Endometrial organoids: a reservoir of functional mitochondria for uterine repair.

Background: Asherman's syndrome (AS) is a dreadful gynecological disorder of the uterus characterized by intrauterine adhesion with severe fibrotic lesions, resulting in a damaged basalis layer with infertility. Despite extensive research on overcoming AS, evidence-based effective and reproducible treatments to improve the structural and functional morphology of the AS endometrium have not been established. Methods: Endometrial organoids generated from human or mouse endometrial tissues were transplanted into the uterine cavity of a murine model of AS to evaluate their transplantable feasibility to improve the AS uterine environment. The successful engraftment of organoid was confirmed by detection of human mitochondria and cytosol (for human endometrial organoid) or enhanced green fluorescent protein signals (for mouse endometrial organoid) in the recipient endometrium. The therapeutic effects mediated by organoid transplantation were examined by the measurements of fibrotic lesions, endometrial receptivity and angiogenesis, and fertility assessment by recording the number of implantation sites and weighing the fetuses and placenta. To explore the cellular and molecular mechanisms underlying the recovery of AS endometrium, we evaluated the status of mitochondrial movement and biogenetics in organoid transplanted endometrium. Results: Successfully engrafted endometrial organoids with similar morphological and molecular features to the parental tissues dramatically repaired the AS-induced damaged endometrium, significantly reducing fibrotic lesions and increasing fertility outcomes in mice. Moreover, dysfunctional mitochondria in damaged tissues, which we propose might be a key cellular feature of the AS endometrium, was fully recovered by functional mitochondria transferred from engrafted endometrial organoids. Endometrial organoid-originating mitochondria restored excessive collagen accumulation in fibrotic lesions and shifted uterine metabolic environment to levels observed in the normal endometrium. Conclusions: Our findings suggest that endometrial organoid-originating mitochondria might be key players to mediate uterine repair resulting in fertility enhancement by recovering abrogated metabolic circumstance of the endometrium with AS. Further studies addressing the clinical applicability of endometrial organoids may aid in identifying new therapeutic strategies for infertility in patients with AS.

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis.

The integrity of the structure and function of the endometrium is essential for the maintenance of fertility. However, the repair mechanisms of uterine injury remain largely unknown. Here, we showed that the disturbance of mechanical cue homeostasis occurs after uterine injury. Applying a multimodal approach, we identified YAP as a sensor of biophysical forces that drives endometrial regeneration. Through protein activation level analysis of the combinatorial space of mechanical force strength and of the presence of particular kinase inhibitors and gene silencing reagents, we demonstrated that mechanical cues related to extracellular matrix rigidity can turn off the Rap1a switch, leading to the inactivation of ARHGAP35and then induced activation of RhoA, which in turn depends on the polymerization of the agonist protein F-actin to activate YAP. Further study confirmed that mechanotransduction significantly accelerates remodeling of the uterus by promoting the proliferation of endometrial stromal cells in vitro and in vivo. These studies provide new insights into the dynamic regulatory mechanisms behind uterine remodeling and the function of mechanotransduction. Video Abstract.

Unscarred uterine rupture and subsequent pregnancy outcome - a tertiary centre experience.

OBJECTIVES: The aim of this study was to investigate the incidence, etiology and obstetric outcomes of rupture in unscarred uterine rupture and in those with a history of uterine rupture MATERIAL AND METHODS: The hospital records of women who had delivered between May 2005 and May 2017 at a tertiary center were examined retrospectively. Data on patients with unscarred uterine rupture in pregnancy who had undergone fertility-preserving surgery were evaluated. RESULTS: During the study period, 185,609 deliveries occurred. Of those, unscarred uterine rupture has occurred in 67 women. There were no ruptures reported in nulliparous women. The rupture was observed in the isthmic region in 60 (89.6%) patients and in the fundus in 7 (10.4%) patients. Thirty-eight (56.7%) patients had undergone a total or subtotal hysterectomy, and 29 (43.3%) patients had received primary repair. Ten patients had reconceived after the repair. Of these, eight patients who had a history of isthmic rupture, successfully delivered by elective C-section at 36-37 wk. of gestation, and two experienced recurrent rupture at 33 and 34 wk. of gestation, respectively. Both patients had a history of fundal rupture, and their inter-pregnancy interval was 9 and 11 mo., respectively. CONCLUSIONS: The incidence of rupture in unscarred pregnant uteri was found to be one per 2,770 deliveries. Owing to the high morbidity, regarding more than half of the cases with rupture eventuated in hysterectomy, clinicians should be prudent in induction of labour for multiparous women since it was the main cause of rupture in this series. Short inter-pregnancy intervals and history of fundal rupture may confer a risk for rupture recurrence. Those risk factors for recurrence should be validated in another studies.

[Chirality Self-assembling peptide for rats endometrial regeneration model].

Here we investigate the physical and chemical properties of chiral self-assembling peptides and the role of uterine trauma regeneration. The circular dichroism was used to analyze secondary structure of chiral self-assembled peptide, and Congo red staining was used to observe the macroscopic process of peptide self-assembling. Erythrocyte lysis assay was used to examine the cleavage of peptide on cell membrane. The nanofiber scaffolds self-assembled by Chiral self-assembling peptides were used as the three-dimensional culture material to observe the growth effect of Hela cell. CCK-8 (cell counting kit-8) was used to study cell viability level between 2D (2-dimensional) and 3D (3-dimensional) culture environment. Rats endometrium curettage model was founded to evaluate the changes by immunohistochemistry staining and and HE staining. The secondary structure of chiral self-assembling peptides was stable ß-sheet, and peptide could form dense membrane structure after 24 hours self-assembling cultured in salt ions. There was no harmful for the cell membrane of the peptide before and after self-assembling. Animal experiments show that chiral self-assembling peptide can significantly reduce the inflammatory response, promote the production of neovascularization, and accelerate the repair process. Chiral self-assembling peptide, as a new type of scaffold material, can construct a three-dimensional cell culture environment and used to repair uterine trauma.

Barbed Versus Conventional Suture for Uterine Repair During Caesarean Section: A Randomized Controlled Study.

OBJECTIVE: This study sought to compare the short-term outcome of uterine incision repair during a Caesarean section (CS) using a bidirectional knotless barbed suture versus polyglactin suture. METHODS: A randomized controlled trial was conducted at a university hospital. Participants undergoing a CS were randomly assigned to uterine incision closure by bidirectional knotless barbed suture (group A) or polyglactin (group B). The primary outcome was the time needed to repair the uterine incision. The analysis was by intent to treat. A sample size of 35 per group (n = 70) was planned to detect a 30% reduction in uterine repair time (Canadian Task Force Classification I). RESULTS: From July 2016 through October 2017, 150 women were screened, and 70 were statistically analyzed: group A (n = 35) and group B (n = 35). Time to complete uterine incision repair was 308 ± 57 seconds for group A and 411 ± 74 seconds for group B (P < 0.001). Total surgery time (33.4 ± 8.8 minutes vs. 33.2 ± 7.5 minutes; P = 0.64) was not significantly different between groups A and B, respectively. CONCLUSION: Repair of the CS uterine incision with barbed suture compared with polyglactin suture reduces suturing time.

Risk of hysterectomy and salpingectomy or oophorectomy compared to repair after pelvic gynecologic trauma.

PURPOSE: Pelvic gynecologic trauma (PGT) includes injury to the uterus, ovaries or fallopian tubes. We hypothesized Injury Severity Score (ISS) ≥ 25, hypotension on admission and age ≥ 51 (average age for menopause) would be independent risk factors for resection compared to repair. METHODS: A retrospective analysis of the National Trauma Data Bank was performed between 2007 and 2015. RESULTS: Of 2,040,235 female patients, 1938 (< 0.1%) presented with PGT with the majority sustaining injury to the ovary or fallopian tubes (52.9%). Most patients were managed nonoperatively (77.1 vs 22.9%). On multivariable analysis, in patients with injury to the uterus, ISS ≥ 25 (OR 3.52, CI 1.67-7.48, p < 0.05) was associated with higher risk for hysterectomy compared to repair. In patients with injury to the ovaries or fallopian tubes, gunshot wound (OR 3.73, CI 1.43-9.68, p < 0.05) was associated with a higher risk for salpingectomy or oophorectomy compared to repair. Age ≥ 51 and hypotension on admission were not independent risk factors for resection in patients with PGT. Operative treatment was associated with a lower risk for mortality in patients with an injury to the uterus (OR 0.27, CI 0.14-0.51, p < 0.001) or ovaries/fallopian tubes (OR 0.37, CI 0.19-0.72, p < 0.001) compared to those managed nonoperatively. CONCLUSION: In the largest study reported, PGT occurred in < 0.1% of traumas involving women. Patients with ISS ≥ 25 have higher risk for hysterectomy compared to repair. Gunshot injuries have higher risk for salpingectomy or oophorectomy compared to repair. Hypotension on arrival or age ≥ 51 are not independent risk factors for resection in PGT. Operative management is associated with lower risk of mortality in PGT patients.

Uterine exteriorization versus intraperitoneal repair: effect on intraoperative nausea and vomiting during repeat cesarean delivery - A randomized clinical trial.

OBJECTIVE: The current study aims to compare the rate of intraoperative nausea and vomiting after repeat cesarean delivery (CD) under two different approaches: by intraperitoneal incision repair or by uterus exteriorization for incision reapair. MATERIALS AND METHODS: We conducted a single-blinded randomized clinical trial (NCT03009994) at a tertiary University Hospital between the 1st of September 2016 and the 31st of December 2017. The study included pregnant women at term of gestation (>37 weeks) scheduled for repeat CD under spinal anesthesia. Women were assigned to either uterine exteriorization for incision repair (Group I) or intraperitoneal incision repair (Group II). The primary assessed was the rate of nausea and vomiting during CD. RESULTS: The study included 1028 women in the final analysis. The rate of intraoperative nausea and vomiting was significantly lower in the intraperitoneal repair group compared to the exteriorization group (24% versus 38.7%, p= 0.001). Likewise, occurrence of uterine atony and the need for additional uterotonics were significantly lower in the intraperitoneal repair group (p= 0.001 and 0.02 respectively). Postoperatively, the rate of nausea and vomiting (12.6 % versus 21 %; P=0.001), and the time to the first recognized bowel movement (12.3 hours versus 14.1 hours; P=0.003) were significantly lower in the intraperitoneal repair group compared to the exteriorization group. CONCLUSIONS: Intraperitoneal repair of the uterine incision during repeat CD is beneficial compared to exteriorization. Improvements in the rate of intra- and postoperative nausea, vomiting, uterine atony and time to the first recognized bowel movement were observed in patients operated with this technique.

Successful delivery after surgical repair of uterine rupture at 15 weeks of gestation: case report and brief review.

OBJECTIVE: Second-trimester uterine rupture is a rare disorder and it is unclear if it should be managed with caesarean section, repair or hysterectomy. This article provides a case report of second-trimester uterine rupture repair, and reviews the risk factors, signs and symptoms, suturing technique and newborn outcome. METHODS: PubMed was searched using the terms 'uterine rupture', 'second trimester' and 'repair' Only cases of second-trimester uterine rupture repair that led to successful prolongation of pregnancy were included. RESULTS: The main risk factor of uterine rupture is previous caesarean section (5/10, 50%). Eight of 10 cases presented with abdominal pain and three cases presented in shock. Haemoperitoneum was present in five cases. The mean and median gestational age at delivery were 33.4 and 33.5 weeks, respectively (range 28-37 weeks), with mean and median delayed interval delivery of 95.5 and 91 days, respectively (range 14-147 days). Neonatal outcome was good for 10 of 11 newborns. Despite the early onset of uterine rupture, there were no cases of extremely preterm delivery. One early preterm infant, seven moderate-to-late preterm infants and one term infant were delivered. CONCLUSIONS: The lack of extremely preterm deliveries and good neonatal outcomes encourage attempts to repair the uterus after second-trimester rupture.

What are the best surgical techniques for caesarean sections? A contemporary review.

The aim of this study was to evaluate the reported techniques used in caesarean sections in order to form a general perspective of the procedural options for this frequently performed operation. The PubMed database and Cochrane Reviews were searched separately with the key words 'caesarean', 'abdominal entry', 'abdominal incision', 'uterine repair', 'peritoneal repair', 'closure of abdominal incision', 'suture materials', 'extraction of the placenta' and 'review'. Reviews, meta-analyses and prospective randomised trials were included in this review. In conclusion, although caesarean delivery is a very common operation, standardised and globally accepted techniques for caesarean section have not been described. The best surgical techniques for this operation are still unknown. Although the long-term follow-up results from two large, prospective, randomised studies are pending, further research is needed to establish an evidence-based, standardised approach for caesarean sections.

Analysis of uterine rupture at university teaching hospital Pakistan.

OBJECTIVE: To determine the risk factors, management modalities, fetomaternal outcome of uterine rupture cases at University teaching hospital in Pakistan. METHODS: This retrospective descriptive study was conducted at the Department of Gynaecology and Obstetrics Liaquat University of Medical and Health Sciences (LUMHS) for a period of one year from January 1st to December 31st 2012. Main outcome measures were frequency, age, parity, booking status, risk factors, management modalities, fetal and maternal mortality associated with uterine rupture. The data was collected on pre-designed proforma analysed using SPSS Version 16 statistical package. RESULTS: The frequency of ruptured uteri was calculated to be 0.67%, giving a ratio of 1:148 deliveries. Highest incidence was found in age group 25-30 (44.26%) with mean age of 30.36 years. and parity group 2-3 (57.37%) with mean parity 4.08. The risk factors for ruptured uterus include Caesarean section 43(70.49%), injudicious use of oxytocin 33(54.09%), obstructed labour 15 (24.59%) and multiparty 18 (29.50%). Repair of uterus was performed in 47(77.04%) cases. Maternal case fatality was 5(8.19%), while foetal wastage was 51 (83.60%). CONCLUSION: This study confirms the existence of a serious preventable obstetric problem, with significant maternal mortality and foetal wastage. Integrated efforts include Health education, focused antenatal care, skilled attendance, avoidance of injudicious use of oxytocin, and need of hospital based deliveries in patients with caesarean section which should be intensified to reduce this drastic obstetrical complication.

A randomized controlled trial of uterine exteriorization versus in situ repair of the uterine incision during cesarean delivery.

OBJECTIVE: To compare extra-abdominal repair of the uterine incision at cesarean delivery with in situ repair. METHODS: The present study was a double-blind randomized controlled trial conducted at a university hospital in Egypt during 2012-2013, and included women with an indication for cesarean delivery. Extra-abdominal repair was used in group 1 (n=500) and in situ repair in group 2 (n=500). The primary outcome measure was the surgery duration. RESULTS: Surgery duration was significantly longer in group 1 than group 2 (49.9±2.3 minutes vs 39.9±1.8 minutes; P<0.001). More patients in group 1 than in group 2 had postoperative moderate-to-severe pain (165 [33.0%] vs 115 [23.0%]; P=0.001) and needed additional postoperative analgesia (100 [20.0%] vs 50 [10.0%]; P<0.001). Moreover, mean time to bowel movement was longer in group 1 than in group 2 (17.0±2.7 hours vs 14.0±1.9 hours; P<0.001). CONCLUSION: In situ uterine closure is more advantageous than extra-abdominal repair in terms of surgery duration, postoperative pain and need for additional analgesia, and return of bowel movement. ClinicalTrials.gov:NCT01723605.