Department of Materials, Imperial College London, Exhibition Road, London, SW7 2AZ, UK; Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, W12 0NN, UK.
Department of Materials, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
Biomaterials. 2021 Oct;277:121099. doi: 10.1016/j.biomaterials.2021.121099. Epub 2021 Sep 3.
Follicle development in the ovary must be tightly regulated to ensure cyclical release of oocytes (ovulation). Disruption of this process is a common cause of infertility, for example via polycystic ovary syndrome (PCOS) and premature ovarian insufficiency (POI). Recent ex vivo studies suggest that follicle growth is mechanically regulated, however, crucially, the actual mechanical properties of the follicle microenvironment have remained unknown. Here we use atomic force microscopy (AFM) spherical probe indentation to map and quantify the mechanical microenvironment in the mouse ovary, at high resolution and across the entire width of the intact (bisected) ovarian interior. Averaging over the entire organ, we find the ovary to be a fairly soft tissue comparable to fat or kidney (mean Young's Modulus 3.3±2.5 kPa). This average, however, conceals substantial spatial variations, with the overall range of tissue stiffnesses from c. 0.5-10 kPa, challenging the concept that a single Young's Modulus can effectively summarize this complex organ. Considering the internal architecture of the ovary, we find that stiffness is low at the edge and centre which are dominated by stromal tissue, and highest in an intermediate zone that is dominated by large developmentally-advanced follicles, confirmed by comparison with immunohistology images. These results suggest that large follicles are mechanically dominant structures in the ovary, contrasting with previous expectations that collagen-rich stroma would dominate. Extending our study to the highest resolutions (c. 5 μm) showed substantial mechanical variations within the larger zones, even over very short (sub-100 μm) lengths, and especially within the stiffer regions of the ovary. Taken together, our results provide a new, physiologically accurate, framework for ovarian biomechanics and follicle tissue engineering.
卵巢中的卵泡发育必须受到严格调控，以确保卵母细胞（排卵）周期性释放。这一过程的破坏是导致不孕的常见原因，例如多囊卵巢综合征（PCOS）和卵巢早衰（POI）。最近的离体研究表明，卵泡生长受到机械调控，然而，至关重要的是，卵泡微环境的实际机械特性仍然未知。在这里，我们使用原子力显微镜（AFM）球形探针压痕来绘制和量化小鼠卵巢的机械微环境，分辨率高，横跨完整（切开）卵巢内部的整个宽度。对整个器官进行平均，我们发现卵巢是一种相当柔软的组织，类似于脂肪或肾脏（平均杨氏模量 3.3±2.5kPa）。然而，这种平均值掩盖了实质性的空间变化，组织硬度的总范围从 c.0.5-10kPa，这挑战了一个单一的杨氏模量可以有效地概括这个复杂器官的概念。考虑到卵巢的内部结构，我们发现边缘和中心的硬度较低，这些区域主要由基质组织组成，而在以大发育成熟卵泡为主的中间区域硬度最高，这一点通过与免疫组织化学图像的比较得到了证实。这些结果表明，大卵泡是卵巢中机械上占主导地位的结构，与之前认为富含胶原蛋白的基质会占主导地位的预期形成对比。将我们的研究扩展到最高分辨率（c.5μm），即使在非常短的（小于 100μm）长度内，甚至在卵巢的较硬区域内，也显示出了大量的机械变化。总之，我们的研究结果为卵巢生物力学和卵泡组织工程提供了一个新的、生理上准确的框架。
