|
1
|
Zhang X, Wang S, Wang S, Long Z, Lu C, Wang J, Yang L, Yao C, He B, Chen X, Zhuang T, Xu X, Zheng Y. A double network composite hydrogel with enhanced transdermal delivery by ultrasound for endometrial injury repair and fertility recovery. Bioact Mater 2025; 50:273-286. [PMID: 40270550 PMCID: PMC12017869 DOI: 10.1016/j.bioactmat.2025.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 03/09/2025] [Accepted: 04/04/2025] [Indexed: 04/25/2025] Open
Abstract
Endometrial injury and resulting female infertility pose significant clinical challenges due to the notable shortcomings of traditional treatments. Herein, we proposed a double network composite hydrogel, CSMA-RC-Zn-PNS, which forms a physical barrier on damaged tissue through photo-crosslinking while enabling sustained release of the active ingredient PNS. Based on this, we developed a combined strategy to enhance transdermal delivery efficiency using ultrasound cavitation. In vitro experiments demonstrated that CSMA-RC-Zn-PNS exhibits excellent biosafety, biodegradability, and promotes cell proliferation, migration, and tube formation, along with antioxidant and antibacterial properties. In a rat endometrial injury model, the ultrasound cavitation effect was demonstrated to enhance transdermal delivery efficiency, and the ability of CSMA-RC-Zn-PNS to promote endometrial regeneration, anti-fibrosis and fertility restoration was verified. Overall, this strategy combining CSMA-RC-Zn-PNS hydrogel and ultrasound treatment shows promising applications in endometrial regeneration and female reproductive health.
Collapse
Affiliation(s)
- Xin Zhang
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
| | - Shufang Wang
- Department of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, China
| | - Siyu Wang
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
| | - Zeyi Long
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
| | - Cong Lu
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
- Qingdao Blood Center, Qingdao, Shandong, 266071, China
| | - Jianlin Wang
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
| | - Lijun Yang
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
| | - Cancan Yao
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
| | - Bin He
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
| | - Xihua Chen
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
| | - Taifeng Zhuang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Xiangbo Xu
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
| | - Yufeng Zheng
- School of Materials Science and Engineering, Peking University, Beijing, 100871, China
| |
Collapse
|
|
2
|
Zhang Q, Qin D, Liu C, Chen Z, Gong X, Wang S, Gao R, Yu S, Qi J, Niu Y, Xing S, Bi S, Tang B. Injectable Hydrogel Loaded with Plasma-Rich Platelets Repairing Endometrial Injury and Remodeling Reproductive Function by Regulating PI3K/AKT Pathway. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2412177. [PMID: 40165776 DOI: 10.1002/smll.202412177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 02/18/2025] [Indexed: 04/02/2025]
Abstract
Infertility resulting from uterine damage has emerged as a significant challenge confronting the development of modern society. Existing therapeutic approaches frequently encounter limitations due to the intricate physical and physiological environment of uterus. Platelet-rich plasma (PRP), a concentrate of platelets enriched with various growth factors, has been used in uterine injury repair. However, the rapid release of activating factors from PRP limits its timeliness in therapeutic applications. This work involves the synthesis of a biodegradable hydrogel based on natural polysaccharides through dynamic Schiff base. The hydrogel demonstrates tissue adhesion, self-healing, and injectability. Furthermore, its internal porous architecture facilitates the loading and sustained release of PRP. In vitro experiments, the hydrogel loaded with RPR (HOHP) exhibits a significant enhancement in cell proliferation and migration and promotes vascular regeneration by upregulating the expression of VEGFA and further activating the intracellular phosphatidylinositol kinase (PI3K)/protein kinase B (AKT) pathway. In vivo experiments on uterine endometrial injury model, HOHP restores endometrial thickness and gland number, reduces collagen deposition, promotes angiogenesis to repair uterine damage and restore fertility, which provides reinforced endorsement for the clinical management of uterine injury and enhances fertility.
Collapse
Affiliation(s)
- Qing Zhang
- Qingdao University, 308 Ningxia Road, Qingdao, Shandong, 266071, China
| | - Di Qin
- Shandong Second Medical University, Bao Tong West Street, Weifang, Shandong Province, 7166, China
| | - Chengyang Liu
- Qingdao University, 308 Ningxia Road, Qingdao, Shandong, 266071, China
| | - Zeqiang Chen
- Women and Children's Hospital, Qingdao University, 6th Tongfu Road, 308 Ningxia Road, Qingdao, Shandong, 266071, China
| | - Xuelin Gong
- Qingdao University, 308 Ningxia Road, Qingdao, Shandong, 266071, China
| | - Shuang Wang
- Qingdao University, 308 Ningxia Road, Qingdao, Shandong, 266071, China
| | - Ruipeng Gao
- Qingdao University, 308 Ningxia Road, Qingdao, Shandong, 266071, China
| | - Sun Yu
- Qingdao University, 308 Ningxia Road, Qingdao, Shandong, 266071, China
| | - Jiaojiao Qi
- Qingdao University, 308 Ningxia Road, Qingdao, Shandong, 266071, China
| | - Yusheng Niu
- Qingdao University, 308 Ningxia Road, Qingdao, Shandong, 266071, China
| | - Shichao Xing
- Qingdao University, 308 Ningxia Road, Qingdao, Shandong, 266071, China
- Qingdao Municipal Center for Disease Control and Prevention, 175th Shandong Road, Qingdao, Shandong, 266033, China
| | - Shichao Bi
- Laoshan Laboratory, 168 Wenhai Middle Road, Qingdao, Shandong, 266237, China
| | - Bo Tang
- Laoshan Laboratory, 168 Wenhai Middle Road, Qingdao, Shandong, 266237, China
| |
Collapse
|
|
3
|
Rajabloo Y, Al-Asady AM, Akbarzadeh H, Avan A, Khazaei M, Ryzhikov M, Hassanian SM. The Application of Hydrogels in the Treatment of Intrauterine Adhesions. Curr Pharm Des 2025; 31:1057-1066. [PMID: 39754766 DOI: 10.2174/0113816128348746241030110806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 09/30/2024] [Accepted: 10/03/2024] [Indexed: 01/06/2025]
Abstract
Intrauterine Adhesions (IUA) are a significant cause of infertility and miscarriage, often resulting from trauma to the endometrium. While hysteroscopic adhesiolysis is the primary treatment, the use of hydrogels as anti-adhesion barriers and drug delivery systems is gaining traction for improving patient outcomes. This review aims to explore various hydrogel types, their role in tissue repair, and the integration of stem cell therapy. Recent advancements in biomaterial scaffolds have demonstrated potential in preventing adhesion recurrence and promoting endometrial regeneration. These emerging treatments provide promising avenues for enhancing the efficacy of traditional therapies in IUA management.
Collapse
Affiliation(s)
- Yasamin Rajabloo
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abdulridha Mohammed Al-Asady
- Department of Medical Sciences, Faculty of Nursing, University of Warith Al-Anbiyaa, Karbala, Iraq
- Department of Medical Sciences, Faculty of Dentistry, University of Kerbala, Karbala, Iraq
- Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanieh Akbarzadeh
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4059, Australia
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mikhail Ryzhikov
- School of Medicine, Saint Louis University, St. Louis, MO 63103, USA
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
4
|
Sanjeev K, Guruprasad M, Vikram R, Priyadarshini S, Mazumder A, Inderchand M. Uterine Biosynthesis through Tissue Engineering: An Overview of Current Methods and Status. Curr Pharm Biotechnol 2025; 26:208-221. [PMID: 39161137 DOI: 10.2174/0113892010316780240807104149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 07/19/2024] [Accepted: 07/23/2024] [Indexed: 08/21/2024]
Abstract
In the last few decades, the rates of infertility among women have been on the rise, usually due to complications with the uterus and related tissue. A wide variety of reasons can cause uterine factor infertility and can be congenital or a result of disease. Uterine transplantation is currently used as a means to enable women with fertility issues to have a natural birth. However, multiple risk factors are involved in uterine transplantation that threaten the lives of the growing fetus and the mother, as a result of which the procedure is not prominently practiced. Uterine tissue engineering provides a potential solution to infertility through the regeneration of replacement of damaged tissue, thus allowing healing and restoration of reproductive capacity. It involves the use of stem cells from the patient incorporated within biocompatible scaffolds to regenerate the entire tissue. This manuscript discusses the need for uterine tissue engineering, giving an overview of the biological and organic material involved in the process. There are numerous existing animal models in which this procedure has been actualized, and the observations from them have been compiled here. These models are used to develop a further understanding of the integration of engineered tissues and the scope of tissue engineering as a treatment for uterine disorders. Additionally, this paper examines the scope and limitations of the procedure.
Collapse
Affiliation(s)
- Krithika Sanjeev
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Megaswana Guruprasad
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Rachna Vikram
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Snigdha Priyadarshini
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Adhish Mazumder
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Manjubala Inderchand
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| |
Collapse
|
|
5
|
Jia M, Wang J, Lin C, Zhang Q, Xue Y, Huang X, Ren Y, Chen C, Liu Y, Xu Y. Hydrogel Strategies for Female Reproduction Dysfunction. ACS NANO 2024; 18:30132-30152. [PMID: 39437800 DOI: 10.1021/acsnano.4c05634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Infertility is an important issue for human reproductive health, with over half of all cases of infertility associated with female factors. Dysfunction of the complex female reproductive system may cause infertility. In clinical practice, female infertility is often treated with oral medications and/or surgical procedures, and ultimately with assisted reproductive technologies. Owing to their excellent biocompatibility, low immunogenicity, and adjustable mechanical properties, hydrogels are emerging as valuable tools in the reconstruction of organ function, supplemented by tissue engineering techniques to increase their structure and functionality. Hydrogel-based female reproductive reconstruction strategies targeting the pathological mechanisms of female infertility may provide alternatives for the treatment of ovarian, endometrium/uterine, and fallopian tube dysfunction. In this review, we provide a general introduction to the basic physiology and pathology of the female reproductive system, the limitations of current infertility treatments, and the lack of translation from animal models to human reproductive physiology. We further provide an overview of the current and future potential applications of hydrogels in the treatment of female reproductive system dysfunction, highlighting the great prospects of hydrogel-based strategies in the field of translational medicine, along with the significant challenges to be overcome.
Collapse
Affiliation(s)
- Minxuan Jia
- New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China
- GBA National Institute for Nanotechnology Innovation, Guangzhou, Guangdong 510535, China
- School of Biomedical Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510006, China
| | - Jiamin Wang
- Reproductive Medical Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- The Key Laboratory of Reproductive Medicine of Guangdong Province, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, Guangdong 510080, China
| | - Chubing Lin
- New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China
- GBA National Institute for Nanotechnology Innovation, Guangzhou, Guangdong 510535, China
- School of Biomedical Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510006, China
| | - Qingyan Zhang
- Reproductive Medical Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- The Key Laboratory of Reproductive Medicine of Guangdong Province, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, Guangdong 510080, China
| | - Yueguang Xue
- New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China
- GBA National Institute for Nanotechnology Innovation, Guangzhou, Guangdong 510535, China
- School of Biomedical Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510006, China
| | - Xin Huang
- New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China
- GBA National Institute for Nanotechnology Innovation, Guangzhou, Guangdong 510535, China
- School of Biomedical Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510006, China
| | - Yan Ren
- New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China
| | - Chunying Chen
- New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China
| | - Ying Liu
- New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China
| | - Yanwen Xu
- Reproductive Medical Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- The Key Laboratory of Reproductive Medicine of Guangdong Province, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, Guangdong 510080, China
| |
Collapse
|
|
6
|
Zhang Y, Li D, Han Y, Wu M, Zhang S, Ma H, Liu L, Ju X. Intraovarian injection of 3D-MSC-EVs-ECM gel significantly improved rat ovarian function after chemotherapy. Reprod Biol Endocrinol 2024; 22:125. [PMID: 39415205 PMCID: PMC11481453 DOI: 10.1186/s12958-024-01299-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 10/07/2024] [Indexed: 10/18/2024] Open
Abstract
BACKGROUND Restoring the function of the ovary is important for chemotherapy-induced ovarian failure (COF) patients. Stem cell and extracellular vesicles (EVs) therapy show promise but need further improvement. METHODS Human umbilical cord mesenchymal stem cells (hUC-MSCs) were primarily cultured and further three-dimensional (3D) cultured using an ultra-low attachment surface method. The expression levels of nutritional cytokines and immunomodulatory and stemness-related genes of 3D-cultured hUC-MSCs were analyzed. EVs were isolated by ultracentrifugation and characterized. Ovaries were decellularized with sodium dodecyl sulfate to obtain extracellular matrix (ECM). Lyophilized EVs from three-dimensional (2D) or 3D hUC-MSCs were mixed with ECM to prepare the 2D/3D-MSC-EVs-ECM gels. The therapeutic effect of the MSC-EVs-ECM gel on cyclophosphamide (CTX) -treated rats was analyzed through various tests. RNA sequencing was used to analyze the expression changes of genes before and after treatment. RESULTS After culturing in ultra-low attachment dishes, hUC-MSCs aggregated into spheroids and significantly upregulated the expression levels of immunomodulatory and stemness-related genes. The total EVs yield was also upregulated (5.6-fold) after 3D culture. The cell viability of CTX-treated ovarian granulosa cells (OGCs) was significantly rescued by coculture with the 3D-MSC-EVs-ECM gel. Hormones indicative of ovarian function, AMH, E2, and FSH, were recovered in both the CTX + 2D-MSC-EVs-ECM gel group and the CTX + 3D-MSC-EVs-ECM gel group, while the apoptosis-related protein Bax was significantly downregulated. The 3D-MSC-EVs-ECM gel was more effective than the 2D-MSC-EVs-ECM gel. Significantly differentially expressed genes, such as Hbb-b1, Gpd1, and Sirpa, were detected by RNA sequencing. Hbb-b1 was increased in the ovaries of CTX-treated rats, and this increase was attenuated by injecting the 2D/3D-MSC-EVs-ECM gel. Gpd1 was increased after CTX treatment, and this increase was reversed by the 3D-MSC-EVs-ECM gel. Sirpa was decreased in the ovaries of CTX-treated rats, and this decrease was attenuated by injecting the 3D-MSC-EVs-ECM gel. CONCLUSIONS Our study demonstrated that the 3D-MSC-EVs-ECM gel is an efficient strategy for the recovery of ovarian function in CTX-induced ovarian failure.
Collapse
Affiliation(s)
- Yaping Zhang
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan, Shandong Province, 250012, China
- Department of Anesthesiology, Shanghai Jiaotong University First People's Hospital (Shanghai General Hospital), Shanghai, China
| | - Dong Li
- Laboratory of Cryomedicine, Qilu Hospital of Shandong University, Jinan, Shandong Province, 250012, China
| | - Yi Han
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan, Shandong Province, 250012, China
- Laboratory of Cryomedicine, Qilu Hospital of Shandong University, Jinan, Shandong Province, 250012, China
| | - Min Wu
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan, Shandong Province, 250012, China
- Laboratory of Cryomedicine, Qilu Hospital of Shandong University, Jinan, Shandong Province, 250012, China
| | - Shule Zhang
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan, Shandong Province, 250012, China
- Laboratory of Cryomedicine, Qilu Hospital of Shandong University, Jinan, Shandong Province, 250012, China
| | - Huixian Ma
- Laboratory of Cryomedicine, Qilu Hospital of Shandong University, Jinan, Shandong Province, 250012, China
| | - Linghong Liu
- Laboratory of Cryomedicine, Qilu Hospital of Shandong University, Jinan, Shandong Province, 250012, China
| | - Xiuli Ju
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan, Shandong Province, 250012, China.
- Laboratory of Cryomedicine, Qilu Hospital of Shandong University, Jinan, Shandong Province, 250012, China.
| |
Collapse
|
|
7
|
Rodríguez-Eguren A, Bueno-Fernandez C, Gómez-Álvarez M, Francés-Herrero E, Pellicer A, Bellver J, Seli E, Cervelló I. Evolution of biotechnological advances and regenerative therapies for endometrial disorders: a systematic review. Hum Reprod Update 2024; 30:584-613. [PMID: 38796750 PMCID: PMC11369227 DOI: 10.1093/humupd/dmae013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 04/12/2024] [Indexed: 05/28/2024] Open
Abstract
BACKGROUND The establishment and maintenance of pregnancy depend on endometrial competence. Asherman syndrome (AS) and intrauterine adhesions (IUA), or endometrial atrophy (EA) and thin endometrium (TE), can either originate autonomously or arise as a result from conditions (i.e. endometritis or congenital hypoplasia), or medical interventions (e.g. surgeries, hormonal therapies, uterine curettage or radiotherapy). Affected patients may present an altered or inadequate endometrial lining that hinders embryo implantation and increases the risk of poor pregnancy outcomes and miscarriage. In humans, AS/IUA and EA/TE are mainly treated with surgeries or pharmacotherapy, however the reported efficacy of these therapeutic approaches remains unclear. Thus, novel regenerative techniques utilizing stem cells, growth factors, or tissue engineering have emerged to improve reproductive outcomes. OBJECTIVE AND RATIONALE This review comprehensively summarizes the methodologies and outcomes of emerging biotechnologies (cellular, acellular, and bioengineering approaches) to treat human endometrial pathologies. Regenerative therapies derived from human tissues or blood which were studied in preclinical models (in vitro and in vivo) and clinical trials are discussed. SEARCH METHODS A systematic search of full-text articles available in PubMed and Embase was conducted to identify original peer-reviewed studies published in English between January 2000 and September 2023. The search terms included: human, uterus, endometrium, Asherman syndrome, intrauterine adhesions, endometrial atrophy, thin endometrium, endometritis, congenital hypoplasia, curettage, radiotherapy, regenerative therapy, bioengineering, stem cells, vesicles, platelet-rich plasma, biomaterials, microfluidic, bioprinting, organoids, hydrogel, scaffold, sheet, miRNA, sildenafil, nitroglycerine, aspirin, growth hormone, progesterone, and estrogen. Preclinical and clinical studies on cellular, acellular, and bioengineering strategies to repair or regenerate the human endometrium were included. Additional studies were identified through manual searches. OUTCOMES From a total of 4366 records identified, 164 studies (3.8%) were included for systematic review. Due to heterogeneity in the study design and measured outcome parameters in both preclinical and clinical studies, the findings were evaluated qualitatively and quantitatively without meta-analysis. Groups using stem cell-based treatments for endometrial pathologies commonly employed mesenchymal stem cells (MSCs) derived from the human bone marrow or umbilical cord. Alternatively, acellular therapies based on platelet-rich plasma (PRP) or extracellular vesicles are gaining popularity. These are accompanied by the emergence of bioengineering strategies based on extracellular matrix (ECM)-derived hydrogels or synthetic biosimilars that sustain local delivery of cells and growth factors, reporting promising results. Combined therapies that target multiple aspects of tissue repair and regeneration remain in preclinical testing but have shown translational value. This review highlights the myriad of therapeutic material sources, administration methods, and carriers that have been tested. WIDER IMPLICATIONS Therapies that promote endometrial proliferation, vascular development, and tissue repair may help restore endometrial function and, ultimately, fertility. Based on the existing evidence, cost, accessibility, and availability of the therapies, we propose the development of triple-hit regenerative strategies, potentially combining high-yield MSCs (e.g. from bone marrow or umbilical cord) with acellular treatments (PRP), possibly integrated in ECM hydrogels. Advances in biotechnologies together with insights from preclinical models will pave the way for developing personalized treatment regimens for patients with infertility-causing endometrial disorders such as AS/IUA, EA/TE, and endometritis. REGISTRATION NUMBER https://osf.io/th8yf/.
Collapse
Affiliation(s)
- Adolfo Rodríguez-Eguren
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Clara Bueno-Fernandez
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
- Department of Paediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - María Gómez-Álvarez
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Emilio Francés-Herrero
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
- Department of Paediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Antonio Pellicer
- Department of Paediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of Valencia, Valencia, Spain
- IVIRMA Global Research Alliance, IVI Rome, Rome, Italy
| | - José Bellver
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
- Department of Paediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of Valencia, Valencia, Spain
- IVIRMA Global Research Alliance, IVI Valencia, Valencia, Spain
| | - Emre Seli
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
- IVIRMA Global Research Alliance, IVIRMA New Jersey, Basking Ridge, NJ, USA
| | - Irene Cervelló
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| |
Collapse
|
|
8
|
Francés-Herrero E, Bueno-Fernandez C, Rodríguez-Eguren A, Gómez-Álvarez M, Faus A, Soto-Prado A, Buigues A, Herraiz S, Pellicer A, Cervelló I. Growth factor-loaded ovarian extracellular matrix hydrogels promote in vivo ovarian niche regeneration and enhance fertility in premature ovarian insufficiency preclinical models. Acta Biomater 2024; 186:125-140. [PMID: 39111680 DOI: 10.1016/j.actbio.2024.07.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/25/2024] [Accepted: 07/30/2024] [Indexed: 08/16/2024]
Abstract
Premature ovarian insufficiency (POI) means menopause before 40 years of age affecting about 1 % of women. Approaches based on cell therapy and the paracrine effects of stem cells or bioproducts such as platelet-rich plasma have been proposed, but concerns remain about undesired systemic effects, as well as the need to optimize delivery methods through bioengineering methods. This study explores the efficacy of decellularized bovine ovarian cortex extracellular matrix (OvaECM) hydrogels alone and as a growth factor (GF) carrier (OvaECM+GF) in a chemotherapy-induced POI murine model. In vitro assays showed a gradual release of GF from the OvaECM sustained for two weeks. Chemotherapy drastically reduced follicle numbers, but OvaECM+GF treatment restored pre-antral follicle development. Moreover, this treatment notably regenerated the ovarian microenvironment by increasing cell proliferation and microvessel density while reducing chemotherapy-induced apoptosis and fibrosis. Whole-ovary RNA sequencing and gene set enrichment analysis revealed an upregulation of regeneration-related genes and a downregulation of apoptotic pathways. The OvaECM+GF treatment also yielded significantly better outcomes following ovarian stimulation and in vitro fertilization. After two consecutive crossbreeding cycles, OvaECM+GF-treated mice showed normal reproductive function. This research showcases the biocompatibility and efficacy of OvaECM to reverse POI in mice, setting a foundation to explore innovative bioengineering-based POI therapies. STATEMENT OF SIGNIFICANCE: Premature ovarian insufficiency (POI) affects about 1 % of women worldwide, causing early menopause before 40 years old. Current treatments alleviate symptoms but do not restore ovarian function. This study explores an innovative approach using ovarian cortex extracellular matrix hydrogels to deliver growth factors into the murine ovarian niche and reverse POI. In vitro release kinetic assays demonstrated a gradual and sustained release of growth factors. In a POI-induced mouse model, intraovarian injections of the hydrogel encapsulating growth factors restored pre-antral follicle development, increased cell proliferation, reduced apoptosis and fibrosis, and improved ovarian response and in vitro fertilization outcomes. Long-term benefits included larger litter sizes. This innovative technique shows promise in regenerating the ovarian environment and improving reproductive outcomes.
Collapse
Affiliation(s)
- Emilio Francés-Herrero
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Clara Bueno-Fernandez
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Adolfo Rodríguez-Eguren
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - María Gómez-Álvarez
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Amparo Faus
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Alexandra Soto-Prado
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain
| | - Anna Buigues
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Sonia Herraiz
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Antonio Pellicer
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain; IVIRMA Global Research Alliance, IVI Roma Parioli, 00197 Rome, Italy
| | - Irene Cervelló
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain.
| |
Collapse
|
|
9
|
Liu Y, Jia D, Li L, Wang M. Advances in Nanomedicine and Biomaterials for Endometrial Regeneration: A Comprehensive Review. Int J Nanomedicine 2024; 19:8285-8308. [PMID: 39161362 PMCID: PMC11330863 DOI: 10.2147/ijn.s473259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 07/30/2024] [Indexed: 08/21/2024] Open
Abstract
The endometrium is an extremely important component of the uterus and is crucial for individual health and human reproduction. However, traditional methods still struggle to ideally repair the structure and function of damaged endometrium and restore fertility. Therefore, seeking and developing innovative technologies and materials has the potential to repair and regenerate damaged or diseased endometrium. The emergence and functionalization of various nanomedicine and biomaterials, as well as the proposal and development of regenerative medicine and tissue engineering techniques, have brought great hope for solving these problems. In this review, we will summarize various nanomedicine, biomaterials, and innovative technologies that contribute to endometrial regeneration, including nanoscale exosomes, nanomaterials, stem cell-based materials, naturally sourced biomaterials, chemically synthesized biomaterials, approaches and methods for functionalizing biomaterials, as well as the application of revolutionary new technologies such as organoids, organ-on-chips, artificial intelligence, etc. The diverse design and modification of new biomaterials endow them with new functionalities, such as microstructure or nanostructure, mechanical properties, biological functions, and cellular microenvironment regulation. It will provide new options for the regeneration of endometrium, bring new hope for the reconstruction and recovery of patients' reproductive abilities.
Collapse
Affiliation(s)
- Yanhong Liu
- Center for Prenatal Diagnosis, Center for Reproductive Medicine, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Dongyun Jia
- Center for Prenatal Diagnosis, Center for Reproductive Medicine, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Lin Li
- Center for Prenatal Diagnosis, Center for Reproductive Medicine, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Meiyan Wang
- Center for Prenatal Diagnosis, Center for Reproductive Medicine, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| |
Collapse
|
|
10
|
Liu Y, Sun Y, Cheng S. Advances in the use of organoids in endometrial diseases. Int J Gynaecol Obstet 2024; 166:502-511. [PMID: 38391201 DOI: 10.1002/ijgo.15422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 01/29/2024] [Indexed: 02/24/2024]
Abstract
The endometrium undergoes cyclical changes in response to hormones and there is a certain degree of heterogeneity among individuals. In vivo identification of the physiologic changes of the endometrium and the pathologic process of related diseases is challenging. There have been recent advances in the use of organoids that mimic the characteristics of the corresponding organs and the morphologic, functional, and personalized characteristics involved in different stages of diseases. In this paper, we discuss the process of creating endometrial organoids, cell sources, types of extracellular matrices, and their application in the study of physiologic endometrial states and various diseases.
Collapse
Affiliation(s)
- Yaofang Liu
- Department of Reproductive Technology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yue Sun
- Department of Reproductive Technology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Shaolong Cheng
- Department of Reproductive Technology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| |
Collapse
|
|
11
|
Sanguansook P, Martínez-López C, Izquierdo-Rico MJ, Martínez-Cáceres C, López-Orozco M, Chatdarong K, García-Vázquez FA. Development of decellularization protocols for female cat reproductive organs. Res Vet Sci 2024; 173:105257. [PMID: 38636324 DOI: 10.1016/j.rvsc.2024.105257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 03/27/2024] [Accepted: 04/08/2024] [Indexed: 04/20/2024]
Abstract
Decellularization is an innovative method to create natural scaffolds by removing all cellular materials while preserving the composition and three-dimensional ultrastructure of the extracellular matrix (ECM). The obtention of decellularized reproductive organs in cats might facilitate the development of assisted reproductive techniques not only in this species but also in other felids. The aim was to compare the efficiency of three decellularization protocols on reproductive organs (ovary, oviduct, and uterine horn) in domestic cats. The decellularization protocol involved 0.1% sodium dodecyl sulfate and 1%Triton X-100. Protocol 1 (P1) entailed 2-cycles of decellularization using these detergents. Protocol 2 (P2) was like P1 but included 3-cycles. Protocol 3 (P3) was similar to P2, with the addition of deoxyribonuclease incubation. Reproductive organs from nine cats were separated into two sides. One side served as the control (non-decellularized organ) while the contralateral side was the treated group (decellularized organ). The treated organs were subdivided into 3 groups (n = 3 per group) for each protocol. Both control and treated samples were analyzed for DNA content, histology (nuclear and ECM (collagen, elastin, and glycosaminoglycans (GAGs)) density), ultrastructure by electron microscopy, and cytotoxicity. The results of the study showed that P3 was the only protocol that displayed no nucleus residue and significantly reduced DNA content in decellularized samples (in all the studied organs) compared to the control (P < 0.05). The ECM content in the ovaries remained similar across all protocols compared with controls (P > 0.05). However, elastic fibers and GAGs decreased in decellularized oviducts (P < 0.05), while collagen levels remained unchanged (P > 0.05). Regarding the uterus, the ECM content decreased in decellularized uterine horns from P3 (P < 0.05). Electron microscopy revealed that the microarchitecture of the decellularized samples was maintained compared to controls. The decellularized tissues, upon being washed for 24 h, showed cytocompatibility following co-incubation with sperm. In conclusion, when comparing different decellularization methods, P3 proved to be the most efficient in removing nuclear material from reproductive organs compared to P1 and P2. P3 demonstrated its success in decellularizing ovarian samples by significantly decreasing DNA content while maintaining ECM components and tissue microarchitecture. However, P3 was less effective in maintaining ECM contents in decellularized oviducts and uterine horns.
Collapse
Affiliation(s)
- Phakjira Sanguansook
- Department of Obstetrics, Gynaecology and Reproduction, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Cristina Martínez-López
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Pascual Parrilla (IMIB), Murcia, Spain; Departamento de Fisiología, Facultad de Veterinaria, Universidad de Murcia, Murcia, Spain
| | - Mª José Izquierdo-Rico
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Pascual Parrilla (IMIB), Murcia, Spain
| | | | - Marina López-Orozco
- Departamento de Producción Animal, Facultad de Veterinaria, Campus de Excelencia Internacional para la Educación Superior y la Investigación "Campus Mare Nostrum", Universidad de Murcia, Murcia, Spain
| | - Kaywalee Chatdarong
- Department of Obstetrics, Gynaecology and Reproduction, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand.
| | - Francisco Alberto García-Vázquez
- Instituto Murciano de Investigación Biosanitaria Pascual Parrilla (IMIB), Murcia, Spain; Departamento de Fisiología, Facultad de Veterinaria, Universidad de Murcia, Murcia, Spain.
| |
Collapse
|
|
12
|
Xie X, Ao X, Xu R, Lv H, Tan S, Wu J, Zhao L, Wang Y. Injectable, stable, and biodegradable hydrogel with platelet-rich plasma induced by l-serine and sodium alginate for effective treatment of intrauterine adhesions. Int J Biol Macromol 2024; 270:132363. [PMID: 38754675 DOI: 10.1016/j.ijbiomac.2024.132363] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/16/2024] [Accepted: 05/11/2024] [Indexed: 05/18/2024]
Abstract
The combination of pharmacological and physical barrier therapy is a highly promising strategy for treating intrauterine adhesions (IUAs), but there lacks a suitable scaffold that integrates good injectability, proper mechanical stability and degradability, excellent biocompatibility, and non-toxic, non-rejection therapeutic agents. To address this, a novel injectable, degradable hydrogel composed of poly(ethylene glycol) diacrylate (PEGDA), sodium alginate (SA), and l-serine, and loaded with platelet-rich plasma (PRP) (referred to as PSL-PRP) is developed for treating IUAs. l-Serine induces rapid gelation within 1 min and enhances the mechanical properties of the hydrogel, while degradable SA provides the hydrogel with strength, toughness, and appropriate degradation capabilities. As a result, the hydrogel exhibits an excellent scaffold for sustained release of growth factors in PRP and serves as an effective physical barrier. In vivo testing using a rat model of IUAs demonstrates that in situ injection of the PSL-PRP hydrogel significantly reduces fibrosis and promotes endometrial regeneration, ultimately leading to fertility restoration. The combined advantages make the PSL-PRP hydrogel very promising in IUAs therapy and in preventing adhesions in other internal tissue wounds.
Collapse
Affiliation(s)
- Xiangyan Xie
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Xue Ao
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Ruijuan Xu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Hongyi Lv
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Shiqiao Tan
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Jinrong Wu
- State Key Laboratory of Polymer Materials Engineering, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
| | - Lijuan Zhao
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China.
| | - Yi Wang
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China.
| |
Collapse
|
|
13
|
Dai W, Liang J, Guo R, Zhao Z, Na Z, Xu D, Li D. Bioengineering approaches for the endometrial research and application. Mater Today Bio 2024; 26:101045. [PMID: 38600921 PMCID: PMC11004221 DOI: 10.1016/j.mtbio.2024.101045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/07/2024] [Accepted: 03/29/2024] [Indexed: 04/12/2024] Open
Abstract
The endometrium undergoes a series of precise monthly changes under the regulation of dynamic levels of ovarian hormones that are characterized by repeated shedding and subsequent regeneration without scarring. This provides the potential for wound healing during endometrial injuries. Bioengineering materials highlight the faithful replication of constitutive cells and the extracellular matrix that simulates the physical and biomechanical properties of the endometrium to a larger extent. Significant progress has been made in this field, and functional endometrial tissue bioengineering allows an in-depth investigation of regulatory factors for endometrial and myometrial defects in vitro and provides highly therapeutic methods to alleviate obstetric and gynecological complications. However, much remains to be learned about the latest progress in the application of bioengineering technologies to the human endometrium. Here, we summarize the existing developments in biomaterials and bioengineering models for endometrial regeneration and improving the female reproductive potential.
Collapse
Affiliation(s)
- Wanlin Dai
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Junzhi Liang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Renhao Guo
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- NHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health Commission, Shenyang, China
| | - Zhongyu Zhao
- Innovation Institute, China Medical University, Shenyang, China
| | - Zhijing Na
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- NHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health Commission, Shenyang, China
| | - Dake Xu
- Shenyang National Laboratory for Materials Science, Northeastern University, Shenyang, China
| | - Da Li
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- NHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health Commission, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Shenyang, China
| |
Collapse
|
|
14
|
Wei S, Li Z, Xia H, Wang Z, Deng J, Li L, Huang R, Ye T, Huang Y, Yang Y. An endometrial biomimetic extracellular matrix (ECM) for enhanced endometrial regeneration using hyaluronic acid hydrogel containing recombinant human type III collagen. Int J Biol Macromol 2024; 268:131723. [PMID: 38649072 DOI: 10.1016/j.ijbiomac.2024.131723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/13/2024] [Accepted: 04/18/2024] [Indexed: 04/25/2024]
Abstract
Endometrial injury poses a significant challenge in tissue regeneration, with type III collagen (COL III) playing a pivotal role in maintaining endometrial integrity and facilitating repair. Our study explored the utility of recombinant human type III collagen (RHC) as an intervention for endometrial damage. To address the challenges associated with the inherent instability and rapid degradation of COL III in vivo, we developed an RHC-HA hydrogel by conjugating RHC with hyaluronic acid (HA), thus ensuring a more stable and sustained delivery. Our findings suggested that the RHC-HA hydrogel significantly promoted endometrial regeneration and restored fertility. The hydrogel facilitated prolonged retention of RHC in the uterus, leading to a substantial improvement in the repair process. The synergistic interaction between RHC and HA greatly enhances cell proliferation and adhesion, surpassing the efficacy of HA or RHC alone. Additionally, the RHC-HA hydrogel demonstrated notable anti-fibrotic effects, which are crucial for preventing abnormalities during endometrial healing. These findings suggested that the RHC-HA hydrogel presented a therapeutic strategy in the treatment of uterine endometrial injuries, which may improve female reproductive health.
Collapse
Affiliation(s)
- Siying Wei
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Ziyi Li
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Huan Xia
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Zhaoyang Wang
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Jingxian Deng
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Lu Li
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Rufei Huang
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Tao Ye
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Yadong Huang
- Department of Cell Biology, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China.
| | - Yan Yang
- Department of Cell Biology, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China.
| |
Collapse
|
|
15
|
Liang Y, Shuai Q, Zhang X, Jin S, Guo Y, Yu Z, Xu X, Ao R, Peng Z, Lv H, He S, Wang C, Song G, Liu Z, Zhao H, Feng Q, Du R, Zheng B, Chen Z, Xie J. Incorporation of Decidual Stromal Cells Derived Exosomes in Sodium Alginate Hydrogel as an Innovative Therapeutic Strategy for Advancing Endometrial Regeneration and Reinstating Fertility. Adv Healthc Mater 2024; 13:e2303674. [PMID: 38315148 DOI: 10.1002/adhm.202303674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Indexed: 02/07/2024]
Abstract
Intrauterine adhesion (IUA) stands as a prevalent medical condition characterized by endometrial fibrosis and scar tissue formation within the uterine cavity, resulting in infertility and, in severe cases, recurrent miscarriages. Cell therapy, especially with stem cells, offers an alternative to surgery, but concerns about uncontrolled differentiation and tumorigenicity limit its use. Exosomes, more stable and immunogenicity-reduced than parent cells, have emerged as a promising avenue for IUA treatment. In this study, a novel approach has been proposed wherein exosomes originating from decidual stromal cells (DSCs) are encapsulated within sodium alginate hydrogel (SAH) scaffolds to repair endometrial damage and restore fertility in a mouse IUA model. Current results demonstrate that in situ injection of DSC-derived exosomes (DSC-exos)/SAH into the uterine cavity has the capability to induce uterine angiogenesis, initiate mesenchymal-to-epithelial transformation (MET), facilitate collagen fiber remodeling and dissolution, promote endometrial regeneration, enhance endometrial receptivity, and contribute to the recovery of fertility. RNA sequencing and advanced bioinformatics analysis reveal miRNA enrichment in exosomes, potentially supporting endometrial repair. This finding elucidates how DSC-exos/SAH mechanistically fosters collagen ablation, endometrium regeneration, and fertility recovery, holding the potential to introduce a novel IUA treatment and offering invaluable insights into the realm of regenerative medicine.
Collapse
Affiliation(s)
- Yuxiang Liang
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
- Shanxi Key Laboratory of Human Disease and Animal Models, Experimental Animal Center of Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Qizhi Shuai
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Xiao Zhang
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Shanshan Jin
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Yuqian Guo
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Zhaowei Yu
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Xinrui Xu
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Ruifang Ao
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Zhiwei Peng
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Huimin Lv
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
- Department of Obstetrics and Gynecology, Third Hospital of Shanxi Medical University (Shanxi Bethune Hospital), Shanxi Academy of Medical Sciences, Taiyuan, 030032, China
| | - Sheng He
- Department of Radiology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Chunfang Wang
- Shanxi Key Laboratory of Human Disease and Animal Models, Experimental Animal Center of Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Guohua Song
- Shanxi Key Laboratory of Human Disease and Animal Models, Experimental Animal Center of Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Zhizhen Liu
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Hong Zhao
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Qilong Feng
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| | - Ruochen Du
- Shanxi Key Laboratory of Human Disease and Animal Models, Experimental Animal Center of Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Bin Zheng
- School of Pharmacy, Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Zhaoyang Chen
- Shanxi Key Laboratory of Human Disease and Animal Models, Experimental Animal Center of Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Jun Xie
- Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Taiyuan, Shanxi, 030001, China
| |
Collapse
|
|
16
|
Cao Y, Qi J, Wang J, Chen L, Wang Y, Long Y, Li B, Lai J, Yao Y, Meng Y, Yu X, Chen X, Ng LG, Li X, Lu Y, Cheng X, Cui W, Sun Y. Injectable "Homing-Like" Bioactive Short-Fibers for Endometrial Repair and Efficient Live Births. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306507. [PMID: 38504456 PMCID: PMC11132084 DOI: 10.1002/advs.202306507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 12/14/2023] [Indexed: 03/21/2024]
Abstract
The prevalence of infertility caused by endometrial defects is steadily increasing, posing a significant challenge to women's reproductive health. In this study, injectable "homing-like" bioactive decellularized extracellular matrix short-fibers (DEFs) of porcine skin origin are innovatively designed for endometrial and fertility restoration. The DEFs can effectively bind to endometrial cells through noncovalent dipole interactions and release bioactive growth factors in situ. In vitro, the DEFs effectively attracted endometrial cells through the "homing-like" effect, enabling cell adhesion, spreading, and proliferation on their surface. Furthermore, the DEFs effectively facilitated the proliferation and angiogenesis of human primary endometrial stromal cells (HESCs) and human umbilical vein endothelial cells (HUVECs), and inhibited fibrosis of pretreated HESCs. In vivo, the DEFs significantly accelerated endometrial restoration, angiogenesis, and receptivity. Notably, the deposition of endometrial collagen decreased from 41.19 ± 2.16% to 14.15 ± 1.70% with DEFs treatment. Most importantly, in endometrium-injured rats, the use of DEFs increased the live birth rate from 30% to an impressive 90%, and the number and development of live births close to normal rats. The injectable "homing-like" bioactive DEFs system can achieve efficient live births and intrauterine injection of DEFs provides a new promising clinical strategy for endometrial factor infertility.
Collapse
Affiliation(s)
- Yumeng Cao
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Jia Qi
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Juan Wang
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Liang Chen
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Yuan Wang
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Yijing Long
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Boyu Li
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Junliang Lai
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Yejie Yao
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Yiwen Meng
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Xiaohua Yu
- Hangzhou Phil Stone Biotech Co., Ltd.HangzhouZhejiang311215P. R. China
| | - Xiao‐Dong Chen
- Department of Comprehensive DentistryUniversity of Texas Health Science Center at San AntonioSan AntonioTX78229USA
- Research ServiceSouth Texas Veterans Health Care SystemAudie Murphy VA Medical CenterSan AntonioTX78229USA
| | - Lai Guan Ng
- Shanghai Immune Therapy InstituteShanghai Jiao Tong University School of Medicine affiliated Renji HospitalShanghai200127P. R. China
| | - Xinyu Li
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Yao Lu
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Xiaoyue Cheng
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| | - Wenguo Cui
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Yun Sun
- Department of Reproductive Medicine, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200135P. R. China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai200135P. R. China
| |
Collapse
|
|
17
|
Gómez‐Álvarez M, Bueno‐Fernandez C, Rodríguez‐Eguren A, Francés‐Herrero E, Agustina‐Hernández M, Faus A, Gisbert Roca F, Martínez‐Ramos C, Galán A, Pellicer A, Ferrero H, Cervelló I. Hybrid Endometrial-Derived Hydrogels: Human Organoid Culture Models and In Vivo Perspectives. Adv Healthc Mater 2024; 13:e2303838. [PMID: 37983675 PMCID: PMC11468130 DOI: 10.1002/adhm.202303838] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Indexed: 11/22/2023]
Abstract
The endometrium plays a vital role in fertility, providing a receptive environment for embryo implantation and development. Understanding the endometrial physiology is essential for developing new strategies to improve reproductive healthcare. Human endometrial organoids (hEOs) are emerging as powerful models for translational research and personalized medicine. However, most hEOs are cultured in a 3D microenvironment that significantly differs from the human endometrium, limiting their applicability in bioengineering. This study presents a hybrid endometrial-derived hydrogel that combines the rigidity of PuraMatrix (PM) with the natural scaffold components and interactions of a porcine decellularized endometrial extracellular matrix (EndoECM) hydrogel. This hydrogel provides outstanding support for hEO culture, enhances hEO differentiation efficiency due to its biochemical similarity with the native tissue, exhibits superior in vivo stability, and demonstrates xenogeneic biocompatibility in mice over a 2-week period. Taken together, these attributes position this hybrid endometrial-derived hydrogel as a promising biomaterial for regenerative treatments in reproductive medicine.
Collapse
Affiliation(s)
- María Gómez‐Álvarez
- IVIRMA Global Research AllianceIVI FoundationInstituto de Investigación Sanitaria La Fe (IIS La Fe)Valencia46026Spain
| | - Clara Bueno‐Fernandez
- IVIRMA Global Research AllianceIVI FoundationInstituto de Investigación Sanitaria La Fe (IIS La Fe)Valencia46026Spain
- Universitat de ValènciaDepartment of PediatricsObstetrics and GynaecologyValencia46010Spain
| | - Adolfo Rodríguez‐Eguren
- IVIRMA Global Research AllianceIVI FoundationInstituto de Investigación Sanitaria La Fe (IIS La Fe)Valencia46026Spain
| | - Emilio Francés‐Herrero
- IVIRMA Global Research AllianceIVI FoundationInstituto de Investigación Sanitaria La Fe (IIS La Fe)Valencia46026Spain
- Universitat de ValènciaDepartment of PediatricsObstetrics and GynaecologyValencia46010Spain
| | - Marcos Agustina‐Hernández
- IVIRMA Global Research AllianceIVI FoundationInstituto de Investigación Sanitaria La Fe (IIS La Fe)Valencia46026Spain
| | - Amparo Faus
- IVIRMA Global Research AllianceIVI FoundationInstituto de Investigación Sanitaria La Fe (IIS La Fe)Valencia46026Spain
| | - Fernando Gisbert Roca
- Universitat Politècnica de ValènciaCentre for Biomaterials and Tissue EngineeringValencia46022Spain
| | - Cristina Martínez‐Ramos
- Universitat Politècnica de ValènciaCentre for Biomaterials and Tissue EngineeringValencia46022Spain
- Unitat Predepartamental de MedicinaUniversitat Jaume ICastellón de la Plana12071Spain
| | - Amparo Galán
- Laboratory of NeuroendocrinologyPrince Felipe Research Center (CIPF)Valencia46012Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)Instituto de Salud Carlos IIIMadrid28029Spain
| | | | - Hortensia Ferrero
- IVIRMA Global Research AllianceIVI FoundationInstituto de Investigación Sanitaria La Fe (IIS La Fe)Valencia46026Spain
| | - Irene Cervelló
- IVIRMA Global Research AllianceIVI FoundationInstituto de Investigación Sanitaria La Fe (IIS La Fe)Valencia46026Spain
| |
Collapse
|
|
18
|
Hu X, Wu H, Yong X, Wang Y, Yang S, Fan D, Xiao Y, Che L, Shi K, Li K, Xiong C, Zhu H, Qian Z. Cyclical endometrial repair and regeneration: Molecular mechanisms, diseases, and therapeutic interventions. MedComm (Beijing) 2023; 4:e425. [PMID: 38045828 PMCID: PMC10691302 DOI: 10.1002/mco2.425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 10/21/2023] [Accepted: 10/27/2023] [Indexed: 12/05/2023] Open
Abstract
The endometrium is a unique human tissue with an extraordinary ability to undergo a hormone-regulated cycle encompassing shedding, bleeding, scarless repair, and regeneration throughout the female reproductive cycle. The cyclical repair and regeneration of the endometrium manifest as changes in endometrial epithelialization, glandular regeneration, and vascularization. The mechanisms encompass inflammation, coagulation, and fibrinolytic system balance. However, specific conditions such as endometriosis or TCRA treatment can disrupt the process of cyclical endometrial repair and regeneration. There is uncertainty about traditional clinical treatments' efficacy and side effects, and finding new therapeutic interventions is essential. Researchers have made substantial progress in the perspective of regenerative medicine toward maintaining cyclical endometrial repair and regeneration in recent years. Such progress encompasses the integration of biomaterials, tissue-engineered scaffolds, stem cell therapies, and 3D printing. This review analyzes the mechanisms, diseases, and interventions associated with cyclical endometrial repair and regeneration. The review discusses the advantages and disadvantages of the regenerative interventions currently employed in clinical practice. Additionally, it highlights the significant advantages of regenerative medicine in this domain. Finally, we review stem cells and biologics among the available interventions in regenerative medicine, providing insights into future therapeutic strategies.
Collapse
Affiliation(s)
- Xulin Hu
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Haoming Wu
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | - Xin Yong
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of BiotherapySichuan UniversityChengduSichuanChina
| | - Yao Wang
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | - Shuhao Yang
- Department of OrthopedicsThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Diyi Fan
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | - Yibo Xiao
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | - Lanyu Che
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | - Kun Shi
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Kainan Li
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | | | - Huili Zhu
- Department of Reproductive Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of EducationWest China Second University Hospital of Sichuan UniversityChengduSichuanChina
| | - Zhiyong Qian
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduSichuanChina
| |
Collapse
|
|
19
|
Wu F, Lei N, Yang S, Zhou J, Chen M, Chen C, Qiu L, Guo R, Li Y, Chang L. Treatment strategies for intrauterine adhesion: focus on the exosomes and hydrogels. Front Bioeng Biotechnol 2023; 11:1264006. [PMID: 37720318 PMCID: PMC10501405 DOI: 10.3389/fbioe.2023.1264006] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 08/21/2023] [Indexed: 09/19/2023] Open
Abstract
Intrauterine adhesion (IUA), also referred to as Asherman Syndrome (AS), results from uterine trauma in both pregnant and nonpregnant women. The IUA damages the endometrial bottom layer, causing partial or complete occlusion of the uterine cavity. This leads to irregular menstruation, infertility, or repeated abortions. Transcervical adhesion electroreception (TCRA) is frequently used to treat IUA, which greatly lowers the prevalence of adhesions and increases pregnancy rates. Although surgery aims to disentangle the adhesive tissue, it can exacerbate the development of IUA when the degree of adhesion is severer. Therefore, it is critical to develop innovative therapeutic approaches for the prevention of IUA. Endometrial fibrosis is the essence of IUA, and studies have found that the use of different types of mesenchymal stem cells (MSCs) can reduce the risk of endometrial fibrosis and increase the possibility of pregnancy. Recent research has suggested that exosomes derived from MSCs can overcome the limitations of MSCs, such as immunogenicity and tumorigenicity risks, thereby providing new directions for IUA treatment. Moreover, the hydrogel drug delivery system can significantly ameliorate the recurrence rate of adhesions and the intrauterine pregnancy rate of patients, and its potential mechanism in the treatment of IUA has also been studied. It has been shown that the combination of two or more therapeutic schemes has broader application prospects; therefore, this article reviews the pathophysiology of IUA and current treatment strategies, focusing on exosomes combined with hydrogels in the treatment of IUA. Although the use of exosomes and hydrogels has certain challenges in treating IUA, they still provide new promising directions in this field.
Collapse
Affiliation(s)
- Fengling Wu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ningjing Lei
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Shenyu Yang
- Medical 3D Printing Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Junying Zhou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mengyu Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Cheng Chen
- Department of Gynaecology and Obstetrics, Chongqing General Hospital, Chongqing, China
| | - Luojie Qiu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ruixia Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yong Li
- St George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW, Australia
| | - Lei Chang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| |
Collapse
|
|
20
|
Cai D, Weng W. Development potential of extracellular matrix hydrogels as hemostatic materials. Front Bioeng Biotechnol 2023; 11:1187474. [PMID: 37383519 PMCID: PMC10294235 DOI: 10.3389/fbioe.2023.1187474] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 06/02/2023] [Indexed: 06/30/2023] Open
Abstract
The entry of subcutaneous extracellular matrix proteins into the circulation is a key step in hemostasis initiation after vascular injury. However, in cases of severe trauma, extracellular matrix proteins are unable to cover the wound, making it difficult to effectively initiate hemostasis and resulting in a series of bleeding events. Acellular-treated extracellular matrix (ECM) hydrogels are widely used in regenerative medicine and can effectively promote tissue repair due to their high mimic nature and excellent biocompatibility. ECM hydrogels contain high concentrations of extracellular matrix proteins, including collagen, fibronectin, and laminin, which can simulate subcutaneous extracellular matrix components and participate in the hemostatic process. Therefore, it has unique advantages as a hemostatic material. This paper first reviewed the preparation, composition and structure of extracellular hydrogels, as well as their mechanical properties and safety, and then analyzed the hemostatic mechanism of the hydrogels to provide a reference for the application and research, and development of ECM hydrogels in the field of hemostasis.
Collapse
|
|
21
|
Francés-Herrero E, Lopez R, Campo H, de Miguel-Gómez L, Rodríguez-Eguren A, Faus A, Pellicer A, Cervelló I. Advances of xenogeneic ovarian extracellular matrix hydrogels for in vitro follicle development and oocyte maturation. BIOMATERIALS ADVANCES 2023; 151:213480. [PMID: 37267748 DOI: 10.1016/j.bioadv.2023.213480] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 06/04/2023]
Abstract
Research aimed at preserving female fertility is increasingly using bioengineering techniques to develop new platforms capable of supporting ovarian cell function in vitro and in vivo. Natural hydrogels (alginate, collagen, and fibrin) have been the most exploited approaches; however they are biologically inert and/or biochemically simple. Thus, establishing a suitable biomimetic hydrogel from decellularized ovarian cortex (OC) extracellular matrix (OvaECM) could provide a complex native biomaterial for follicle development and oocyte maturation. The objectives of this work were (i) to establish an optimal protocol to decellularize and solubilize bovine OC, (ii) to characterize the histological, molecular, ultrastructural, and proteomic properties of the resulting tissue and hydrogel, and (iii) to assess its biocompatibility and adequacy for murine in vitro follicle growth (IVFG). Sodium dodecyl sulfate was identified as the best detergent to develop bovine OvaECM hydrogels. Hydrogels added into standard media or used as plate coatings were employed for IVFG and oocyte maturation. Follicle growth, survival, hormone production, and oocyte maturation and developmental competence were evaluated. OvaECM hydrogel-supplemented media best supported follicle survival, expansion, and hormone production, while the coatings provided more mature and competent oocytes. Overall, the findings support the xenogeneic use of OvaECM hydrogels for future human female reproductive bioengineering.
Collapse
Affiliation(s)
- Emilio Francés-Herrero
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Rosalba Lopez
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Hannes Campo
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Lucía de Miguel-Gómez
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Adolfo Rodríguez-Eguren
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Amparo Faus
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
| | - Antonio Pellicer
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain; IVI Roma Parioli, IVI-RMA Global, 00197 Rome, Italy
| | - Irene Cervelló
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain.
| |
Collapse
|
|
22
|
Rodríguez-Eguren A, Gómez-Álvarez M, Francés-Herrero E, Romeu M, Ferrero H, Seli E, Cervelló I. Human Umbilical Cord-Based Therapeutics: Stem Cells and Blood Derivatives for Female Reproductive Medicine. Int J Mol Sci 2022; 23:ijms232415942. [PMID: 36555583 PMCID: PMC9785531 DOI: 10.3390/ijms232415942] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/04/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
There are several conditions that lead to female infertility, where traditional or conventional treatments have limited efficacy. In these challenging scenarios, stem cell (SC) therapies have been investigated as alternative treatment strategies. Human umbilical cord (hUC) mesenchymal stem cells (hUC-MSC), along with their secreted paracrine factors, extracts, and biomolecules, have emerged as promising therapeutic alternatives in regenerative medicine, due to their remarkable potential to promote anti-inflammatory and regenerative processes more efficiently than other autologous treatments. Similarly, hUC blood derivatives, such as platelet-rich plasma (PRP), or isolated plasma elements, such as growth factors, have also demonstrated potential. This literature review aims to summarize the recent therapeutic advances based on hUC-MSCs, hUC blood, and/or other plasma derivatives (e.g., extracellular vesicles, hUC-PRP, and growth factors) in the context of female reproductive medicine. We present an in-depth analysis of the principal molecules mediating tissue regeneration, compiling the application of these therapies in preclinical and clinical studies, within the context of the human reproductive tract. Despite the recent advances in bioengineering strategies that sustain delivery and amplify the scope of the therapeutic benefits, further clinical trials are required prior to the wide implementation of these alternative therapies in reproductive medicine.
Collapse
Affiliation(s)
- Adolfo Rodríguez-Eguren
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 05610, USA
| | | | - Emilio Francés-Herrero
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain
| | - Mónica Romeu
- Gynecological Service, Consortium General University Hospital of Valencia, 46014 Valencia, Spain
| | - Hortensia Ferrero
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
| | - Emre Seli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 05610, USA
- IVIRMA New Jersey, Basking Ridge, NJ 07920, USA
| | - Irene Cervelló
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Correspondence: or
| |
Collapse
|
|
23
|
Rodríguez-Eguren A, de Miguel-Gómez L, Francés-Herrero E, Gómez-Álvarez M, Faus A, Gómez-Cerdá M, Moret-Tatay I, Díaz A, Pellicer A, Cervelló I. Human umbilical cord platelet-rich plasma to treat endometrial pathologies: methodology, composition and pre-clinical models. Hum Reprod Open 2022; 2023:hoac053. [PMID: 36523324 PMCID: PMC9747096 DOI: 10.1093/hropen/hoac053] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/17/2022] [Indexed: 09/25/2024] Open
Abstract
STUDY QUESTION Can human umbilical cord platelet-rich plasma (hUC-PRP) efficiently treat endometrial damage and restore fertility in a preclinical murine model? SUMMARY ANSWER Local application of hUC-PRP promotes tissue regeneration and fertility restoration in a murine model of Asherman syndrome and endometrial atrophy (AS/EA). WHAT IS KNOWN ALREADY AS/EA are well-described endometrial pathologies that cause infertility; however, there are currently no gold-standard treatments available. Recent reports have described the successful use of human platelet-rich plasma in reproductive medicine, and its regenerative potential is further enhanced using hUC-PRP, due to the ample growth factors and reduced pro-inflammatory cytokines in the latter. STUDY DESIGN SIZE DURATION hUC-PRP (n = 3) was processed, characterized and delivered locally to endometrial damage in a murine model (n = 50). The hUC-PRP was either used alone or loaded into a decellularized porcine endometrium-derived extracellular matrix (EndoECM) hydrogel; endometrial regeneration, fertility outcomes and immunocompatibility were evaluated 2 weeks following treatment administration. PARTICIPANTS/MATERIALS SETTING METHODS Umbilical cord blood was obtained from women in childbirth. Endometrial damage (mimicking AS/EA) was induced using ethanol in 8-week-old C57BL/6 mice, and treated with the most concentrated hUC-PRP sample 4 days later. Characterization of hUC-PRP and immunotolerance was carried out with multiplex technology, while uterine samples were analyzed by immunohistochemistry and quantitative PCR. The number of embryos and their morphology was determined visually. MAIN RESULTS AND THE ROLE OF CHANCE Platelet density was enhanced 3-fold in hUC-PRP compared to that in hUC blood (P < 0.05). hUC-PRP was enriched with growth factors related to tissue regeneration (i.e. hepatocyte growth factor, platelet-derived growth factor-BB and epidermal growth factor), which were released constantly (in vitro) when hUC-PRP was loaded into EndoECM. Both treatments (hUC-PRP alone and hUC-PRP with EndoECM) were immunotolerated and caused significantly regeneration of the damaged endometrium, evidenced by increased endometrial area, neoangiogenesis, cell proliferation and gland density and lower collagen deposition with respect to non-treated uterine horns (P < 0.05). Additionally, we detected augmented gene expression of Akt1, VEGF and Ang, which are involved in regenerative and proliferation pathways. Finally, hUC-PRP treatment restored pregnancy rates in the mouse model. LARGE SCALE DATA N/A. LIMITATIONS REASONS FOR CAUTION This proof-of-concept pilot study was based on a murine model of endometrial damage and the use of EndoECM requires further validation prior to clinical implementation for women affected by AS/EA. WIDER IMPLICATIONS OF THE FINDINGS The local administration of hUC-PRP has high impact and is immunotolerated in a murine model of AS/EA, as has been reported in other tissues, making it a promising candidate for heterologous treatment of these endometrial pathologies. STUDY FUNDING/COMPETING INTERESTS This study was supported by the Ministerio de Ciencia, Innovación y Universidades; Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana; and Instituto de Salud Carlos III. The authors do not have any conflicts of interest to declare.
Collapse
Affiliation(s)
| | | | - Emilio Francés-Herrero
- IVI Foundation, Health Research Institute La Fe, Valencia, Spain
- University of Valencia, Valencia, Spain
| | | | - Amparo Faus
- IVI Foundation, Health Research Institute La Fe, Valencia, Spain
| | | | - Inés Moret-Tatay
- Inflammatory Bowel Disease Research Group/Multiplex Analysis Unit, Health Research Institute La Fe, Valencia, Spain
| | - Ana Díaz
- University of Valencia, Valencia, Spain
| | - Antonio Pellicer
- University of Valencia, Valencia, Spain
- IVI-RMA Rome, Rome, Italy
| | - Irene Cervelló
- IVI Foundation, Health Research Institute La Fe, Valencia, Spain
| |
Collapse
|
|
24
|
Three-in-one customized bioink for islet organoid: GelMA/ECM/PRP orchestrate pro-angiogenic and immunoregulatory function. Colloids Surf B Biointerfaces 2022; 221:113017. [DOI: 10.1016/j.colsurfb.2022.113017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/30/2022] [Accepted: 11/10/2022] [Indexed: 11/15/2022]
|
|
25
|
Cai G, Hou Z, Sun W, Li P, Zhang J, Yang L, Chen J. Recent Developments in Biomaterial-Based Hydrogel as the Delivery System for Repairing Endometrial Injury. Front Bioeng Biotechnol 2022; 10:894252. [PMID: 35795167 PMCID: PMC9251415 DOI: 10.3389/fbioe.2022.894252] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/23/2022] [Indexed: 02/01/2023] Open
Abstract
Endometrial injury caused by intrauterine surgery often leads to pathophysiological changes in the intrauterine environment, resulting in infertility in women of childbearing age. However, clinical treatment strategies, especially for moderate to severe injuries, often fail to provide satisfactory therapeutic effects and pregnancy outcomes. With the development of reproductive medicine and materials engineering, researchers have developed bioactive hydrogel materials, which can be used as a physical anti-adhesion barrier alone or as functional delivery systems for intrauterine injury treatment by loading stem cells or various active substances. Studies have demonstrated that the biomaterial-based hydrogel delivery system can provide sufficient mechanical support and improve the intrauterine microenvironment, enhance the delivery efficiency of therapeutic agents, prolong intrauterine retention time, and perform efficiently targeted repair compared with ordinary drug therapy or stem cell therapy. It shows the promising application prospects of the hydrogel delivery system in reproductive medicine. Herein, we review the recent advances in endometrial repair methods, focusing on the current application status of biomaterial-based hydrogel delivery systems in intrauterine injury repair, including preparation principles, therapeutic efficacy, repair mechanisms, and current limitations and development perspectives.
Collapse
Affiliation(s)
- Guiyang Cai
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhipeng Hou
- Center for Molecular Science and Engineering, College of Science, Northeastern University, Shenyang, China
- NHC Key Laboratory of Reproductive Health and Medical Genetics (China Medical University), Liaoning Research Institute of Family Planning (The Reproductive Hospital of China Medical University), Shenyang, China
| | - Wei Sun
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Peng Li
- NHC Key Laboratory of Reproductive Health and Medical Genetics (China Medical University), Liaoning Research Institute of Family Planning (The Reproductive Hospital of China Medical University), Shenyang, China
| | - Jinzhe Zhang
- NHC Key Laboratory of Reproductive Health and Medical Genetics (China Medical University), Liaoning Research Institute of Family Planning (The Reproductive Hospital of China Medical University), Shenyang, China
| | - Liqun Yang
- NHC Key Laboratory of Reproductive Health and Medical Genetics (China Medical University), Liaoning Research Institute of Family Planning (The Reproductive Hospital of China Medical University), Shenyang, China
- *Correspondence: Liqun Yang, ; Jing Chen,
| | - Jing Chen
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Liqun Yang, ; Jing Chen,
| |
Collapse
|
|
26
|
Francés-Herrero E, Rodríguez-Eguren A, Gómez-Álvarez M, de Miguel-Gómez L, Ferrero H, Cervelló I. Future Challenges and Opportunities of Extracellular Matrix Hydrogels in Female Reproductive Medicine. Int J Mol Sci 2022; 23:3765. [PMID: 35409119 PMCID: PMC8998701 DOI: 10.3390/ijms23073765] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 02/01/2023] Open
Abstract
Bioengineering and reproductive medicine have progressed shoulder to shoulder for several decades. A key point of overlap is the development and clinical translation of technologies to support reproductive health, e.g., scaffold-free constructs, polymeric scaffolds, bioprinting or microfluidics, and hydrogels. Hydrogels are the focus of intense study, and those that are derived from the extracellular matrix (ECM) of reproductive tissues and organs are emerging as promising new players given their results in pre-clinical models. This literature review addresses the recent advances in the use of organ-specific ECM hydrogels in reproductive medicine, considering the entire female reproductive tract. We discuss in-depth papers describing the development of ECM hydrogels, their use in in vitro models, and their in vivo application in preclinical studies. We also summarize the functions of hydrogels, including as grafts, carriers for cell transplantation, or drug depots, and present the potential and possible scope for use of ECM hydrogels in the near future based on recent scientific advances.
Collapse
Affiliation(s)
- Emilio Francés-Herrero
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain;
- Fundación IVI, IVI-RMA Global, 46026 Valencia, Spain; (A.R.-E.); (M.G.-Á.); (L.d.M.-G.); (H.F.)
| | - Adolfo Rodríguez-Eguren
- Fundación IVI, IVI-RMA Global, 46026 Valencia, Spain; (A.R.-E.); (M.G.-Á.); (L.d.M.-G.); (H.F.)
- Reproductive Medicine Research Group, IIS La Fe, 46026 Valencia, Spain
| | - María Gómez-Álvarez
- Fundación IVI, IVI-RMA Global, 46026 Valencia, Spain; (A.R.-E.); (M.G.-Á.); (L.d.M.-G.); (H.F.)
- Reproductive Medicine Research Group, IIS La Fe, 46026 Valencia, Spain
| | - Lucía de Miguel-Gómez
- Fundación IVI, IVI-RMA Global, 46026 Valencia, Spain; (A.R.-E.); (M.G.-Á.); (L.d.M.-G.); (H.F.)
| | - Hortensia Ferrero
- Fundación IVI, IVI-RMA Global, 46026 Valencia, Spain; (A.R.-E.); (M.G.-Á.); (L.d.M.-G.); (H.F.)
- Reproductive Medicine Research Group, IIS La Fe, 46026 Valencia, Spain
| | - Irene Cervelló
- Fundación IVI, IVI-RMA Global, 46026 Valencia, Spain; (A.R.-E.); (M.G.-Á.); (L.d.M.-G.); (H.F.)
- Reproductive Medicine Research Group, IIS La Fe, 46026 Valencia, Spain
| |
Collapse
|
|
27
|
Francés-Herrero E, Lopez R, Hellström M, de Miguel-Gómez L, Herraiz S, Brännström M, Pellicer A, Cervelló I. OUP accepted manuscript. Hum Reprod Update 2022; 28:798-837. [PMID: 35652272 PMCID: PMC9629485 DOI: 10.1093/humupd/dmac025] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 04/13/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND To provide the optimal milieu for implantation and fetal development, the female reproductive system must orchestrate uterine dynamics with the appropriate hormones produced by the ovaries. Mature oocytes may be fertilized in the fallopian tubes, and the resulting zygote is transported toward the uterus, where it can implant and continue developing. The cervix acts as a physical barrier to protect the fetus throughout pregnancy, and the vagina acts as a birth canal (involving uterine and cervix mechanisms) and facilitates copulation. Fertility can be compromised by pathologies that affect any of these organs or processes, and therefore, being able to accurately model them or restore their function is of paramount importance in applied and translational research. However, innate differences in human and animal model reproductive tracts, and the static nature of 2D cell/tissue culture techniques, necessitate continued research and development of dynamic and more complex in vitro platforms, ex vivo approaches and in vivo therapies to study and support reproductive biology. To meet this need, bioengineering is propelling the research on female reproduction into a new dimension through a wide range of potential applications and preclinical models, and the burgeoning number and variety of studies makes for a rapidly changing state of the field. OBJECTIVE AND RATIONALE This review aims to summarize the mounting evidence on bioengineering strategies, platforms and therapies currently available and under development in the context of female reproductive medicine, in order to further understand female reproductive biology and provide new options for fertility restoration. Specifically, techniques used in, or for, the uterus (endometrium and myometrium), ovary, fallopian tubes, cervix and vagina will be discussed. SEARCH METHODS A systematic search of full-text articles available in PubMed and Embase databases was conducted to identify relevant studies published between January 2000 and September 2021. The search terms included: bioengineering, reproduction, artificial, biomaterial, microfluidic, bioprinting, organoid, hydrogel, scaffold, uterus, endometrium, ovary, fallopian tubes, oviduct, cervix, vagina, endometriosis, adenomyosis, uterine fibroids, chlamydia, Asherman’s syndrome, intrauterine adhesions, uterine polyps, polycystic ovary syndrome and primary ovarian insufficiency. Additional studies were identified by manually searching the references of the selected articles and of complementary reviews. Eligibility criteria included original, rigorous and accessible peer-reviewed work, published in English, on female reproductive bioengineering techniques in preclinical (in vitro/in vivo/ex vivo) and/or clinical testing phases. OUTCOMES Out of the 10 390 records identified, 312 studies were included for systematic review. Owing to inconsistencies in the study measurements and designs, the findings were assessed qualitatively rather than by meta-analysis. Hydrogels and scaffolds were commonly applied in various bioengineering-related studies of the female reproductive tract. Emerging technologies, such as organoids and bioprinting, offered personalized diagnoses and alternative treatment options, respectively. Promising microfluidic systems combining various bioengineering approaches have also shown translational value. WIDER IMPLICATIONS The complexity of the molecular, endocrine and tissue-level interactions regulating female reproduction present challenges for bioengineering approaches to replace female reproductive organs. However, interdisciplinary work is providing valuable insight into the physicochemical properties necessary for reproductive biological processes to occur. Defining the landscape of reproductive bioengineering technologies currently available and under development for women can provide alternative models for toxicology/drug testing, ex vivo fertility options, clinical therapies and a basis for future organ regeneration studies.
Collapse
Affiliation(s)
| | | | - Mats Hellström
- Laboratory for Transplantation and Regenerative Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lucía de Miguel-Gómez
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, Valencia, Spain
- Fundación IVI, IVI-RMA Global, Valencia, Spain
| | - Sonia Herraiz
- Fundación IVI, IVI-RMA Global, Valencia, Spain
- Reproductive Medicine Research Group, IIS La Fe, Valencia, Spain
| | - Mats Brännström
- Laboratory for Transplantation and Regenerative Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Stockholm IVF-EUGIN, Stockholm, Sweden
| | - Antonio Pellicer
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, Valencia, Spain
- IVI Roma Parioli, IVI-RMA Global, Rome, Italy
| | | |
Collapse
|
|
28
|
Klontzas ME, Protonotarios A. High-Resolution Imaging for the Analysis and Reconstruction of 3D Microenvironments for Regenerative Medicine: An Application-Focused Review. Bioengineering (Basel) 2021; 8:182. [PMID: 34821748 PMCID: PMC8614770 DOI: 10.3390/bioengineering8110182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/07/2021] [Accepted: 11/08/2021] [Indexed: 11/29/2022] Open
Abstract
The rapid evolution of regenerative medicine and its associated scientific fields, such as tissue engineering, has provided great promise for multiple applications where replacement and regeneration of damaged or lost tissue is required. In order to evaluate and optimise the tissue engineering techniques, visualisation of the material of interest is crucial. This includes monitoring of the cellular behaviour, extracellular matrix composition, scaffold structure, and other crucial elements of biomaterials. Non-invasive visualisation of artificial tissues is important at all stages of development and clinical translation. A variety of preclinical and clinical imaging methods-including confocal multiphoton microscopy, optical coherence tomography, magnetic resonance imaging (MRI), and computed tomography (CT)-have been used for the evaluation of artificial tissues. This review attempts to present the imaging methods available to assess the composition and quality of 3D microenvironments, as well as their integration with human tissues once implanted in the human body. The review provides tissue-specific application examples to demonstrate the applicability of such methods on cardiovascular, musculoskeletal, and neural tissue engineering.
Collapse
Affiliation(s)
- Michail E. Klontzas
- Department of Medical Imaging, University Hospital of Heraklion, 71110, Heraklion, Crete, Greece
- Computational Biomedicine Laboratory, Institute of Computer Science, Foundation for Research and Technology (FORTH), 70013 Heraklion, Crete, Greece
- Department of Radiology, School of Medicine, Voutes Campus, University of Crete, 71003 Heraklion, Crete, Greece
| | | |
Collapse
|
|
29
|
Wang J, Yang C, Xie Y, Chen X, Jiang T, Tian J, Hu S, Lu Y. Application of Bioactive Hydrogels for Functional Treatment of Intrauterine Adhesion. Front Bioeng Biotechnol 2021; 9:760943. [PMID: 34621732 PMCID: PMC8490821 DOI: 10.3389/fbioe.2021.760943] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 09/09/2021] [Indexed: 12/19/2022] Open
Abstract
Intrauterine adhesion (IUA) is a common endometrial disease and one of the main causes of infertility in women of childbearing age. Current treatment strategies, such as hysteroscopic adhesion resection, hysteroscopic transcervical resection of adhesion (TCRA), the use of local hormone drugs, and anti-adhesion scaffold implantation, do not provide a satisfactory pregnancy outcome for moderate-severe IUA, which presents a great challenge in reproductive medicine. With the development of material engineering, various bioactive and functional hydrogels have been developed using natural and synthetic biomaterials. These hydrogels are not only used as barely physical barriers but are also designed as vectors of hormone drugs, growth factors, and stem cells. These characteristics give bioactive hydrogels potentially important roles in the prevention and treatment of IUA. However, there is still no systematic review or consensus on the current advances and future research direction in this field. Herein, we review recent advances in bioactive hydrogels as physical anti-adhesion barriers, in situ drug delivery systems, and 3D cell delivery and culture systems for seeded cells in IUA treatment. In addition, current limitations and future perspectives are presented for further research guidance, which may provide a comprehensive understanding of the application of bioactive hydrogels in intrauterine adhesion treatment.
Collapse
Affiliation(s)
- Jingying Wang
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, Changchun, China
| | - Chao Yang
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, Changchun, China
| | - Yuxin Xie
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, Changchun, China
| | - Xiaoxu Chen
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, Changchun, China
| | - Ting Jiang
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, Changchun, China
| | - Jing Tian
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, Changchun, China
| | - Sihui Hu
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, Changchun, China
| | - Yingli Lu
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, Changchun, China
| |
Collapse
|