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Effect of autologous bone marrow stem cells-scaffold transplantation on the ongoing pregnancy rate in intrauterine adhesion women:a randomized,controlled trial

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Science China(Life Sciences) 2024年第1期67卷 113-121页

作者： Hui Zhu Taishun Li Peizhen Xu Lijun Ding Xianghong Zhu Bin Wang Xiaoqiu Tang Juan Li Pengfeng Zhu Huiyan Wang Chenyan Dai Haixiang Sun Jianwu Dai Yali Hu Department of Obstetrics and Gynecology Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing 210008China Department of Biostatistics Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing 210008China Department of Gynecology Changzhou Maternal and Child Health Care HospitalChangzhou Medical CenterNanjing Medical UniversityChangzhou 213004China Clinical Center for Stem Cell Research Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing 210008China Department of Hematology Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing 210008China Institute of Genetics and Developmental Biology Chinese Academy of SciencesBeijing 100190China

intrauterine adhesion is a major cause of female reproductive disorders.Although we and others uncontrolled pilot studies showed that treatment with autologous bone marrow stem cells made a few patients with severe intrauterine adhesion obtain live birth,no large sample randomized controlled studies on this therapeutic strategy in such patients have been reported so far.To verify if the therapy of autologous bone marrow stem cells-scaffold is superior to traditional treatment in moderate to severe intrauterine adhesion patients in increasing their ongoing pregnancy rate,we conducted this randomized controlled clinical trial.Totally 195 participants with moderate to severe intrauterine adhesion were screened and 152 of them were randomly assigned in a 1:1 ratio to either group with autologous bone marrow stem cells-scaffold plus Foley balloon catheter or group with only Foley balloon catheter(control group)from February 2016 to January 2020.The per-protocol analysis included 140 participants:72 in bone marrow stem cells-scaffold group and 68 in control group.The ongoing pregnancy occurred in 45/72(62.5%)participants in the bone marrow stem cells-scaffold group which was significantly higher than that in the control group(28/68,41.2%)(RR=1.52,95%CI 1.08–2.12,P=0.012).The situation was similar in live birth rate(bone marrow stem cells-scaffold group 56.9%(41/72)vs.control group 38.2%(26/68),RR=1.49,95%CI 1.04–2.14,P=0.027).Compared with control group,participants in bone marrow stem cells-scaffold group showed more menstrual blood volume in the 3rd and 6th cycles and maximal endometrial thickness in the 6th cycle after hysteroscopic adhesiolysis.The incidence of mild placenta accrete was increased in bone marrow stem cells-scaffold group and no severe adverse effects were observed.In conclusion,transplantation of bone marrow stem cells-scaffold into uterine cavities of the participants with moderate to severe intrauterine adhesion increased their ongoing pregnancy and live birth rates,and this therapy was relatively

关键词： intrauterine adhesion Asherman’s syndrome uterine infertility autologous bone marrow stem cells transplantation endometrial regeneration ongoing pregnancy rate

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Engineering self-healing adhesive hydrogels with antioxidant properties for intrauterine adhesion prevention

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Bioactive Materials 2023年第9期27卷 82-97页

作者： Luyao Feng Liqun Wang Yao Ma Wanglin Duan Sergio Martin-Saldana Ye Zhu Xianpeng Zhang Bin Zhu Chaowei Li Shibo Hu Mingjie Bao Ting Wang Yuan Zhu Fei Yang Yazhong Bu Institute of Medical Engineering Department of BiophysicsSchool of Basic Medical SciencesHealth Science CenterXi’an Jiaotong UniversityXi’an710061China Department of Reproductive Health Jiangxi Maternal and Child Health HospitalNanchangJiangxi330006China POLYMAT Applied Chemistry DepartmentFaculty of ChemistryUniversity of the Basque Country UPV/EHUPaseo Manuel de Lardizabal 320018Donostia-San SebastianSpain JXHC Key Laboratory of Fertility Preservation Jiangxi Maternal and Child Health HospitalNanchangJiangxi330006China School of Chemical Sciences University of Chinese Academy of SciencesBeijing100049China Beijing National Laboratory for Molecular Sciences State Key Laboratory of Polymer Physics&ChemistryInstitute of ChemistryChinese Academy of SciencesBeijing100190China

intrauterine adhesion (IUA) is the fibrosis within the uterine cavity. It is the second most common cause of female infertility, significantly affecting women’s physical and mental health. Current treatment strategies fail to provide a satisfactory therapeutic outcome for IUA patients, leaving an enormous challenge for reproductive science. A self-healing adhesive hydrogel with antioxidant properties will be highly helpful in IUA prevention. In this work, we prepare a series of self-healing hydrogels (P10G15, P10G20, and P10G25) with antioxidant and adhesive properties. Those hydrogels exhibit good self-healing properties and can adapt themselves to different structures. They possess good injectability and fit the shape of the human uterus. Moreover, the hydrogels exhibit good tissue adhesiveness, which is desirable for stable retention and therapeutic efficacy. The in vitro experiments using P10G20 show that the adhesive effectively scavenges ABTS+, DPPH, and hydroxyl radicals, rescuing cells from oxidative stress. In addition, P10G20 offers good hemocompatibility and in vitro and in vivo biocompatibility. Furthermore, P10G20 lowers down the in vivo oxidative stress and prevents IUA with less fibrotic tissue and better endometrial regeneration in the animal model. It can effectively downregulate fibrosis-related transforming growth factor beta 1 (TGF-β1) and vascular endothelial growth factor (VEGF). Altogether, these adhesives may be a good alternative for the clinical treatment of intrauterine adhesion.

关键词： Adhesive Hydrogel intrauterine adhesion Self-healing Antioxidant

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Advanced Role of Hippo Signaling in Endometrial Fibrosis： Implications for intrauterine adhesion

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Chinese Medical Journal 2017年第22期130卷 2732-2737页

作者： Hai-Yan Zhu Tian-Xiang Ge Yi-Bin Pan Song-Ying Zhang Assisted Reproduction Unit Department of Obstetrics and Gynecology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310016 China

Objective： intrauterine adhesion （IUA） is a major health problem that causes infertility, menstrual irregularities, and recurrent pregnancy losses in women. Unfortunately, treatments for IUA are limited, and there are currently no effective strategies for preventing IUA recurrence. In this review, we introduced the role of Hippo signaling in the normal endometrium and IUA and described the mechanisms by which the Hippo pathway integrates with the Wnt and transforming growth factor-β （TGF-β） signaling pathways to form an intricate network governing the development of fibrosis. Data Sources： Original research articles in English that were published until July 2017 were collected from the PubMed database. Study Selection： Literature search was conducted using the search terms ＂endometrial fibrosis OR fibrosis AND or OR intrauterine adhesion OR Asherman syndrome OR IUA,＂＂Hippo AND or OR Hippo/TAZ,＂＂TGF-β,＂ and ＂Wnt.＂ Related original research articles were included in the comprehensive analysis. Results： Endometrial fibrosis is recognized as a key pathological event in the development of IUA, which is characterized by epithelial/fibroblast-myofibroblast transition. Myofibroblasts play crucial roles in the pathogenesis of fibrous scarring, and myofibroblast differentiation can be triggered by multiple signaling pathways. H ippo signaling is a critical regulator of the epithelial/fibroblast-myofibroblast transition and α-smooth muscle actin, which exhibits a specific spatiotemporal expression in the endometrium. Conclusions： Hippo signaling plays a critical role in fibrous diseases and participates in cross talks with Wnt and TGF-β signaling. Our findings not only contributed to knowledge on the pathogenesis of endometrial fibrosis, but can also serve as a useful resource for developing specific molecular inhibitors for IUA treatment and prevention.

关键词： Endometrial Fibrosis： Hippo Signaling intrauterine adhesion Transforming Growth Factor-β Wnt Signaling

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Safety of menstrual blood-derived stromal cell transplantation in treatment of intrauterine adhesion

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World Journal of Stem Cells 2020年第5期12卷 368-380页

作者： Qi-Yuan Chang Si-Wen Zhang Ping-Ping Li Zheng-Wei Yuan Ji-Chun Tan Department of Obstetrics and Gynecology Shengjing Hospital of China Medical UniversityShenyang 110022Liaoning ProvinceChina Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province Shenyang 110004Liaoning ProvinceChina Key Laboratory of Health Ministry for Congenital Malformation Shengjing Hospital of China Medical UniversityBenxi 117004Liaoning ProvinceChina

BACKGROUND intrauterine adhesion(IUA)can cause serious damage to women’s reproductive health,yet current treatment methods are difficult to achieve satisfactory results.In our previous studies,we demonstrated that menstrual-derived stromal stem cells(MenSCs),with high proliferative capacity and self-renewal ability,have a powerful therapeutic effect in patients with severe IUA.However,safety assessment of MenSCs transplantation is essential for its further application.AIM To evaluate the short-,medium-,and long-term biosafety of MenSCs via intrauterine transplantation in a rat model of IUA,with a focus on toxicity and tumorigenicity.METHODS MenSCs were injected into the sub-serosal layer of the uterus in an IUA rat model,for 3 d,3 mo,and 6 mo separately,to monitor the corresponding acute,sub-chronic,and chronic effects.Healthy rats of the same age served as negative controls.Toxicity effects were evaluated by body weight,organ weight,histopathology,hematology,and biochemistry tests.Tumorigenicity of MenSCs was investigated in Balb/c-nu mice in vivo and by colony formation assays in vitro.RESULTS Compared with the same week-old control group,all of the IUA rats receiving MenSC transplantation demonstrated no obvious changes in body weight,mainorgan weight,or blood cell composition during the acute,sub-chronic,and chronic observation periods.At the same time,serum biochemical tests showed no adverse effects on metabolism or liver and kidney function.After 4 wk of subcutaneous injection of Men SCs in Balb/c-nu nude mice,no tumor formation or cell metastasis was observed.Moreover,there was no tumor colony formation of Men SCs during soft agar culture in vitro.CONCLUSION There is no acute,sub-chronic,or chronic poisoning,infection,tumorigenesis,or endometriosis in rats with IUA after Men SC transplantation.The above results suggest that intrauterine transplantation of Men SCs is safe for endometrial treatment.

关键词： Menstrual blood-derived stromal cells Endometrial treatment intrauterine adhesion Stem cell transplantation Biosafety Toxicity

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The Clinical Value of Ultrasound Image Texture Analysis in the Diagnosis of Uterine adhesions

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Open Journal of Obstetrics and Gynecology 2024年第2期14卷 312-320页

作者： Meng Li Chanyu Zhang Department of Gynaecology and Obstetrics The Second Affiliated Hospital of Chongqing Medical University Chongqing China

Purpose: This review examines the diagnostic value of transvaginal 3D ultrasound image texture analysis for the diagnosis of uterine adhesions. Materials and Methods: The total clinical data of 53 patients with uterine adhesions diagnosed by hysteroscopy and the imaging data of transvaginal three-dimensional ultrasound from the Second Affiliated Hospital of Chongqing Medical University from June 2022 to August 2023 were retrospectively analysed. Based on hysteroscopic surgical records, patients were divided into two independent groups: normal endometrium and uterine adhesion sites. The samples were divided into a training set and a test set, and the transvaginal 3D ultrasound was used to outline the region of interest (ROI) and extract texture features for normal endometrium and uterine adhesions based on hysteroscopic surgical recordings, the training set data were feature screened and modelled using lasso regression and cross-validation, and the diagnostic efficacy of the model was assessed by applying the subjects’ operating characteristic (ROC) curves. Results: For each group, 290 texture feature parameters were extracted and three higher values were screened out, and the area under the curve of the constructed ultrasonographic scoring model was 0.658 and 0.720 in the training and test sets, respectively. Conclusion Relative clinical value of transvaginal three-dimensional ultrasound image texture analysis for the diagnosis of uterine adhesions.

关键词： Transvaginal 3D Ultrasound intrauterine adhesion Texture Analysis

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Clinical Study of Changmaile II Combined with Estrogen and Progesterone in Preventing and Treating intrauterine adhesion

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Chinese Medicine 2021年第2期12卷 29-35页

作者： Qian Liu Xueli Chen Department of Obstetrics and Gynecology The Second People’s Hospital Affiliated to Fujian University of Traditional Chinese Medi-cine Fuzhou China Fujian University of Traditional Chinese Medicine Fuzhou China

Purpose: To explore the clinical efficacy of Changmaile II combined with cyclic estrogen/progesterone therapy in treating hypomenorrhea caused by intrauterine adhesion (IUA) and its effect on the endometrium after the separation procedure for intrauterine adhesion. Methods: Sixty patients with IUA confirmed by hysteroscopy in the Second People’s Hospital of Fujian University of Traditional Chinese Medicine from March 2020 to December 2020 were selected and randomly divided into the control group and the observation group, with 30 cases in each group. After the separation procedure for intrauterine adhesion, the observation group underwent the cyclic estrogen/progesterone therapy alone, while the observation group was administered the in-hospital preparation of Changmaile II in addition to the therapy of the observation group. Menstrual recovery, endometrial thickness, and the diagnostic grading scores of IUA after 3 menstrual cycles were measured in both groups. Results: After the treatment for 3 menstrual cycles, the total effective rate was higher in the observation group (73.33%) than in the control group (53.33%) (P < 0.05). The period flow was heavier in the observation group than in the control group (P < 0.05). The endometrial thickness of both groups was thicker than before treatment (P < 0.05), nonetheless the difference between the groups w

关键词： intrauterine adhesion Changmaile II Estrogen/Progesterone

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Expression of miR-195 in intrauterine adhesion and its relationship with TGF-β1/Smads and FGF2/FGFR1/ERK pathways

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Journal of Hainan Medical University 2020年第7期26卷 46-49页

作者： Ling-Ge Jin Jian-Hong Wu Yu-Di Zhang Department of Gynecology Beijing Gynecology&Obstetrics Hospital of Capital Medical UniversityBeijing100026

Objective:To investigate the expression of miR-195 in intrauterine adhesion(IUA)and its relationship with TGF-β1/Smads and FGF2/FGFR1/ERK pathways.Methods:118 cases of IUA patients who underwent hysteroscopic treatment in our hospital between September 2017 and February 2019 were regarded as IUA group,80 cases of dysfunctional uterine bleeding patients who underwent hysteroscopic curettage in our hospital during the same period were regarded as control group.Differences in the expression levels of miR-195 as well as TGF-β1/Smads and FGF2/FGFR1/ERK signaling pathway-related molecules in the focal tissues obtained by hysteroscopy were compared between the two groups.Pearson test was used to evaluate the correlation of miR-195 expression in the intrauterine adhesion tissues with TGF-β1/Smads and FGF2/FGFR1/ERK pathways in IUA patients.Results:miR-195 expression in intrauterine adhesion tissues of IUA group was higher than that in endometrial tissues of control group(Pintrauterine adhesion tissues of IUA group were higher than those in endometrial tissues of control group;FGF2,FGFR1 and ERK mRNA expression in intrauterine adhesion tissues were higher than those in endometrial tissues of control group(Pintrauterine adhesion tissues of IUA group was positively correlated with the TGF-β1/Smads pathway-related molecules TGF-β1,Smad2 and Smad3 mRNA expression,and positively correlated with the FGF2/FGFR1/ERK pathway-related molecules FGF2,FGFR1 and ERK mRNA expression(P<0.05).Conclusion:miR-195 is highly expressed in IUA lesion tissues and may promote disease progression by activating TGF-β1/Smads and FGF2/FGFR1/ERK signaling pathways.

关键词： intrauterine adhesion MiR-195 TGF-β1/Smads FGF2/FGFR1/ERK

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Diagnostic Accuracy of Hysterosalpingography in the Identification of intrauterine adhesions in Infertile Women in a Referral Centre, Southern Nigeria

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Open Journal of Obstetrics and Gynecology 2023年第2期13卷 291-302页

作者： Inusa Amike Emmanuel Okwudili Oranu Tamunomie Kennedy Nyengidiki Enighe W. Ugboma Kingsley Vademe Oriji Department of Obstetrics and Gynaecology University of Port Harcourt Teaching Hospital Port Harcourt Nigeria Department of Radiology University of Port Harcourt Teaching Hospital Port Harcourt Nigeria

Background: Examination of the endometrial cavity is crucial in the management of infertile women. This evaluation is done by Hysterosalpingography (HSG) in the University of Port Harcourt Teaching Hospital. The diagnostic value and accuracy of hysterosalpingography varies in various centres and has not been assessed in the University of Port Harcourt Teaching Hospital (UPTH), hence this study. Methodology: A prospective cross sectional study done among 101 infertile women at the gynaecology clinic of the UPTH from December 2018 to July 2019. Socio-demographic data of women who met the eligibility criteria were collected. Their hysterosalpingographic and outpatient hysteroscopic findings were statistically analyzed using IBM SPSS for windows version 20.0. The validity and reliability statistics of hysterosalpingography for the identification of endometrial adhesions were determined and significance was reported at p-value intrauterine adhesions;showing sensitivity and specificity of 59.6% and 90.9% respectively. The accuracy of HSG in the identification of intrauterine adhesions in this study was 73.3%. The agreement in the diagnostic accuracy of HSG using Hysteroscopy as a gold standard for intrauterine adhesions was therefore moderately significant (k = 0.482). Conclusion: HSG had an overall fair strength of agreement with office hysteroscopy in the identification of intrauterine adhesions. It is a specific but not a sensitive predictor of intrauterine adhesion.

关键词： intrauterine adhesion HSG Hysteroscopy Port Harcourt

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Collagen-binding basic fibroblast growth factor improves functional remodeling of scarred endometrium in uterine infertile women: a pilot study

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Science China(Life Sciences) 2019年第12期62卷 1617-1629页

作者： Peipei Jiang Xiaoqiu Tang Huiyan Wang Chenyan Dai Jing Su Hui Zhu Minmin Song Jingyu Liu Ziqing Nan Tong Ru Yaling Li Jingmei Wang Jun Yang Bing Chen Jianwu Dai Yali Hu Department of Obstetrics and Gynecology The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Center for Reproductive Medicine Department of Obstetrics and GynecologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Nanjing Drum Tower Hospital Chinese Academy of Medical Science&Peking Union Medical CollageNanjing 210008China Department of Pathology The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Institute of Genetics and Developmental Biology Chinese Academy of SciencesBeijing 100190China

intrauterine adhesion(IUA) is a common cause of uterine infertility and one of the most severe clinical features is endometrial fibrosis namely endometrial scarring for which there are few cures currently. Blocked angiogenesis is the main pathological change in the scarred endometrium. The fibroblast growth factor 2(b FGF), a member of FGF family, is usually applied to promote healing of refractory ulcer and contributes to angiogenesis of tissues. In this study, the sustained-release system of b FGF100 μg was administrated around scarred endometrium guiding by ultrasound every 4 weeks in 18 patients(2–4 times). Results showed that after treatment, the menstrual blood volume, endometrial thickness and the scarred endometrial area were improved.Histological study showed blood vessel density increased obviously. Three patients(3/18) achieved pregnancy over 20 gestational weeks. Therefore, administrating the b FGF surrounding scarred endometrium may provide a new therapeutic approach for the patients with endometrial fibrosis.

关键词： intrauterine adhesion CBD-bFGF endometrial scarring uterine infertility thin endometrium endometrial reconstruction

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