Abstract
To successfully assemble a bio-engineered ovary, we need to create a three-dimensional matrix able to accommodate isolated follicles and cells. The goal of this study was to develop an extracellular matrix hydrogel (oECM) derived from decellularized bovine ovaries able to support, in combination with alginate, human ovarian follicle survival and growth in vitro. Two different hydrogels (oECM1, oECM2) were produced and compared in terms of decellularization efficiency (dsDNA), ECM preservation (collagen and glycosaminoglycan levels), ultrastructure, rigidity, and cytotoxicity. oECM2 showed significantly less dsDNA, greater retention of glycosaminoglycans and better rigidity than oECM1. Isolated human ovarian follicles were then encapsulated in four selected hydrogel combinations: (1) 100% oECM2, (2) 90% oECM2 + 10% alginate, (3) 75% oECM2 + 25% alginate, and (4) 100% alginate. After 1 week of in vitro culture, follicle recovery rate, viability, and growth were analyzed. On day 7 of in vitro culture, follicle recovery rates were 0%, 23%, 65%, 82% in groups 1-4, respectively, rising proportionally with increased alginate content. However, there was no difference in follicle viability or growth between groups 2 and 3 and controls (group 4). In conclusion, since pure alginate cannot be used to graft preantral follicles due to its poor revascularization and degradation after grafting, oECM2 hydrogel combined with alginate may provide a new and promising alternative to graft isolated human follicles in a bio-engineered ovary.
Highlights
Alternative to restore fertility in these patients is development of a transplantable engineered ovary (TEO).[3,4,5]. It consists of isolated ovarian follicles, the morpho-functional units of the ovary, which are coencapsulated with isolated ovarian cells in a three-dimensional (3D) scaffold, essential to providing a bio-engineered environment where follicles can be supported, grow, and interact with ovarian cells.[6]
As expected, when alginate was combined with oECM2, the follicle recovery rates increased proportionally, up to a maximum achieved with alginate alone
Pure oECM2 was not able to sustain human follicle survival in vitro, probably due to its relative softness compared to human ovarian tissue
Summary
In some cancers grafting of frozen/thawed ovarian tissue cannot be performed due to the risk of reintroducing malignant cells.[1,2] AnLisa White and Christiani Andrade Amorim contributed to this manuscript and should be considered joint senior authors.alternative to restore fertility in these patients is development of a transplantable engineered ovary (TEO).[3,4,5] It consists of isolated ovarian follicles, the morpho-functional units of the ovary, which are coencapsulated with isolated ovarian cells in a three-dimensional (3D) scaffold, essential to providing a bio-engineered environment where follicles can be supported, grow, and interact with ovarian cells.[6]J Biomed Mater Res. 2021;1–11.wileyonlinelibrary.com/journal/jbmb CHITI ET AL.Encouraging results with mouse follicles have been obtained in vitro and in vivo with alginate scaffolds.[7,8] While alginate has several advantages for follicle encapsulation, one of the main limitations is its biological inertness, which has hampered its use in in vivo applications due to poor cell adhesion, limited degradation and revascularization after transplantation.[8]. ECM hydrogels are collagenbased and enriched with native sulphated glycosaminoglycans (GAGs), proteoglycans, and ECM proteins.[14] When processed appropriately, ECM hydrogels retain the inherent bioactive features of native ECM, including peptide domains, which play a major role in integrin-cell attachment, cell survival, proliferation, and deposition of de novo ECM components. They can be administered in a minimally invasive manner. Tissue-derived ECM hydrogels have already demonstrated their potential in a variety of different tissues and organs, including heart,[16,17] brain,[18,19] bone,[20,21,22] skin,[23] intestine,[24] liver,[25] kidney,[26] meniscus,[27] and spinal cord.[21]
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