Page 24 - Aspire April -2023 Vol 8 / Issue 2

ENDOMETRIUM & IMPLANTATION SIG
New study reveals
3D bioprinting methods used in endometrial
tissue regeneration
By Drs Rong Li and Keiji Kuroda
Following is an overview of a study published in December 2022 relating to an endometrial construct to restore the full thickness morphology and fertility of injured uterine endometrium.
The authors, who are listed at the bottom of this article, used three dimensional bioprinting technology to provide a unique opportunity for endometrial tissue regeneration.
The upper layer of the 3D bio-printed endometrial construct (EC) was a monolayer of endometrial epithelial cells (EECs), while the lower layer had a grid- like microstructure loaded with endometrial stromal cells (ESCs).
In a partial full thickness uterine excision rat model, their bilayer EC not only restored the morphology and structure of the endometrial wall (including organised luminal/glandular epithelium, stroma, vasculature and the smooth muscle layer), but also significantly improved the reproductive outcome in the surgical area after implantation.
The uterine endometrium, which consists of the epithelial layer and lamina propria, is vital for embryo implantation and pregnancy maintenance. However, events such as myomectomy, dilatation and curettage, endometritis, and endometrial tuberculosis may severely damage the endometrium, causing a disruption of endometrial regeneration and intrauterine adhesions.
As the injury progresses, the epithelial cells are largely lost the exposed stromal zone is replaced by fibrous tissue and becomes avascular. Eventually, the endometrium becomes thin and dysfunctional, and loses its response to periodic hormonal changes. However, the existing treatment methods still have limitations that cannot effectively promote endometrial regeneration and prevent adhesions.
In their study, a 3D bio-printed EC was successfully fabricated for the first time to promote the repair and regeneration of the endometrium. The bilayer EC consists of an epithelial and a stromal layer and was fabricated by extrusion-based 3D bioprinting.
The construct contributed to morphological and functional recovery in the partial full-thickness uterine
excision rat model by improving vascularized endometrium regeneration, the number of gland structures, the inner layer of the myometrium, and the receptive fertility of the injured site.
The study showed a high total pregnancy rate of 93.75 percent, while the pregnancy rate at the injured site was 75 percent.
The 3D bio-printed bilayer EC provides a promising treatment for infertility caused by severe endometrial damage.
Currently, multi-cellular endometrial organoid technology, which attempts to reproduce the cell composition and histological structure of the endometrium, provides a promising model to investigate endometrial physiology and pathology in vitro.
Owing to the disadvantages of imprecise cell distribution, limited size, and undefined standards of protocol establishment and quality control, it is still a challenge to apply organoids to transplantation therapy.
However, 3D bio-printing technology can be used to manufacture tissue analogues with complex structures, uniform cell distribution, and refine spatial cell positioning.
Here, the 3D bio-printed bilayer EC achieved homogenous cell distribution and precise spatial cell positioning. In addition, the stromal layer presented a grid-like porous structure, which not only provides a scaffold for transplanted cell attachment, but also allows the infiltration and migration of native surrounding cells (such as epithelial cells, stromal cells, and smooth muscle cells) to facilitate tissue repair and regeneration.
The authors point out that although 3D bioprinting EC plays an important role in regenerating a damaged uterus and restoring fertility, there are still some defects. For example, double-layer EC cannot regenerate the integrated muscle layer with both circumferential inner and longitudinal outer layers.
Further work will improve the development of more fine structures of endometrium and myometrium, which can be applied to larger animal models and even humans.
L. Kou, X. Jiang, S. Xiao, Y.Z. et al. Therapeutic options and drug delivery strategies for the prevention of intrauterine adhesions, J Control Release 318 (2020)25-37. doi.org/10.1016/j. jconrel.2019.12.007 X. Jiang, X. Li, X. Fei, et al. Endometrial membrane organoids from human embryonic stem cell combined with the 3D Matrigel for endometrium regeneration in asherman syndrome, Bioact Mater 6(11) (2021) 3935-3946. doi.org/10.1016/j. bioactmat.2021.04.006 T. Wiwatpanit, A.R. Murphy, Z. Lu, et al. Scaffold-Free Endometrial Organoids Respond to Excess Androgens Associated with Polycystic Ovarian Syndrome, J Clin Endocrinol Metab 105(3) (2020). doi.org/10.1210/clinem/dgz100 J. Kim, B.K. Koo, J.A. Knoblich, Human organoids: model systems for human biology and medicine, Nature reviews. Molecular cell biology 21(10) (2020) 571-584. doi.org/10.1038/s41580-020-0259-3 A.C. Fonseca, F.P.W. Melchels, M.J.S. Ferreira, et al. Emulating Human Tissues and Organs: A Bioprinting Perspective Toward Personalized Medicine, Chem Rev 120(19) (2020) 11128- 11174.doi.org/ 10.1021/acs.chemrev.0c00342
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