Integration of Bioengineered Tools in Assisted Reproductive Technologies.

This review aims to identify research gaps and possible improvements in the concurrence of reproductive medicine and bioengineering. While some aspects of ART could benefit from the integration of bioengineered platforms into routine practices, such as sperm sorting, the majority, including embryo culture, in vitro fertilization on these platforms, and oocyte handling, could not benefit yet. On the other side of the coin, the contribution of reproductive medicine to regenerative medicine and bioengineering cannot be underestimated. Knowledge and material, such as organs, tissues and cells, gained from patients are contributing tremendously to designing more tools and platforms. These technologies have the potential to streamline and upscale ART procedures, making them safer, more reliable, and potentially more cost‐effective. In addition, microfabrication strategies play a key role in forming and studying stem cell‐based embryo models that may improve our understanding of human development and feed regenerative medicine strategies. Future research should focus on overcoming current limitations, such as scalability, integration with bioanalytical systems, and ethical considerations, to fully realize the potential of these innovative tools in ART. While microfluidics and similar platforms hold great promise for improving assisted reproductive technologies (ART), they come with significant limitations. Designing these platforms is often time‐consuming and expensive, requiring specialized expertise and equipment. Their complexity can also make them impractical for widespread use, limiting their accessibility to only a few advanced laboratories. Moreover, most studies utilizing these platforms are conducted with animal models, and there is a notable lack of research using human samples to validate their efficacy. This is why advanced in vitro models are essential. They serve as substitutes for human samples, providing a controlled environment to refine and test these platforms more effectively. By using in vitro models, researchers can bridge the gap between current technological capabilities and the biological complexities of human tissues. These models are essential for advancing our understanding of implantation biology and improving the success of ART, all while reducing the need for real human samples until the new technologies are fully validated. Finaly, it is imperative to acknowledge the current ethical limitations surrounding reproductive technologies and ensure that scientific advancements are governed ethically for the greater benefit of society. Smooth transitions between these aspects of research and application will facilitate the seamless integration of cutting‐edge techniques into clinical practice, ultimately improving outcomes for individuals seeking reproductive assistance.

Infertility, previously estimated to affect 186 million people globally, [ 1 ] is now understood to impact ≈17.5% of the adult population according to the World Health Organization (WHO)’s 2023 report. [ 2 ] These numbers underscore the scale of infertility as a global health challenge and affecting hundreds of millions across all income levels. ≈85% of infertility cases are attributed to an identifiable cause, [ 3 ] yet there is no consensus on a specific rate. Male and female factors seem equally responsible for varying underlying conditions amongst which low sperm quality, blocked fallopian tubes, endometriosis, and ovulatory problems caused by polycystic ovarian syndrome, or hypothalamic dysfunction. [ 4 , 5 , 6 ] Some studies estimate that unexplained infertility accounts for 30–38% of cases. [ 7 , 8 ] This variability highlights the complexity of diagnosing infertility and underscores the need for deeper investigation into its causes to improve current treatment options. Patients may face psychological and emotional consequences, as they experience lack of hope for future treatments, frustrations towards treatment, and depression due to previous negative outcomes. [ 9 , 10 ] The clinical focus of reproductive medicine, centered on addressing infertility and developing advanced treatments, naturally intersects with reproductive biology. Our understanding of underlying molecular and cellular processes can drive innovations that enhance assisted reproductive technologies (ART) and improve patient outcomes, as well as our ability to create more sophisticated and effective ART methods. This progress has been significantly bolstered by advancements in bioengineering and cell biology, leading to the development of innovative tools and techniques that more closely mimic natural reproductive processes. As such, several microengineered platforms have been developed over the years, including ones based on microfluidics, synthetic matrices, and surface topography. [ 11 ] The overarching goal of these tools is to create a microenvironment that allows directing the number, position, behavior, and fate of the cells. Additionally, we can control the volume and content within the microfluidic systems, physical properties of the extracellular matrix (ECM), and mimic the biochemical and functional aspects of the original tissue. Recent advancements in stem cell‐based modelling, including organoids, have the potential to be of added value for obtaining a more biological complexity resembling in vivo. [ 12 , 13 ] In this review, albeit not exhaustive, we explore how microengineered platforms and advanced stem cell‐based reproductive technologies could enhance two key elements of ART procedures: fertilization and implantation. Additionally, we aimed to address a few important questions. First, what are the key intersections between two distinct fields, reproductive medicine and bioengineering, that have led to advancements, such as improved sperm selection? Second, where do we currently stand in this interdisciplinary collaboration? Are the results thus far successful, and what aspects need improvement? How can we enhance communication and knowledge exchange between these two fields to maximize progress? Finally, where is this intersection headed? Will there be a time when clinicians can routinely use bioengineered models and microengineered platforms for patient diagnosis and treatment? While exploring these questions, we also aim to identify areas where answers are still evolving.

The authors declare no conflict of interest.

Reproduction in humans is highly vulnerable. Various external and internal factors could disrupt the sequence until birth, starting with fertilization. In the case of viable offspring, it does take a village of specific organs, tissues, and cells with well‐orchestrated signaling pathway activity. [ 182 ] The molecular basis of implantation biology remains yet to be discovered in‐depth, mainly because our understanding of these mechanisms is based heavily on animal studies. [ 183 ] When translated into clinical practice, implantation, which is the key to a successful pregnancy, remains to be a limiting factor for IVF success and is also called the “black box” of reproduction. Unraveling the morphogenetic and molecular mechanisms that take place naturally during pre‐ and peri‐implantation will help scientists close in on identifying the underlying causes of infertility and potential therapeutic options. In this section, we highlight two advanced stem cell‐based models of the early embryo and endometrium, as the main players of implantation. By providing a controlled environment to study the multitude of interactions between the embryo and maternal tissues, these models may offer valuable insights that can improve ART outcomes, such as increasing implantation rates and addressing implantation failures, ultimately leading to better clinical practices and personalized treatment strategies. Egg activation is triggered with the penetrance of sperm. With an “out with the old, in with new” approach, a remarkable transition is observed from a fertilized oocyte to a totipotent zygote. [ 184 ] This transition is marked by the formation of pronuclei followed by the initiation of the first mitotic division. During embryonic genome activation, the zygote takes over the genetic control while the maternal genome degrades. [ 185 ] ≈16 cell‐stage, the blastomeres form a compact cluster high in tight junctions, named the morula. [ 186 ] This event leads to the first specialization of cells in the periphery of the embryo becoming the extraembryonic trophoblast cells. These cells will absorb fluid and form the blastocoel cavity, which expands leading to a blastocyst structure. [ 187 ] Following the first lineage bifurcation, the pluripotent inner cell mass (ICM) is formed, as well as trophectoderm (TE), which will differentiate into the trophoblast cells that form the placenta. [ 188 ] Following the second lineage bifurcation, the ICM specializes into epiblast (Epi), which will become the embryo proper, and hypoblast (HYPO), which will give rise to extra‐embryonic endoderm tissues and contribute to the gut. [ 189 , 190 , 191 ] Our knowledge of embryogenesis heavily relies on animal models and is limited by the accessibility to natural embryos and by ethical regulations such as the 14‐day culture limitations [ 192 ] Recently, mouse [ 193 , 194 , 195 ] and human [ 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 ] stem cell‐based models of the blastocyst were developed from both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) expanded in naïve pluripotent conditions, named blastoids (as reviewed in [ 205 ] ). Blastoids offer several advantages over blastocysts, including their generation in large numbers and amenability to genetic engineering. Microwell‐based culture platforms are state‐of‐the‐art platforms for culturing blastoids. Our group has previously generated agarose hydrogel microwell screening platforms using replica molding techniques in order to screen and automate the imaging of the blastoids while keeping them in close contact to each other, as well as homogenizing the formation of the structures. [ 206 ] In an alternative microwell culture platform, the microwell arrays were fabricated using a microthermoforming process of thin thermoplastic polymer films like cyclic olefin copolymer (COP), which improves confocal imaging readouts. [ 206 , 207 ] In 2018, the first blastoid study, mouse ESCs were combined with mouse trophoblast stem cells (TSC) in hydrogel microwells and showed that signals from the epiblast drive trophectoderm development and cavitation. [ 195 ] Following this pivotal study, scaled‐up experimentation using microwell‐based screening combined with high‐content imaging approaches has been used for identifying novel signaling pathway regulators to improve blastoid formation further. [ 208 , 209 , 210 ] In 2021, multiple independent groups [ 196 , 197 , 198 , 202 ] showed the formation of human blastoids using microwell array culture platforms. Kagawa et al. showed efficient formation in the hydrogel microwell screening platform by inhibiting the three developmental signaling pathways: Hippo, TGF‐β, and ERK. [ 202 ] Furthermore, Karvas et al. used the commercial Aggrewell platform to generate blastoids that showed the capacity for extended culture up to 21 days and presented hallmarks of primitive streak and the emergence of embryonic germ layers. [ 211 ] Overall, blastoids provide a model to study the early stages of human development and the implantation process with reduced ethical concerns than associated with using actual human embryos. This can increase our understanding and potentially identify new therapeutic routes for implantation failures and recurrent miscarriages. Embryo models can also be valuable for studying rare events that are difficult to observe in ART but nonetheless occur and can impact ART outcomes. For instance, monochorionic twinning, in which monozygotic twins share the same placenta, appears to be linked to ART procedures, with incidence rates at least twice as high as in natural conception. [ 212 ] Monochorionic twins are associated with significantly increased pregnancy‐related risks, including twin–to–twin transfusion syndrome (TTTS) and placental insufficiency, both of which elevate the risk of pregnancy loss. [ 213 , 214 ] We recently developed a bioengineered human embryo model for monochorionic twinning. [ 215 ] Here, screening assays using microwell arrays have proven useful in identifying the culture conditions that allow reproducible formation of high numbers of monochorionic twin blastoids. Specifically, increased cell numbers in combination with strong Hippo signaling inhibition induced the division of the ICM into two, both surrounded by a single trophectoderm cyst. The thin polymer film‐based thermoformed microwells allowed time‐lapse fluorescence imaging using an OCT4 reporter to further explore twinning morphogenesis. This novel model paves the way to deepen insights into the uncovered mechanisms underlying twinning. Moving towards peri‐ and post‐implantation in human, a distinction can usually be made between integrated and non‐integrated models. Integrated models aim to replicate both the embryo itself and all the supportive tissues essential for embryonic development. These models are designed to mimic the early stages of human embryogenesis, including the formation of extraembryonic structures such as the placenta and yolk sac. Non‐integrated models focus on mimicking only a specific component of the embryo rather than the complete structure. As non‐integrated models do generally not possess trophectoderm/trophoblast cells, these structures cannot form the placenta and are therefore viewed as ethically distinct and in some respects, less morally contentious. With an increasing number being published, and with varying decrease of developmental potential, both integrated and non‐integrated embryo models are valuable tools in biomedical research ( Table 2 ). Recent developments of integrated and non‐integrated human embryo models. human 8C‐like cells (8CLCs) For ART research, human blastoids appear to be the most suitable models by their resemblance to the full integrated preimplantation embryo and their ability to be generated in large quantities. While there is room for improvement in human blastoids, such as improving the HYPO compartment, they offer valuable applications. For instance, they could be used to train embryologists in blastocyst handling techniques, providing an ethical and reproducible alternative to human embryos. In addition, under the right guidelines, blastoids and embryo models by‐pass more strict ethical regulation surrounding the use of blastocyst for experimentation, including the 14‐day rule. [ 225 ] Although the 14‐day rule was originally established to regulate research on fertilized human embryos, stem cell‐derived models such as blastoids occupy a regulatory gray zone due to their non‐embryonic origin and limited developmental potential. In recognition of this, the 2021 guidelines of International Society for Stem Cell Research (ISSCR) reconsidered the strict 14‐day limit, recommending case‐by‐case ethical oversight for extended culture, as in the case of Karvas et al. study. [ 211 ] Advances in bioengineering may further enable the development and analysis of these models beyond traditional boundaries, necessitating renewed ethical frameworks in parallel. Relating single‐cell and omics studies of embryo models and embryos offers a powerful approach to gaining deeper insight into early development and implantation processes. [ 226 , 227 , 228 ] This integrated strategy could improve in vitro culture conditions that in turn could increase success rates in ART. Typically, plastic substrates or ECM‐like matrices are used for the progressive culture of blastoids and blastocysts towards post‐implantation stages. [ 229 , 230 ] However, advanced in vitro models of the endometrium could improve post‐implantation development of blastoids and the spatiotemporal resemblance to natural development, with impact on modelling reproductive health and disorders. Implantation is an intricate yet enigmatic process involving crosstalk between the endometrium and the blastocyst embryo. This critical event unfolds in three steps following blastocyst hatching. [ 231 ] Implantation commences with the apposition of the blastocyst in close proximity to the luminal epithelial lining of the endometrium. [ 232 ] This marks the initial contact between the two entities. [ 233 ] This contact is followed by adhesion, where the trophectoderm at the embryonic pole engages with the luminal epithelium mediate by a myriad of adhesion molecules. [ 234 ] Finally, during the invasion step, the blastocyst invades through the stroma and glandular epithelium of the endometrium and implants. [ 235 ] Implantation requires a fully competent blastocyst and a receptive‐state endometrium, [ 236 ] which is a physiological and phasic state during the mid‐luteal phase of ≈48 h, termed the window of implantation (WOI). This window is characterized by molecular, cellular and morphological changes that prime the endometrium for implantation. [ 237 , 238 ] Implantation relies on numerous factors, and any perturbation can lead to implantation failure. [ 239 ] These include but are not limited to inappropriately developed endometrium due to anatomical, immunological and endocrine complications or an incompetent blastocyst. [ 26 ] Understanding implantation physiology is crucial for advancing ART techniques, improving fertility treatments, and addressing developmental biology questions. However, ethical and practical challenges limit research involving humans due to inaccessibility of the in utero environment. [ 240 ] Thus, an increasing number of studies are being conducted to develop in vitro models of implantation and its molecular and mechanical cues. [ 241 , 242 , 243 , 244 ] The majority of studies have focused on combining human embryos with human primary epithelial cells. [ 245 , 246 , 247 , 248 , 249 ] ECM engineering has become pivotal for the development of organoids by providing essential structural and biochemical cues for growth and organization. [ 250 , 251 ] ECMs are generally categorized as either synthetic or natural. Synthetic matrices allow precise control over composition and stiffness, whereas natural matrices, such as Matrigel and Cultrex, contain many proteins, such as collagen I and IV, fibronectin, and laminin, [ 252 ] and growth factors that mimic the native cellular environment, supporting rapid upscaling of the groundbreaking endometrial organoid cultures. [ 253 , 254 ] Endometrial organoids are 3D, gland‐like structures derived from endometrial epithelial cells that closely mimic the architecture and function of the in vivo endometrial epithelium. These self‐organizing systems retain key physiological features, including hormone responsiveness, which enable them to recapitulate dynamic changes observed throughout the menstrual cycle. [ 255 , 256 , 257 ] Specifically, organoids respond to sex steroid hormones such as estrogen and progesterone by altering gene expression, cellular morphology (distinct ciliated and secretory cell populations; luminal, glandular and stromal cells), secretory activity (MUC1 production), and closely mirroring the proliferative and secretory phases of the endometrium. This makes them valuable in vitro model for studying reproductive disorders [ 258 , 259 ] and implantation‐related processes. Combining our knowledge on native endometrial ECM and tissue engineering have deepened our understanding of endometrial biology. Recently, a group developed a poly‐(ethylene glycol) (PEG) hydrogel to support both endometrial organoids and stromal cells by creating a synthetic ECM using an 8‐arm PEG‐based hydrogel functionalized with GFOGER and PHSRN‐K‐RGD peptides, mimicking collagen and fibronectin adhesion moieties, respectively ( Figure 5 A ). [ 260 ] This synthetic ECM was able to mimic different stages of menstrual cycle, with epithelial cells responding to progestin treatment and stromal cells exhibiting decidualization‐like behavior, including increased prolactin secretion. [ 261 ] Decidualization, a crucial step of endometrial receptivity for implantation, is the molecular and functional transformation of the cells. To study inter‐reproductive organ crosstalk, Park et al. created a dual reproductive organ‐on‐a‐chip with two ovarian chambers and an endometrium chamber to study cross talk between these organs by combining engineered hybrid‐material matrices with microfluidic systems. [ 262 ] The group used PDMS chips and embedded various polymers (agarose (0.6%, w/v), hyaluronic acid (2.5%, w/v), and type I collagen (2.5%, w/v)) to construct a porous endometrial layer, which matched human endometrial stiffness (18 kPa). [ 263 ] In another study, natural ECM derived from decellularized porcine endometrium was mixed with the commercial synthetic PuraMatrix hydrogel in a 50:50 ratio to support the growth of endometrial organoids. [ 264 ] The group thoroughly characterized the hybrid gel using rheology (for stiffness), SEM (for fiber content), and proteomics (for ECM‐related proteins) and showed that the gel promoted differentiation of the organoids by the significant upregulation of receptivity biomarkers. To increase anatomical complexity, in another study, rat endometrial tissue was cultured as 3D endometrial‐like sheets on a fibrin‐collagen gel base, creating a multilayered structure with epithelial and stromal cells, which are extracted from endometrial tissue (Figure  5B ). [ 265 ] Cell sheets preserve natural architecture and direct cell–cell interactions, which are crucial for mimicking the physiological conditions of the endometrium. This approach could lead to a more accurate representation of the cellular environment, supporting better tissue functionality and responses. Advanced endometrial culture methods: from mimicking the endometrium to simulating implantation processes. A) Co‐culture of endometrial organoids with stromal cells in a tailored PEG‐MIX hydrogel for promoting the growth of both cell types. Adapted from. [ 260 ] B) Creating epithelial and stromal cell sheets for co‐culture in fibril collagen gel to study the cell–cell interactions, as well as testing the effect of hormones. Adapted from. [ 265 ] C) Co‐culture of endometrial organoids, stromal cells and blastocysts that were placed in “embryo pockets.” The insert highlights the interaction between the blastocyst and co‐culture in the gel. Adapted from. [ 266 ] D) Generation of assembloids with apical‐out EGFP+ endometrial organoids and stromal cells. Once the assembloids were generated, KuO+ blastoids were co‐cultured and showed implantation‐like behaviors, including disrupting the epithelium and contacting with stromal cells. EGFP = Green fluorescent protein. KuO = Kusabira Orange. Adapted from. [ 267 ] With advances in bioengineering, these sophisticated endometrial models now provide a dynamic platform to study not only cellular complexity but also critical processes like embryo implantation, enabling researchers to simulate and observe early‐stage embryo interactions within a controlled environment. In the Kagawa et al. study, the authors sought to model the initial steps of implantation using endometrial epithelial monolayers, derived from endometrial organoids, in conjunction with blastoids. [ 202 ] The research group demonstrated that hormonally induced monolayers exhibited enhanced adherence of blastoids compared to non‐induced monolayers. Ak et al. used a microfluidic chip‐based platform to precisely quantify blastoid adhesion to endometrial monolayers by exposing them to a controlled step‐wise increasing flow rate. [ 268 ] Luijkx et al. used this platform to show that monochorionic twins have increased adhesion potential compared to singleton blastoids. [ 215 ] In another report, a co‐culture of gland‐like structures and stromal cells, named assembloids, were developed to test how decidual senescence may promote embryo implantation in the endometrium (Figure  5C ). [ 266 ] To test the response of the assembloids in terms of senescence, the group embedded human embryos by creating small pockets within the assembloids. The presence of the senescent decidual cells allowed the blastocyst to interact and expand. However, the continuous secretome production released by the senescent decidual cells led to the disintegration of the assembloids. This study highlights limitations that arise from a non‐dynamic platform, in addition to the absence of luminal epithelium for implantation studies. Advancing the assembloid model, Shibata et al. co‐cultured their assembloids model with blastoids (Figure  5D ). [ 267 ] This assembloids model consisted of apically out endometrial organoids (named AO–EMO), endometrial stromal cells and primary Human Umbilical Vein Endothelial Cells (HUVEC). Hormonally responsive assembloids were cultured with blastoids for 5 days, showcasing events at the feto‐maternal interface, including possibly cell fusion. Aforementioned studies focus on co‐culturing stromal cells with glandular epithelial cells including organoids but are lacking the luminal epithelium, which is crucial for modeling embryo implantation. To overcome that, Tian et al. generated human endometrium assembloids using an air‐liquid interface (ALI) method, which consists of both the glandular and luminal epithelium for the first time. [ 269 ] This comprehensive study indicated that the assembloids faithfully replicated the in vivo endometrial anatomy, Young's modulus (450 Pa for top‐layer endometrium), cell composition, and gene expression profiles, including the WOI genes. Unfortunately, this study did not perform a functional assay to investigate embryo implantation. Recent bioengineering advances have also extended to placental organoids, which together with endometrial organoids provide powerful platforms to model the maternal‐fetal interface and further implantation events. [ 270 , 271 , 272 , 273 ] In particular, trophoblast invasion, a critical step in early pregnancy involving deep interaction between invading placental cells and the remodeling of maternal ECM, relies heavily on finely tuned cell‐matrix signaling. [ 274 ] Park et al. developed an “implantation‐on‐chip” with a fetal chamber, containing extravillous trophoblast (EVT) cells and a vascular chamber, containing endothelial cells, to mimic a further step of the implantation process, invasion through the maternal vessels. [ 275 ] As the first step, the central channel was injected with a Collagen‐Matrigel mixture to mimic the 3D ECM of the endometrium, providing an environment for cell invasion from the side channels. The hydrogel scaffold's stiffness increased from 390.24 ± 146.25 to 826.26 ± 164.84 Pa, effectively mimicking the natural stiffness changes in human decidua and highlighting the crosstalk between endothelial cells and trophoblasts. To further investigate, the team tested the effect of decidualized stromal cells (DSCs) on EVT invasiveness by seeding DSCs in the hydrogel compartment and exposing them to hormonal induction. Importantly, the presence of DSCs reduced EVT invasiveness, as observed in controlled inhibition in vivo. The level of invasion is crucial to maintain, as too much invasion can lead to complications, and too little can result in conditions such as preeclampsia. Collectively, the overarching goal of these models is to create a functional and personalized representation of the endometrium for application for medical application, serving as an additional diagnostic tool. Current diagnostic tools are restricted in their application spectrum, for instance the Endometrial Receptivity Array (ERA) test, which involves taking an endometrial biopsy during the presumed WOI. This procedure aims to assess the gene expression profile to identify the specific transcriptomic signature, ultimately providing a more precise timing for personalized embryo transfer (pET). However, as with many gene‐based methods, there are inconclusive results regarding which specific genes are associated with the WOI and the accuracy of their expression. [ 276 , 277 , 278 ] These challenges are further complicated by the timing and method of sample collection and the mathematical models used. [ 279 ] Therefore, there is an increasing need for broader and more functional assays, enabling ongoing, personalized study of endometrial physiology. Advanced microengineered platforms and in vitro models are well suited to fulfill this need, particularly in conjunction with functional endometrial assays that incorporate actual embryos or stem cell‐based embryo models. The integration of advanced biological models [ 280 ] provides a deeper understanding of the intricate communication between maternal and fetal tissues, offering opportunities for developing personalized and precise ART methods. These models can reflect the complex structure of the endometrium by accurately mimicking its diverse cellular architecture, including the glandular and luminal epithelium, both critical for successful implantation and early pregnancy development. By replicating dynamic physiological conditions, such as hormonal fluctuations and changes in the uterine microenvironment, these systems enable the study of factors that influence endometrial receptivity and embryo development. Additionally, they serve as valuable platforms for testing therapeutic interventions aimed at improving implantation rates and pregnancy outcomes, allowing for the assessment of new drugs, hormones, or treatments in a controlled and reproducible environment. An ideal in vitro model for reproductive medicine would incorporate advanced endometrial platforms integrated with blastoids or embryo‐like structures to replicate early human development and implantation ( Figure 6 ). This patient‐derived model would include multiple essential cell types: glandular and luminal epithelial cells to facilitate attachment, a stromal support layer to enable invasion, and endothelial and immune cells to support post‐implantation development. Integrating microfluidic systems would provide dynamic control over the culture environment, allowing precise delivery of nutrients, hormones, and growth factors while simulating perfusion‐based flow dynamics. These systems could mimic the cyclical changes of the uterine environment, further enhancing physiological relevance. Additionally, the incorporation of advanced imaging techniques and biosensors would enable real‐time monitoring of cellular behavior, embryo‐endometrium interactions, and molecular changes throughout the implantation process. An ideal in vitro model of endometrium for embryo implantation with available tool sets, models, and cells. Clinicians could play a key role in refining and implementing such models by incorporating them into clinical trials to evaluate patient‐specific treatment responses. Their firsthand knowledge, gained through patient interactions, could help identify variability in implantation success and provide critical insights into atypical cases. By feeding this information back into the design of in vitro models, researchers could better capture patient‐to‐patient variability and improve model accuracy. This collaborative feedback loop between clinicians and scientists could enhance personalized ART approaches, ultimately translating laboratory research into practical clinical applications. The left panel illustrates a representative in vitro model of the human endometrium, depicting key cellular and structural components, including the luminal epithelium, glandular epithelium, stromal and immune cells, myometrial layer, vasculature, an implanting blastocyst, and emerging syncytiotrophoblast. A diverse tool set is currently available to engineer these models, including microfluidic devices, bioprinting technologies, synthetic matrices, and thermoformed microwells. Cellular components and model systems include blastoids, integrated embryo models, endometrial organoids, and primary human cells such as stromal, immune, and endothelial populations, enabling the reconstruction of a physiologically relevant implantation microenvironment.