Tanaka Ayaka, Nakamura Hitomi, Tabata Yasuhiko, Fujimori Yuka, Kumasawa Keiichi, Kimura Tadashi
Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
J Obstet Gynaecol Res. 2018 Oct;44(10):1947-1955. doi: 10.1111/jog.13726. Epub 2018 Jul 12.
Ovarian tissue cryopreservation before cancer treatment is the only option to preserve fertility under some circumstances. However, tissue ischemia after transplantation while awaiting angiogenesis induces dysfunctional folliculogenesis and reduces ovarian reserve and is one of the disadvantages of frozen-thawed ovarian tissue transplantation. Basic fibroblast growth factor (bFGF) is a major regulator of angiogenesis. However, bFGF rapidly loses biological activity when its free form is injected in vivo. This study investigated whether administration of active bFGF helps establish a nurturing environment for follicular survival.
A sheet form of a sustained release drug delivery system for bFGF was developed using biodegradable acidic gelatin hydrogel (bFGF sheet). The bFGF sheets or phosphate-buffered saline sheets, as a negative control, were transplanted with frozen-thawed human ovarian tissues subcutaneously into the backs of severe combined immunodeficient mice. Neovascularization, cell proliferation, fibrosis and follicular survival of ovarian grafts were analyzed at 6 weeks after xenografting.
The bFGF sheets were optimized to release bFGF for at least 10 days. The transplantation of bFGF sheets with frozen-thawed ovarian tissues significantly increased human and mouse CD31-positive areas and stromal and endothelial cell proliferations. The administration of bFGF also significantly decreased the percentage of the fibrotic area in the graft, resulting in a significant increase in primordial and primary follicular density.
Local administration of a sustained release of biologically active bFGF induced neovascularization in frozen-thawed ovarian tissue grafts, which could establish the nurturing environment required for follicular survival in heterotopic xenografts.
在某些情况下，癌症治疗前进行卵巢组织冷冻保存是保留生育能力的唯一选择。然而，移植后等待血管生成期间的组织缺血会诱导卵泡发生功能障碍并降低卵巢储备，这是冻融卵巢组织移植的缺点之一。碱性成纤维细胞生长因子（bFGF）是血管生成的主要调节因子。然而，当以游离形式注射到体内时，bFGF会迅速丧失生物活性。本研究调查了活性bFGF的给药是否有助于为卵泡存活建立滋养环境。
使用可生物降解的酸性明胶水凝胶（bFGF片）开发了一种用于bFGF的缓释药物递送系统片状形式。将bFGF片或作为阴性对照的磷酸盐缓冲盐片与冻融的人卵巢组织一起皮下移植到严重联合免疫缺陷小鼠的背部。在异种移植后6周分析卵巢移植物的新血管形成、细胞增殖、纤维化和卵泡存活情况。
bFGF片经过优化，可释放bFGF至少10天。将bFGF片与冻融的卵巢组织一起移植可显著增加人和小鼠CD31阳性区域以及基质和内皮细胞增殖。bFGF的给药还显著降低了移植物中纤维化区域的百分比，导致原始卵泡和初级卵泡密度显著增加。
局部给予生物活性bFGF的缓释可诱导冻融卵巢组织移植物中的新血管形成，这可以为异位异种移植物中卵泡存活所需的滋养环境。
