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15 pages, 3292 KiB

Open AccessArticle

Encapsulation of Bovine Primordial Follicles in Rigid Alginate Does Not Affect Growth Dynamics

by Kathryn L. McElhinney, Erin E. Rowell and Monica M. Laronda

Bioengineering 2024, 11(7), 734; https://doi.org/10.3390/bioengineering11070734 - 19 Jul 2024

Cited by 1 | Viewed by 831

Abstract

The only fertility preservation and subsequent restoration option for many patients facing gonadotoxic treatments is ovarian tissue cryopreservation and transplantation. While this process is successful for some, there is significant room for improvement to extend the life of the transplant and to make [...] Read more.

The only fertility preservation and subsequent restoration option for many patients facing gonadotoxic treatments is ovarian tissue cryopreservation and transplantation. While this process is successful for some, there is significant room for improvement to extend the life of the transplant and to make it safe for patients that may have metastatic disease within their ovarian tissue. We need a deeper understanding of how the physical properties of the ovarian microenvironment may affect folliculogenesis to engineer an environment that supports isolated follicles and maintains primordial follicle quiescence. Bovine ovaries were used here as a monovulatory model of folliculogenesis to examine the effects of primordial follicle activation and growth under different physical conditions. We found that there were no differences in activation, growth or survival when primordial follicles were cultured in isolation or in situ (remaining in the tissue) under two significantly differently rigid alginate gels. To determine if the extra rigid environment did not affect activation in isolated follicles due to an immediate activation event, we used 5-ethynyl-2′-deoxyuridine (EdU) to track follicle activation during the isolation process. We identified EdU incorporation in granulosa cells after primordial follicles were isolated from the surrounding extracellular matrix (ECM). These findings support that isolation of primordial follicles from the ECM is an activating event and that the differentially rigid environments assessed here had no effect on follicle growth. Further work is needed to suppress activation in primordial follicles to maintain the ovarian reserve and extend the life of an ovarian tissue transplant. Full article

(This article belongs to the Special Issue Bioengineering Technologies to Advance Reproductive Health)

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22 pages, 4120 KiB

Open AccessEditor’s ChoiceArticle

Three-Dimensionally Printed Agarose Micromold Supports Scaffold-Free Mouse Ex Vivo Follicle Growth, Ovulation, and Luteinization

by Emily J. Zaniker, Prianka H. Hashim, Samuel Gauthier, James A. Ankrum, Hannes Campo and Francesca E. Duncan

Bioengineering 2024, 11(7), 719; https://doi.org/10.3390/bioengineering11070719 - 15 Jul 2024

Cited by 1 | Viewed by 4140

Abstract

Ex vivo follicle growth is an essential tool, enabling interrogation of folliculogenesis, ovulation, and luteinization. Though significant advancements have been made, existing follicle culture strategies can be technically challenging and laborious. In this study, we advanced the field through development of a custom [...] Read more.

Ex vivo follicle growth is an essential tool, enabling interrogation of folliculogenesis, ovulation, and luteinization. Though significant advancements have been made, existing follicle culture strategies can be technically challenging and laborious. In this study, we advanced the field through development of a custom agarose micromold, which enables scaffold-free follicle culture. We established an accessible and economical manufacturing method using 3D printing and silicone molding that generates biocompatible hydrogel molds without the risk of cytotoxicity from leachates. Each mold supports simultaneous culture of multiple multilayer secondary follicles in a single focal plane, allowing for constant timelapse monitoring and automated analysis. Mouse follicles cultured using this novel system exhibit significantly improved growth and ovulation outcomes with comparable survival, oocyte maturation, and hormone production profiles as established three-dimensional encapsulated in vitro follicle growth (eIVFG) systems. Additionally, follicles recapitulated aspects of in vivo ovulation physiology with respect to their architecture and spatial polarization, which has not been observed in eIVFG systems. This system offers simplicity, scalability, integration with morphokinetic analyses of follicle growth and ovulation, and compatibility with existing microphysiological platforms. This culture strategy has implications for fundamental follicle biology, fertility preservation strategies, reproductive toxicology, and contraceptive drug discovery. Full article

(This article belongs to the Special Issue Bioengineering Technologies to Advance Reproductive Health)

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15 pages, 1326 KiB

Open AccessArticle

Generation of Tailored Extracellular Matrix Hydrogels for the Study of In Vitro Folliculogenesis in Response to Matrisome-Dependent Biochemical Cues

by Hannah B. McDowell, Kathryn L. McElhinney, Elizabeth L. Tsui and Monica M. Laronda

Bioengineering 2024, 11(6), 543; https://doi.org/10.3390/bioengineering11060543 - 25 May 2024

Viewed by 1381

Abstract

While ovarian tissue cryopreservation (OTC) is an important fertility preservation option, it has its limitations. Improving OTC and ovarian tissue transplantation (OTT) must include extending the function of reimplanted tissue by reducing the extensive activation of primordial follicles (PMFs) and eliminating the risk [...] Read more.

While ovarian tissue cryopreservation (OTC) is an important fertility preservation option, it has its limitations. Improving OTC and ovarian tissue transplantation (OTT) must include extending the function of reimplanted tissue by reducing the extensive activation of primordial follicles (PMFs) and eliminating the risk of reimplanting malignant cells. To develop a more effective OTT, we must understand the effects of the ovarian microenvironment on folliculogenesis. Here, we describe a method for producing decellularized extracellular matrix (dECM) hydrogels that reflect the protein composition of the ovary. These ovarian dECM hydrogels were engineered to assess the effects of ECM on in vitro follicle growth, and we developed a novel method for selectively removing proteins of interest from dECM hydrogels. Finally, we validated the depletion of these proteins and successfully cultured murine follicles encapsulated in the compartment-specific ovarian dECM hydrogels and these same hydrogels depleted of EMILIN1. These are the first, optically clear, tailored tissue-specific hydrogels that support follicle survival and growth comparable to the “gold standard” alginate hydrogels. Furthermore, depleted hydrogels can serve as a novel tool for many tissue types to evaluate the impact of specific ECM proteins on cellular and molecular behavior. Full article

(This article belongs to the Special Issue Bioengineering Technologies to Advance Reproductive Health)

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18 pages, 9581 KiB

Open AccessArticle

Comparative Tensile Properties and Collagen Patterns in Domestic Cat (Felis catus) and Dog (Canis lupus familiaris) Ovarian Cortical Tissues

by Jennifer B. Nagashima, Shoshana Zenilman, April Raab, Helim Aranda-Espinoza and Nucharin Songsasen

Bioengineering 2023, 10(11), 1285; https://doi.org/10.3390/bioengineering10111285 - 4 Nov 2023

Viewed by 1624

Abstract

The importance of the ovarian extracellular environment and tissue rigidity on follicle survival and development has gained attention in recent years. Our laboratory has anecdotally observed differences in the rigidity of domestic cat and dog ovarian cortical tissues, which have been postulated to [...] Read more.

The importance of the ovarian extracellular environment and tissue rigidity on follicle survival and development has gained attention in recent years. Our laboratory has anecdotally observed differences in the rigidity of domestic cat and dog ovarian cortical tissues, which have been postulated to underlie the differences in in vitro culture responses between the species, wherein cat ovarian tissues display higher survival in extended incubation. Here, the tensile strengths of cat and dog ovarian cortical tissues were compared via micropipette aspiration. The underlying collagen patterns, including fiber length, thickness, alignment, curvature, branch points and end points, and overall tissue lacunary and high-density matrix (HDM) were quantified via picrosirius red staining and TWOMBLI analysis. Finally, we explored the potential of MMP (−1 and −9) and TIMP1 supplementation in modulating tissue rigidity, collagen structure, and follicle activation in vitro. No differences in stiffness were observed between cat or dog cortical tissues, or pre- versus post-pubertal status. Cat ovarian collagen was characterized by an increased number of branch points, thinner fibers, and lower HDM compared with dog ovarian collagen, and cat tissues exposed to MMP9 in vitro displayed a reduced Young’s modulus. Yet, MMP exposure had a minor impact on follicle development in vitro in either species. This study contributes to our growing understanding of the interactions among the physical properties of the ovarian microenvironment, collagen patterns, and follicle development in vitro. Full article

(This article belongs to the Special Issue Bioengineering Technologies to Advance Reproductive Health)

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18 pages, 5263 KiB

Open AccessArticle

Encapsulated Allografts Preclude Host Sensitization and Promote Ovarian Endocrine Function in Ovariectomized Young Rhesus Monkeys and Sensitized Mice

by James R. Day, Colleen L. Flanagan, Anu David, Dennis J. Hartigan-O’Connor, Mayara Garcia de Mattos Barbosa, Michele L. Martinez, Charles Lee, Jenna Barnes, Evan Farkash, Mary Zelinski, Alice Tarantal, Marilia Cascalho and Ariella Shikanov

Bioengineering 2023, 10(5), 550; https://doi.org/10.3390/bioengineering10050550 - 3 May 2023

Cited by 3 | Viewed by 2258

Abstract

Transplantation of allogeneic donor ovarian tissue holds great potential for female cancer survivors who often experience premature ovarian insufficiency. To avoid complications associated with immune suppression and to protect transplanted ovarian allografts from immune-mediated injury, we have developed an immunoisolating hydrogel-based capsule that [...] Read more.

Transplantation of allogeneic donor ovarian tissue holds great potential for female cancer survivors who often experience premature ovarian insufficiency. To avoid complications associated with immune suppression and to protect transplanted ovarian allografts from immune-mediated injury, we have developed an immunoisolating hydrogel-based capsule that supports the function of ovarian allografts without triggering an immune response. Encapsulated ovarian allografts implanted in naïve ovariectomized BALB/c mice responded to the circulating gonadotropins and maintained function for 4 months, as evident by regular estrous cycles and the presence of antral follicles in the retrieved grafts. In contrast to non-encapsulated controls, repeated implantations of encapsulated mouse ovarian allografts did not sensitize naïve BALB/c mice, which was confirmed with undetectable levels of alloantibodies. Further, encapsulated allografts implanted in hosts previously sensitized by the implantation of non-encapsulated allografts restored estrous cycles similarly to our results in naïve recipients. Next, we tested the translational potential and efficiency of the immune-isolating capsule in a rhesus monkey model by implanting encapsulated ovarian auto- and allografts in young ovariectomized animals. The encapsulated ovarian grafts survived and restored basal levels of urinary estrone conjugate and pregnanediol 3-glucuronide during the 4- and 5-month observation periods. We demonstrate, for the first time, that encapsulated ovarian allografts functioned for months in young rhesus monkeys and sensitized mice, while the immunoisolating capsule prevented sensitization and protected the allograft from rejection. Full article

(This article belongs to the Special Issue Bioengineering Technologies to Advance Reproductive Health)

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21 pages, 2443 KiB

Open AccessArticle

Proteomic Profiling of Fallopian Tube-Derived Extracellular Vesicles Using a Microfluidic Tissue-on-Chip System

by Didi Zha, Sagar Rayamajhi, Jared Sipes, Angela Russo, Harsh B. Pathak, Kailiang Li, Mihaela E. Sardiu, Leonidas E. Bantis, Amrita Mitra, Rajni V. Puri, Camille V. Trinidad, Brian P. Cain, Brett C. Isenberg, Jonathan Coppeta, Shannon MacLaughlan, Andrew K. Godwin and Joanna E. Burdette

Bioengineering 2023, 10(4), 423; https://doi.org/10.3390/bioengineering10040423 - 27 Mar 2023

Cited by 8 | Viewed by 5513

Abstract

The human fallopian tube epithelium (hFTE) is the site of fertilization, early embryo development, and the origin of most high-grade serous ovarian cancers (HGSOCs). Little is known about the content and functions of hFTE-derived small extracellular vesicles (sEVs) due to the limitations of [...] Read more.

The human fallopian tube epithelium (hFTE) is the site of fertilization, early embryo development, and the origin of most high-grade serous ovarian cancers (HGSOCs). Little is known about the content and functions of hFTE-derived small extracellular vesicles (sEVs) due to the limitations of biomaterials and proper culture methods. We have established a microfluidic platform to culture hFTE for EV collection with adequate yield for mass spectrometry-based proteomic profiling, and reported 295 common hFTE sEV proteins for the first time. These proteins are associated with exocytosis, neutrophil degranulation, and wound healing, and some are crucial for fertilization processes. In addition, by correlating sEV protein profiles with hFTE tissue transcripts characterized using GeoMx^® Cancer Transcriptome Atlas, spatial transcriptomics analysis revealed cell-type-specific transcripts of hFTE that encode sEVs proteins, among which, FLNA, TUBB, JUP, and FLNC were differentially expressed in secretory cells, the precursor cells for HGSOC. Our study provides insights into the establishment of the baseline proteomic profile of sEVs derived from hFTE tissue, and its correlation with hFTE lineage-specific transcripts, which can be used to evaluate whether the fallopian tube shifts its sEV cargo during ovarian cancer carcinogenesis and the role of sEV proteins in fallopian tube reproductive functions. Full article

(This article belongs to the Special Issue Bioengineering Technologies to Advance Reproductive Health)

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12 pages, 2445 KiB

Open AccessArticle

Placenta-Targeted Nanoparticles Loaded with PFKFB3 Overexpression Plasmids Enhance Angiogenesis and Placental Function

by Qi Li, Xiaoxia Liu, Weifang Liu, Yang Zhang, Wen Liu, Mengying Wu, Zhirui Chen, Yin Zhao and Li Zou

Bioengineering 2022, 9(11), 652; https://doi.org/10.3390/bioengineering9110652 - 4 Nov 2022

Cited by 5 | Viewed by 1866

Abstract

Placental angiogenesis disorder and placental dysplasia are important causes of many pregnancy complications. Due to safety and economic benefits, effective treatment strategies are currently limited. PFKFB3 is a key regulator of glycolysis that controls angiogenesis through a metabolic pathway independent of genetic signals. [...] Read more.

Placental angiogenesis disorder and placental dysplasia are important causes of many pregnancy complications. Due to safety and economic benefits, effective treatment strategies are currently limited. PFKFB3 is a key regulator of glycolysis that controls angiogenesis through a metabolic pathway independent of genetic signals. In this study, we constructed the nanodrug T-NP_PFKFB3 and explored its feasibility to promote angiogenesis and enhance placental function. First, liposomes containing PFKFB3 overexpression plasmids modified by the placental homing peptide CGKRK were synthesized by the thin film method. In vivo experiments revealed that T-NP_PFKFB3 injected intravenously specifically accumulated in the mouse placenta and therein upregulated the expression of PFKFB3 without affecting its expression in other important organs. In addition, T-NP_PFKFB3 promoted placental angiogenesis and increased the fetal and placental weights of the mice. Finally, we evaluated the safety of T-NP_PFKFB3. The expression levels of ALS/AST/BUN in the sera of pregnant mice were not significantly different from those in the sera of control group mice. However, T-NP_PFKFB3 did not cause obvious fetal abnormalities or alter the average litter size. In conclusion, T-NP_PFKFB3 can specifically target the placenta, promote angiogenesis, and enhance placental function without obvious side effects. Therefore, it has potential as a new strategy for the treatment of pregnancy complications. Full article

(This article belongs to the Special Issue Bioengineering Technologies to Advance Reproductive Health)

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Review

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15 pages, 1647 KiB

Open AccessReview

Bioengineered 3D Ovarian Models as Paramount Technology for Female Health Management and Reproduction

by Julieta S. Del Valle and Susana M. Chuva de Sousa Lopes

Bioengineering 2023, 10(7), 832; https://doi.org/10.3390/bioengineering10070832 - 13 Jul 2023

Cited by 5 | Viewed by 2966

Abstract

Ovarian dysfunction poses significant threats to the health of female individuals. Ovarian failure can lead to infertility due to the lack or inefficient production of fertilizable eggs. In addition, the ovary produces hormones, such as estrogen and progesterone, that play crucial roles not [...] Read more.

Ovarian dysfunction poses significant threats to the health of female individuals. Ovarian failure can lead to infertility due to the lack or inefficient production of fertilizable eggs. In addition, the ovary produces hormones, such as estrogen and progesterone, that play crucial roles not only during pregnancy, but also in maintaining cardiovascular, bone, and cognitive health. Decline in estrogen and progesterone production due to ovarian dysfunction can result in menopausal-associated syndromes and lead to conditions, such as osteoporosis, cardiovascular disease, and Alzheimer’s disease. Recent advances in the design of bioengineered three-dimensional (3D) ovarian models, such as ovarian organoids or artificial ovaries, have made it possible to mimic aspects of the cellular heterogeneity and functional characteristics of the ovary in vitro. These novel technologies are emerging as valuable tools for studying ovarian physiology and pathology and may provide alternatives for fertility preservation. Moreover, they may have the potential to restore aspects of ovarian function, improving the quality of life of the (aging) female population. This review focuses on the state of the art of 3D ovarian platforms, including the latest advances modeling female reproduction, female physiology, ovarian cancer, and drug screening. Full article

(This article belongs to the Special Issue Bioengineering Technologies to Advance Reproductive Health)

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