Advances in the Application of Biomimetic Endometrium Interfaces for Uterine Bioengineering in Female Infertility

MINI REVIEW published: 28 February 2020 doi: 10.3389/fbioe.2020.00153 Advances in the Application of Biomimetic Endometrium Interfaces for Uterine Bioengineering in Female Infertility Qixin Han 1,2 and Yanzhi Du 1,2* 1 2 Edited by: Francesca Taraballi, Houston Methodist Research Institute, United States Reviewed by: Stephanie Michelle Willerth, University of Victoria, Canada Gianluca Ciardelli, Politecnico di Torino, Italy Dong-Wook Han, Pusan National University, South Korea *Correspondence: Yanzhi Du Specialty section: This article was submitted to Biomaterials, a section of the journal Frontiers in Bioengineering and Biotechnology Received: 20 November 2019 Accepted: 14 February 2020 Published: 28 February 2020 Citation: Han Q and Du Y (2020) Advances in the Application of Biomimetic Endometrium Interfaces for Uterine Bioengineering in Female Infertility. Front. Bioeng. Biotechnol. 8:153. doi: 10.3389/fbioe.2020.00153 Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China The Asherman’s syndrome, also known as intrauterine adhesion, often follows endometrium injuries resulting from dilation and curettage, hysteroscopic resection, and myomectomy as well as infection. It often leads to scarring formation and female infertility. Pathological changes mainly include gland atrophy, lack of vascular stromal tissues and hypoxia and anemia microenvironment in the adhesion areas. Surgical intervention, hormone therapy and intrauterine device implantation are the present clinical treatments for Asherman’s syndrome. However, they do not result in functional endometrium recovery or pregnancy rate improvement. Instead, an increasing number of researches have paid attention to the reconstruction of biomimetic endometrium interfaces with advanced tissue engineering technology in recent decades. From micro-scale cell sheet engineering and cell-seeded biological scaffolds to nanoscale extracellular vesicles and bioactive molecule delivery, biomimetic endometrium interfaces not only recreate physiological multi-layered structures but also restore an appropriate nutritional microenvironment by increasing vascularization and reducing immune responses. This review comprehensively discusses the advances in the application of novel biocompatible functionalized endometrium interface scaffolds for uterine tissue regeneration in female infertility. Keywords: endometrium interface, uterus regeneration, nano-scale, biomimetic scaffold, female infertility INTRODUCTION Secondary infertility is the most common type of female infertility worldwide, often because of endometrium injuries and subsequent intrauterine adhesion (IUA). It poses a great threat to female physical and mental health (Deans et al., 2018; Vander Borght and Wyns, 2018; Dreisler and Kjer, 2019). The uterus tissue is made up of three layers, among which the endometrium, composed of functional and basal layers, is the inner-most layer. The functional endometrium is the site of embryo implantation and is regulated by changes in ovarian hormones. The basal endometrium regenerates and repairs the endometrium wound after menstruation, and forms the functional layer again, possibly via the intrinsic endometrial cells, such as endometrial epithelial and stromal cells, Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 1 February 2020 | Volume 8 | Article 153 Han and Du Biomimetic Endometrium Interfaces for Uterine Bioengineering endometrial stem cells and perivascular cells. They may secrete bioactive molecules, growth factors, hormones and contribute to angiogenesis and endometrium regeneration after uterus injuries. The pathological changes include endometrial fibrosis and scarring, loss or thinning of endometrium due to different degrees of damage to the basal layer of endometrium, IUA between anterior and posterior walls, and shrinkage of uterine cavity (Conforti et al., 2013). Microscopic observation shows gland atrophy, lack of vascular stromal tissues and hypoxia and anemia microenvironment in the adhesion areas (EvansHoeker and Young, 2014; Healy et al., 2016). Present clinical techniques, such as hormonal therapy, surgical synechiotomy and subsequent intrauterine device (IUD) implantation, show unsatisfactory outcomes, recurrent adhesion and secondary infection during the treatment of IUA, also known as Asherman’s syndrome (Cai et al., 2016, 2017; Mo et al., 2019). The surgical synechiotomy helps surgeons release the adhesive fibrosis with blunt-end scissors. However, the postoperative recovery shows a huge variation among different patients due to adhesion severity. Some of them even experienced greater adhesion recurrence. Hormonal therapy works effectively after surgical release of IUA. Nevertheless, it is still hard to confirm a suitable medication dosage and route due to the short halflife period, low water solubility and big differences in response. As for the IUDs, they only function as physical barriers. However, they can barely induce regenerative process and thus yield low endometrium recovery. Therefore, it is urgent and vital to find alternative treatments for Asherman’s syndrome (Dreisler and Kjer, 2019). The development of biomimetic tissue engineering provides an alternative therapy that may increase the success of uterine regeneration and reproductive capacity (Cervelló et al., 2015). Biomaterial is an important factor in the tissue engineering because it can provide structural support that mimics native endometrium tissues and uterine organs (Zhang et al., 2020). In addition, some biomedical materials are characterized by physical, chemical and biological properties that are closely related to uterus regeneration. The other two factors in the tissue engineering are supporting cells and bioactive molecules. They both facilitate cellular and extracellular signaling, nutrient transport, stem cell recruitment, proliferation and differentiation. Biomaterials can release drugs, growth factors, small molecules and other bioactive compounds in a controlled style, with or without cell loading and modification. Recent researches have shown that, in addition to traditional biomaterial based uterus regeneration, combination and modification of cells and biomaterials, such as cell sheets, cell-scaffold interfaces, surface-functionalized scaffolds and decellularization of biological tissues may also display functional or structural advantages and repair injured uterus to different extents by inducing biomimetic changes and recreating regenerative microenvironment (Liu et al., 2019a). Therefore, we comprehensively reviewed current advances in the biological interactions and applications of different types of biomimetic endometrium and uterus scaffolds for female infertility treatment and compared their potential therapeutic effects in this re (...truncated)