kremer B, Menck J, Lierse W (1987) [Phrenico-esophageal membrane: anchoring of the terminal esophagus and cardia at the diaphragm]. Langenbecks Arch Chir 371:59–67. https://doi.org/10.1007/BF01259244 Kwok H, Marriz Y, Al-Ali S, Windsor JA (1999) Phrenoesophageal ligament re-visited. Clin Anat N Y N 12:164–170. https://doi.org/10.1002/(SICI)1098-2353(1999)12:33.0.CO;2-N Nakajima F, Murakami G, Ohyama S, et al (2001) Potential fascial dome made by the upper leaf of the phreno-esophageal membrane. Okajimas Folia Anat Jpn 77:201–209. https://doi.org/10.2535/ofaj1936.77.6_201 Apaydin N, Uz A, Evirgen O, et al (2008) The phrenico-esophageal ligament: an anatomical study. Surg Radiol Anat SRA 30:29–36. https://doi.org/10.1007/s00276-007-0279-0 Watanabe Y, Lister J (1993) Development of the human fetal phreno-esophageal membrane and its role in the anti-reflux mechanism. Surg Today 23:722–727. https://doi.org/10.1007/BF00311712 Daniels BT (1965) The phrenoesophageal membrane. Am J Surg 110:814–817. https://doi.org/10.1016/0002-9610(65)90130-3 Botros KG, El-Ayat AA, El-Naggar MM, State FA (1983) The development of the human phreno-oesophageal membrane. Acta Anat (Basel) 115:23–30. https://doi.org/10.1159/000145673 Kinugasa Y, Niikura H, Murakami G, et al (2008) Development of the human hypogastric nerve sheath with special reference to the topohistology between the nerve sheath and other prevertebral fascial structures. Clin Anat 21:558–567. https://doi.org/10.1002/ca.20654 Cho BH, Kimura W, Song CH, et al (2009) An investigation of the embryologic development of the fascia used as the basis for pancreaticoduodenal mobilization. J Hepatobiliary Pancreat Surg 16:824–831. https://doi.org/10.1007/s00534-009-0126-2 Kim JH, Kinugasa Y, Hwang SE, et al (2015) Denonvilliers’ fascia revisited. Surg Radiol Anat 37:187–197. https://doi.org/10.1007/s00276-014-1336-0 Henry JJ, Charlebois TS, Grainger RM (1993) Differential expression of type II cytokeratin mRNA defines early developmental boundaries within the ectoderm, mesoderm and endoderm during chick development. Rouxs Arch Dev Biol Off Organ EDBO 202:355–363. https://doi.org/10.1007/BF00188734 Lungova V, Verheyden JM, Herriges J, et al (2015) Ontogeny of the mouse vocal fold epithelium. Dev Biol 399:263–282. https://doi.org/10.1016/j.ydbio.2014.12.037 Botha GSM (1958) The Gastro-oesophageal Region in Infants. Arch Dis Child 33:78–94 Hayashi S, Kim JH, Jin Z-W, et al (2023) Cavitation processes in a space filled with loose mesenchymal tissues: a comparison between the retrosternal space and the middle ear tympanic cavity in human fetuses. Folia Morphol 82:332–338. https://doi.org/10.5603/FM.a2022.0026 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 02 Dec, 2024 Read the published version in Surgical and Radiologic Anatomy → Version 1 posted Reviews received at journal 12 Aug, 2024 Reviewers agreed at journal 10 Jul, 2024 Reviewers agreed at journal 23 Jun, 2024 Reviewers invited by journal 17 Jun, 2024 Editor assigned by journal 10 Jun, 2024 Submission checks completed at journal 10 Jun, 2024 First submitted to journal 06 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4540171","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":317983884,"identity":"269d1383-7d34-4a73-92db-e9b830d78409","order_by":0,"name":"Ai Hirano-Kawamoto","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYDACZjYQeYAHzPkAxGzspGhhnAHSwkzQGogWiHawRkJa+NvZEj/z1NyRMW8/e/Cxza9t8nzMDIwfPubg1iJxmO2wNM+xZzwyZ/KSjXP7bhu2MTMwS87chseaw+wN0jlsh3kkGHLMpHN7bjMCtbAx8+LRIn+Yvfl3zj+gFv43ZtKWPbftCWoxOMx2TDq3DahFAmgLw4/biQS1GB5mS7P+2wfS8sbYsLfhdnIbM2MzXr/InT9mfHPGt8P2Evw5hg9+/LltO7+9+eCHj/i8jwIY28BkA7HqQeAPKYpHwSgYBaNgpAAATgJLvZZQV74AAAAASUVORK5CYII=","orcid":"","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Ai","middleName":"","lastName":"Hirano-Kawamoto","suffix":""},{"id":317983885,"identity":"4606c4ac-9303-4610-9c82-4c976016c915","order_by":1,"name":"Yohei Honkura","email":"","orcid":"","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yohei","middleName":"","lastName":"Honkura","suffix":""},{"id":317983886,"identity":"ed65a5e9-1581-4924-8d9b-2309956b47df","order_by":2,"name":"Gen Murakami","email":"","orcid":"","institution":"Iwamizawa Asuka Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gen","middleName":"","lastName":"Murakami","suffix":""},{"id":317983887,"identity":"9d656944-e8ae-4e5f-a1f4-9a8f85af3c62","order_by":3,"name":"Shin-ichi Abe","email":"","orcid":"","institution":"Tokyo Dental College","correspondingAuthor":false,"prefix":"","firstName":"Shin-ichi","middleName":"","lastName":"Abe","suffix":""},{"id":317983888,"identity":"10b29dd5-3a16-495f-8177-45a7133fcdeb","order_by":4,"name":"Jose Francisco Rodríguez-Vázquez","email":"","orcid":"","institution":"Complutense University","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"Francisco","lastName":"Rodríguez-Vázquez","suffix":""},{"id":317983889,"identity":"0bde8c13-c267-4d7e-a5ea-27d8950163dd","order_by":5,"name":"Yukio Katori","email":"","orcid":"","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yukio","middleName":"","lastName":"Katori","suffix":""}],"badges":[],"createdAt":"2024-06-06 11:57:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4540171/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4540171/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00276-024-03517-4","type":"published","date":"2024-12-02T15:58:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":59515114,"identity":"31300eff-6db3-466f-a97c-5e2336990034","added_by":"auto","created_at":"2024-07-02 17:30:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":116775,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFascial configuration at the esophageal hiatus: modifications of Kremer et al. (1987) and Apaydin et al. (2008)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKremer et al. reported 4 or more types of variations (panels A-D). In panel A, the superior fascia of diaphragm divides into the upper and lower leaves of the PEM (colored green). In panel B, the inferior fascia joins the fasciae shown in panel A. In panel C, the inferior fascia extends upward to continue to the PEM. In panel D, the superior fascia joins the fasciae shown in panel C [5]. Apaydin et al. did not consider the superior fascia (their “endothoracic fascia”) as a component of the PEM (panel E) and, thus, the inferior fascia (their “transversalis fascia”) divides into the upper and lower leaves, resulting in a morphology similar to panel C [8]. The left-hand side of each panel corresponds to the left side of the body in all figures\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4540171/v1/cba096204136c3063d2c4556.png"},{"id":59515117,"identity":"70c7cc69-ac57-43a8-ab93-96fd05e33579","added_by":"auto","created_at":"2024-07-02 17:30:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2893299,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTopographical anatomy in the present frontal sections\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePanels A and B (Azan staining) display a midterm specimen at 12 weeks (86 mm CRL; the specimen same as shown in Figure 4A-C). Panel B is a plane 1.8 mm anterior to panel A. The liver in the midterm specimen is broken due to insufficient dehydration in the histological procedure. Panels C and D (HE staining) exhibit a near-term specimen at 28 weeks (228 mm CRL; the specimen same as shown in Fig. 6). Panel D is 3.5 mm posterior to panel A. The stomach is located in the left side of the abdomen. The liver caudate lobe is divided into 2 parts by the diaphragmatic crus in panel C, but it was fused to provide a single mass in the plane 0.5 mm anterior to the panel. Arrows indicate the diaphragm. AO, aorta; AD, adrenal cortex; ESO, esophagus. Scale bars in panels A and C, 10 mm\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4540171/v1/df119b73e08317e143ef4d71.png"},{"id":59516354,"identity":"d14555d9-3cb9-48fb-8936-694a26a63dd5","added_by":"auto","created_at":"2024-07-02 17:38:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":5642833,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInferior fascia of the diaphragm extending upward along the adventitia of the esophagus in two midterm fetuses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAzan staining. Two fetuses at 12 weeks. Panels A-C display a specimen of a fetus with 105 mm CRL different from shown in panels D-F with 100 mm CRL. Triangles indicate the adventitia of esophagus. In the two specimens, the inferior fascia of diaphragm (black stars) joins the adventitia (triangle + black star) in the left side of the hiatus (panels B and E). The superior fascia of diaphragm (open star) is clear in panel B but not in panel E. The fascia is unclear in the right side in both specimens (panels C and F). Panels A and D or panels B, C, E and F were prepared at the same magnification (scale bars in panels A, C, D, and F, 1 mm)\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4540171/v1/86952e382d22358ed7f4b7dd.png"},{"id":59516353,"identity":"47154759-bb15-4784-b46a-3b83d024049f","added_by":"auto","created_at":"2024-07-02 17:38:21","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":4681963,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInferior fascia of the diaphragm joining the adventitia of the esophagus in the left side of the hiatus in two midterm fetuses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAzan staining. Panels A-C display a specimen of a fetus at 12 weeks with 86 mm CRL. Panels D-F exhibit a specimen at 16 weeks with 137 mm CRL. Triangles indicate the adventitia of esophagus. In the two specimens, the superior fascia of diaphragm (open stars) is underdeveloped (panels B, C and E). The inferior fascia of diaphragm (black stars) is extending upward along the adventitia (semicircle in panels B and C) or bundled with the adventitia (semicircle in panels E and F). Panels A and D or panels B, C, E and F were prepared at the same magnification (scale bars in panels A and B, 1 mm)\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4540171/v1/e1583d4463d95f62b496858d.png"},{"id":59515120,"identity":"cdee85a8-5a89-47dd-9ed6-9d2c0522ba5b","added_by":"auto","created_at":"2024-07-02 17:30:21","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":6540513,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInferior and superior fasciae of the diaphragm joining the adventitia of the esophagus in the left side of the hiatus at 26 weeks.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePanels A-D (HE staining) display the esophageal hiatus of a fetus with 214 mm CRL. Panel E exhibits immunohistochemistry of cytokeratin 5/6 (CK5/6) in the esophagus of a fetus with 125 mm CRL. In the former specimen, both the inferior and superior fasciae of diaphragm (black and open stars) join the adventitia (triangle) in the left side of the hiatus (triangle + star in panel C). In the right side, the inferior fascia merges with the adventitia (triangle + black star in panel D), but the superior fascia is unclear possibly due to a recess of the pleural cavity (panel B). In the latter specimen, the foregut-midgut border appears to exist in the hiatus. Panels B-D were prepared at the same magnification (scale bars in panels A, B and E, 1 mm)\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4540171/v1/052ed806072cd8896e903d79.png"},{"id":59515119,"identity":"8b3a7c76-cd35-4a0d-9ab2-659e4e74155f","added_by":"auto","created_at":"2024-07-02 17:30:21","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":5396297,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInferior and superior fasciae of the diaphragm joining the adventitia of the esophagus in the left side of the hiatus at 28 weeks.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHE staining of a fetus with 228 mm CRL. A recess of the pleural cavity is seen in the left side of the hiatus (panel A). Both the inferior and superior fasciae (black and open stars) join the adventitia (triangle) in the left side of the hiatus (triangle + star in panel C). Fragmented striated muscle fibers exist beneath the peritoneum (insert of panel D). Panels B-D were prepared at the same magnification (scale bars: 1mm in panels A and B; 0.1 mm in insert)\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-4540171/v1/a6544ba0168dbde2f9211b48.png"},{"id":59515115,"identity":"9320ca52-3f03-46b0-9c29-34c9b546c39e","added_by":"auto","created_at":"2024-07-02 17:30:21","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":5879518,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSuperior fascia meeting the adventitia in the right side at 28 weeks.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHE staining of a fetus with 232 mm CRL. The inferior fascia of diaphragm (black stars) meets the adventitia (triangle) in the left side of the hiatus (panel B). In the right side (panel C), the superior fascia meets the adventitia (triangle + open star). A recess of the pleural cavity is seen in the right side and the adventitia loosely overs the vagus nerve and veins (panel C). Panel D summarizes the timing and sequence of fascial connections. Panels B and C were prepared at the same magnification (scale bars in panels A and B, 1 mm)\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-4540171/v1/09994fc7e315e8ca4168b66d.png"},{"id":70965337,"identity":"6ffb6b61-38f1-402b-a124-bbc99c2e3cf5","added_by":"auto","created_at":"2024-12-09 16:19:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":41665354,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4540171/v1/9e2a4a5a-5651-4bb2-914b-df62a69eb389.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Development and growth of fasciae in and around the esophageal hiatus: a histological study using human fetuses","fulltext":[{"header":"Introduction","content":"\u003cp\u003eA structure of the esophageal hiatus is critically important for surgery of gastroesophageal reflux disease and severe hiatal hernia. The hiatus is lined by the phreno-esophageal membrane or ligament (PEM) according to the macroscopic observation [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], but lots of variations were reported in the fascial configuration (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e): in short, the superior and inferior fasciae of diaphragm continued to the upper and lower leaves of PEM, respectively, and these leaves joined the adventitia of esophagus.\u003c/p\u003e \u003cp\u003eMost of previous histological studies of the PEM focused on striated muscle and elastic fibers in normal development [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and hiatal hernia [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Daniels [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and Botros et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] seemed to be 2 limited studies showing histology of a junction between the inferior fascia of diaphragm and the adventitia of esophagus. However, Daniels used tissue materials after bad fixation and Botros et al. demonstrated a very small area at the diaphragmatic edge at the hiatus. Fasciae around viscera are more clearly identified in histology of fetuses than adults because of no inflammation and degeneration [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Consequently, to consider which factor is likely to make the individual variation, we aimed to demonstrate the entire structure of the PEM in mid- and late-stage human fetuses.\u003c/p\u003e \u003cp\u003eIn addition, whether an esophageal epithelium in the hiatus is derived from the foregut or midgut was also our interest. Small molecule cytokeratin is known to be a marker of the foregut-derived structures [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThe study was performed in accordance with the provisions of the Declaration of Helsinki 1995 (as revised in 2013). We observed histological sections from 12 midterm at 12\u0026ndash;16 weeks of GA (crown-rump length or CRL, 85\u0026ndash;137 mm) and 10 near-term fetuses at 26\u0026ndash;30 weeks of GA (CRL, 214\u0026ndash;250 mm). These paraffin-embedded sections were part of the large collection kept at the Department of Anatomy of the Universidad Complutense, Madrid, and the resulting embryos were obtained from miscarriages and ectopic pregnancies from the Department of Obstetrics of the University. The sectional planes were all frontal. Almost all sections were stained with hematoxylin and eosin (HE), azan or elastica-Masson (a variation of Masson-Goldner staining) and a few were applied to immunohistochemistry using monoclonal anti-human cytokeratin 5/6 (Dako, Glostrup, Denmark). This study was approved by the Ethics Committees of Complutense University (B08/374) and Tokyo Dental College (No. 932).\u003c/p\u003e \u003cp\u003eMost photographs of histology were taken with a Nikon Eclipse 80, while some photos were prepared using a high-quality trans-illumination scanner Epson GTX970 at a magnification under x0.5 objective.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTopographical anatomy in the present frontal sections\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e demonstrate four sections from two specimens at the ultra-low magnification. Sections of midterm specimens contain almost entire thoracoabdominal region, whereas near-term sections missed the anterior or posterior half because the trunk is too thick to attach the microtome. The liver extended in the left and right sides of the esophagus. To reduce the size of paraffin block at near-term, lateral tissues including the spleen were usually removed. We identified the left-right orientation according to the stomach. In all seven figures, the left-hand side of each panel corresponds to the left side of the body.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eObservations of midterm specimens\u003c/h2\u003e \u003cp\u003eAt and near the hiatus, the adventitia of the esophagus was identified as a thick membrane along the circular muscle layer of the esophagus since the longitudinal muscle layer was still underdeveloped (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Development of fascial structures appeared to advance in the left side. The left side morphology was characterized by 1) the inferior fascia turning upward to extend along the margin of diaphragm (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003eB); 2) the inferior fascia bundled with the adventitia of the esophagus at the next step (Fig.\u0026nbsp;3BE). Notably, these fasciae were usually underdeveloped in the right side (10 of the 12 specimens; Figs.\u0026nbsp;3CF and 4CF). A foregut-midgut junction, suggested by cytokeratin 5/6 immunoreactivity (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e5\u003c/span\u003eE), was located at the upper half of the hiatus.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eObservations of near-term specimens\u003c/h2\u003e \u003cp\u003eBoth the inferior and superior fasciae of diaphragm often joined the adventitia of the esophagus in the left side of the hiatus (6 of the 10 specimens; Figs.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e5\u003c/span\u003eC and \u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e6\u003c/span\u003eC). In the residual 4 specimens, the left superior fascia was unclear (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e7\u003c/span\u003eB). In the right side, we almost always found the connection between the inferior fascia and adventitia (Figs.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e5\u003c/span\u003eD and \u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e6\u003c/span\u003eD), but the right superior facia rarely met the adventitia (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e7\u003c/span\u003eC). Fragmented striated muscle fibers of diaphragm were sometimes seen at and near hiatus (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e6\u003c/span\u003eD insert).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eDistrurbing factors of the developing fascial structure\u003c/h2\u003e \u003cp\u003eAt midterm as well as near-term, the right fascial connection between the esophagus and diaphragm was delayed and disturbed by 1) a transient pleural recess (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003eC, \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e5\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e7\u003c/span\u003eC) and 2) up-standing muscle fibers at the right edge or crus of diaphragm (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003eF, \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e5\u003c/span\u003eD, \u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e6\u003c/span\u003eD and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e7\u003c/span\u003eC). The right crus of diaphragm, that was pushed upward by the growing liver and right adrenal, is emphasized in a schematic representation of the present observations (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e6\u003c/span\u003eD).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study might be the first photographic demonstration of the entire fascial configuration at and around the esophageal hiatus. Even at near-tern, the PEM still corresponded to a growing complex of junctions between the esophageal adventitia and the fasciae of diaphragm. The inferior fascia developed earlier than the superior one (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e6\u003c/span\u003eD): this was different from Botros et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Notably, the development and growth of fasciae advanced in the left side of the hiatus (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e6\u003c/span\u003eD). The present configuration in the left side was consistent with Botha who emphasized a simple configuration of the infants\u0026rsquo; hiatus [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In the abdominal approach in infants, surgeons might find an easy and clear separation of the esophagus from the diaphragm after a cutting of the fascial junction between the inferior fascia and adventitia.\u003c/p\u003e \u003cp\u003eIn the right side of the hiatus, the transient pleural recess as well as the upstanding muscle fibers of the right diaphragmatic crus seemed to disturb, break or modify a connection between the superior fascia and adventitia. Therefore, variations might occur especially in the right side: this was contrast to Kremer et al [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) who considered a fascial variation occurring symmetrically. The pleural recess was likely to originate from irregular protrusions during the cavitation process [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Botros et al. reported that, possibly due to muscle fiber degeneration, the diaphragm becomes separated from the esophagus at and until 20 weeks [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. We also found fragmented muscle fibers. We speculated that the regression of diaphragm is synchronized with a migration of a foregut-midgut junction. Further study is necessary to evaluate the migration.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe phreno-esophageal membrane, interposed between the superior and inferior fasciae of diaphragm and the adventitia of esophagus, seemed to be established first in the left side at near-term. The delayed growth in the right side might connect to individual differences in adults.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003eAHK: Staining of specimens, Manuscript writing, YH: Preparing the figures, GM: Project development, Observation of specimens, Manuscript writing, SA: Observation of specimens, manuscript editing, JFR: Preparing of specimens, YK: Staining of specimens, Manuscript editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eNo funding was received to assist with the preparation of this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was performed in accordance with the provisions of the Declaration of Helsinki 1995 (as revised in 2013). Approval was granted by the Ethics Committees of Complutense University (B08/374) and Tokyo Dental College (No. 932).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBombeck CT, Dillard DH, Nyhus LM (1966) Muscular anatomy of the gastroesophageal junction and role of phrenoesophageal ligament; autopsy study of sphincter mechanism. Ann Surg 164:643\u0026ndash;654\u003c/li\u003e\n \u003cli\u003eStrasberg SM, Silver MD (1968) The phrenoesophageal membranne. Surg Forum 19:294\u0026ndash;296\u003c/li\u003e\n \u003cli\u003eLiebermann-Meffert D (1981) [Surgical anatomy of the esophagogastric junction]. Helv Chir Acta 47:667\u0026ndash;677\u003c/li\u003e\n \u003cli\u003eGroszek I, Matysiak WJ (1985) [Morphology of the phrenoesophageal membrane]. Gegenbaurs Morphol Jahrb 131:1\u0026ndash;18\u003c/li\u003e\n \u003cli\u003eKremer B, Menck J, Lierse W (1987) [Phrenico-esophageal membrane: anchoring of the terminal esophagus and cardia at the diaphragm]. Langenbecks Arch Chir 371:59\u0026ndash;67. https://doi.org/10.1007/BF01259244\u003c/li\u003e\n \u003cli\u003eKwok H, Marriz Y, Al-Ali S, Windsor JA (1999) Phrenoesophageal ligament re-visited. Clin Anat N Y N 12:164\u0026ndash;170. https://doi.org/10.1002/(SICI)1098-2353(1999)12:3\u0026lt;164::AID-CA4\u0026gt;3.0.CO;2-N\u003c/li\u003e\n \u003cli\u003eNakajima F, Murakami G, Ohyama S, et al (2001) Potential fascial dome made by the upper leaf of the phreno-esophageal membrane. Okajimas Folia Anat Jpn 77:201\u0026ndash;209. https://doi.org/10.2535/ofaj1936.77.6_201\u003c/li\u003e\n \u003cli\u003eApaydin N, Uz A, Evirgen O, et al (2008) The phrenico-esophageal ligament: an anatomical study. Surg Radiol Anat SRA 30:29\u0026ndash;36. https://doi.org/10.1007/s00276-007-0279-0\u003c/li\u003e\n \u003cli\u003eWatanabe Y, Lister J (1993) Development of the human fetal phreno-esophageal membrane and its role in the anti-reflux mechanism. Surg Today 23:722\u0026ndash;727. https://doi.org/10.1007/BF00311712\u003c/li\u003e\n \u003cli\u003eDaniels BT (1965) The phrenoesophageal membrane. Am J Surg 110:814\u0026ndash;817. https://doi.org/10.1016/0002-9610(65)90130-3\u003c/li\u003e\n \u003cli\u003eBotros KG, El-Ayat AA, El-Naggar MM, State FA (1983) The development of the human phreno-oesophageal membrane. Acta Anat (Basel) 115:23\u0026ndash;30. https://doi.org/10.1159/000145673\u003c/li\u003e\n \u003cli\u003eKinugasa Y, Niikura H, Murakami G, et al (2008) Development of the human hypogastric nerve sheath with special reference to the topohistology between the nerve sheath and other prevertebral fascial structures. Clin Anat 21:558\u0026ndash;567. https://doi.org/10.1002/ca.20654\u003c/li\u003e\n \u003cli\u003eCho BH, Kimura W, Song CH, et al (2009) An investigation of the embryologic development of the fascia used as the basis for pancreaticoduodenal mobilization. J Hepatobiliary Pancreat Surg 16:824\u0026ndash;831. https://doi.org/10.1007/s00534-009-0126-2\u003c/li\u003e\n \u003cli\u003eKim JH, Kinugasa Y, Hwang SE, et al (2015) Denonvilliers\u0026rsquo; fascia revisited. Surg Radiol Anat 37:187\u0026ndash;197. https://doi.org/10.1007/s00276-014-1336-0\u003c/li\u003e\n \u003cli\u003eHenry JJ, Charlebois TS, Grainger RM (1993) Differential expression of type II cytokeratin mRNA defines early developmental boundaries within the ectoderm, mesoderm and endoderm during chick development. Rouxs Arch Dev Biol Off Organ EDBO 202:355\u0026ndash;363. https://doi.org/10.1007/BF00188734\u003c/li\u003e\n \u003cli\u003eLungova V, Verheyden JM, Herriges J, et al (2015) Ontogeny of the mouse vocal fold epithelium. Dev Biol 399:263\u0026ndash;282. https://doi.org/10.1016/j.ydbio.2014.12.037\u003c/li\u003e\n \u003cli\u003eBotha GSM (1958) The Gastro-oesophageal Region in Infants. Arch Dis Child 33:78\u0026ndash;94\u003c/li\u003e\n \u003cli\u003eHayashi S, Kim JH, Jin Z-W, et al (2023) Cavitation processes in a space filled with loose mesenchymal tissues: a comparison between the retrosternal space and the middle ear tympanic cavity in human fetuses. Folia Morphol 82:332\u0026ndash;338. https://doi.org/10.5603/FM.a2022.0026\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"surgical-and-radiologic-anatomy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sara","sideBox":"Learn more about [Surgical and Radiologic Anatomy](http://link.springer.com/journal/276)","snPcode":"276","submissionUrl":"https://submission.nature.com/new-submission/276/3","title":"Surgical and Radiologic Anatomy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Esophageal hiatus, diaphragm, fascia, phreno-esophageal membrane, human fetus","lastPublishedDoi":"10.21203/rs.3.rs-4540171/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4540171/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eAn entire fascial configuration at the esophageal hiatus might not be demonstrated histologically. According to observations of human fetus histology, the aim of this study was to consider which factor is likely to make the individual variation in adults.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe observed frontal histological sections containing the esophageal hiatus from 12 midterm fetuses at 12\u0026ndash;16 weeks (crown-rump length:CRL, 85\u0026ndash;137 mm) and 10 near-term fetuses at 26\u0026ndash;30 weeks (CRL, 214\u0026ndash;250 mm).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAt midterm, the inferior fascia of diaphragm turned upward to join the adventitia of the esophagus, but the superior fascia was underdeveloped. At near-term, both the inferior and superior fasciae often joined the adventitia in the left side but not in the right side. Fascial development advanced in the left side of the hiatus. The pleural recess as well as the upward protruding right crus of diaphragm was likely to disturb the fascial connection especially in the superior side. The foregut-midgut junction, suggested with cytokeratin 5/6 immunostaining, was located in the hiatus.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe phreno-esophageal membrane, interposed between the superior and inferior fasciae of diaphragm and the adventitia of esophagus, seemed to be established first in the left side at near-term. The delayed growth in the right side might connect to individual differences in adults.\u003c/p\u003e","manuscriptTitle":"Development and growth of fasciae in and around the esophageal hiatus: a histological study using human fetuses","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-02 17:30:16","doi":"10.21203/rs.3.rs-4540171/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2024-08-12T11:04:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"236312569923879004659441157087781077563","date":"2024-07-10T05:12:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"29838968585899825364363999850459715640","date":"2024-06-23T22:14:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-17T10:27:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-10T15:31:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-10T14:11:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Surgical and Radiologic Anatomy","date":"2024-06-06T11:55:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"surgical-and-radiologic-anatomy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sara","sideBox":"Learn more about [Surgical and Radiologic Anatomy](http://link.springer.com/journal/276)","snPcode":"276","submissionUrl":"https://submission.nature.com/new-submission/276/3","title":"Surgical and Radiologic Anatomy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"466e10d5-a404-455b-af7d-a68610586750","owner":[],"postedDate":"July 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-09T16:12:34+00:00","versionOfRecord":{"articleIdentity":"rs-4540171","link":"https://doi.org/10.1007/s00276-024-03517-4","journal":{"identity":"surgical-and-radiologic-anatomy","isVorOnly":false,"title":"Surgical and Radiologic Anatomy"},"publishedOn":"2024-12-02 15:58:03","publishedOnDateReadable":"December 2nd, 2024"},"versionCreatedAt":"2024-07-02 17:30:16","video":"","vorDoi":"10.1007/s00276-024-03517-4","vorDoiUrl":"https://doi.org/10.1007/s00276-024-03517-4","workflowStages":[]},"version":"v1","identity":"rs-4540171","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4540171","identity":"rs-4540171","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}