Bioengineering trends in female reproduction: a systematic review

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.

High-Fat Diet and Female Fertility across Lifespan: A Comparative Lesson from Mammal Models

“…Similarly, assisted reproductive techniques offer high standardized in vitro conditions to demonstrate the adverse impact of high-fat conditions on oocyte maturation and fertilization (IVM/IVF), as well as during embryo development. In addition, modern-engineered reproductive culture systems [ 246 , 247 , 248 , 249 ] enable the increasingly physiological in vitro modelling of homeostasis, development, disease, and aging, thus offering novel cultural approaches to better interpret the multifactorial lifestyle impact on fertility. In this context, besides the increasing evidence that inflammation and ovarian aging are implicated in accelerating the decay of fertility, very little data clarify how obesity may further exacerbate these factors in compromising female reproductive health.…”

Human umbilical cord platelet-rich plasma to treat endometrial pathologies: methodology, composition and pre-clinical models

“…Hydrogels are by far the most prominently used bioengineering strategy for female reproductive medicine ( Francés-Herrero et al , 2022a ) and are composed of hydrophilic polymeric networks, which can deliver controlled drug-release into target wounds ( Narayanaswamy and Torchilin, 2019 ). Since ECM-based hydrogels are proven to mimic the physicochemical properties of the tissue of origin, we hypothesized they could provide the perfect environment for tissue regeneration ( Francés-Herrero et al , 2022b ).…”

Progress in Preclinical Research on Uterus Bioengineering That Utilizes Scaffolds Derived from Decellularized Uterine Tissue

“…Recellularization of the decellularized endometrial tissue was conducted with human endometrial cells that showed functional phenotypic behavior by responding to a 28-day hormonal cycle that mimicked the human menstrual cycle [43]. This bioengineered explant culture may become an attractive in vitro model to better mimic in vivo physiological settings compared to standard 2D in vitro culturing systems to study processes in the human uterus, e.g., drugdose response, invasive cancer mechanisms, or implantation events, in particular if combined with organ-on a-chip strategies [4,11,44,45]. The organ-on-a-chip strategy utilizes a multi-channel microfluidic circuit system that connects several cell culture compartments containing cells of different phenotypes.…”

“…These principles achieved promising results in whole-organ bioengineering studies on rodents for non-reproductive organs [3,[5][6][7][8][9], but was also assessed for novel infertility treatment applications [10]. There are several promising scaffold types evaluated for uterus bioengineering applications which is extensively summarized in a recent systematic review [11]. These include scaffolds derived from different hydrogels [12][13][14], and scaffolds derived from biodegradable polyglycolic acid (PGA) and poly-dl-lactide-co-glycolide (PLGA) polymers [15].…”