Biomaterial technologies for interrogating sex differences in tissue repair and homeostasis

项目总结 个体的生物性别显著影响他们修复和再生组织的能力。一个明显的例子 这就是绝经后女性愈合和再生新的健康组织的能力下降，这导致 由于性激素信号的显著丢失。这种激素水平的降低不成比例地增强了 许多退行性疾病的风险，包括骨质疏松症、骨关节炎、心血管疾病和 组织破损率超过组织修复率的退行性脑病。虽然它是 已知有几个因素导致了组织修复中的性别差异，包括生物力学，营养， 体力活动水平和性激素，这些参数之间的相互作用还不是很清楚。 具体地说，目前尚不清楚原住民在组织结构上的性别差异以及由此导致的 机械功能决定细胞的表型和行为，以及这种效应如何与雌激素信号相互作用 全面控制组织修复。因此，对细胞如何响应的基本机械理解 在调节雌激素信号的同时，其环境的空间和机械线索对于理解为什么 在组织修复和动态平衡以及未来以患者为中心的修复和再生方面存在性别差异 战略。我们研究计划的总体目标是开发生物材料工具来审问性行为 在组织修复和动态平衡方面的差异。主题1：男性和女性间充质干细胞对空间和 细胞微环境的机械特性不同？在许多组织中有证据表明 细胞外基质的结构、组织和结果功能在年龄匹配的男性和 女性。然而，目前还没有研究表明这会如何影响细胞反应。仿生生物材料 天然结构胶原蛋白的纤维性质和蛋白多糖的粘弹性 细胞外基质将用于评估细胞对基质受控变化的反应中的性别差异 属性。主题2：雌激素向细胞递送如何影响下游转录和行为？ 虽然已知雌激素在细胞过程中发挥作用，但这些结果取决于雌激素的浓度和 雌激素向细胞的短暂递送。为了解决这一限制，我们将使用浓度梯度 快速准确测定雌激素浓度和时间对细胞影响的生成器芯片 转录活性。主题3：我们能否设计生物材料系统来控制药物的释放和呈现 雌激素对细胞的作用？在几个小时到几个月的范围内的释放速率将通过调节扩散来控制 通过材料化学和建筑对生物材料的影响。能够控制发布和本地化的速度 对身体中的特定组织至关重要，以促进该部位的雌激素效应，同时减少负面影响 以及潜在的致命偏离目标效应。这些研究的结果将为今后的研究提供途径 了解雌激素和细胞微环境如何驱动干细胞行为的性别差异 对女性和男性的组织修复和动态平衡至关重要。

PROJECT SUMMARY An individuals’ biological sex significantly affects their ability to repair and regenerate tissue. A clear example of this is the reduced ability for women to heal and regenerate new, healthy tissue after menopause, which results from a significant loss of sex hormone signaling. This reduction in hormone levels disproportionately enhances the risk for many degenerative diseases including osteoporosis, osteoarthritis, cardiovascular disease, and degenerative brain diseases in which the rate of tissue breakdown exceeds the rate of tissue repair. While it is known that several factors contribute to sex differences in tissue repair including biomechanics, nutrition, physical activity level and sex hormones, the interplay between these parameters is not well understood. Specifically, it is unknown how the native sex differences in tissue structure and the resulting differences in mechanical function dictate cell phenotype and behavior and how this effect interacts with estrogen signaling to overall control tissue repair. Thus, a fundamental, mechanistic understanding of how a cell responds to the spatial and mechanical cues of its environment while mediating estrogen signaling is critical to understand why sex differences occur in tissue repair and homeostasis and for future patient-centered repair and regeneration strategies. The overall goal of our research program aims to develop biomaterial tools to interrogate sex differences in tissue repair and homeostasis. Theme 1: Do male and female MSCs respond to spatial and mechanical properties of the cell microenvironment differently? There is evidence in many tissues that extracellular matrix structure, organization, and resulting function differs between age-matched males and females. However, there are no studies showing how this affects cell response. Biomaterials engineered to mimic both the fibrous properties of structural collagens and the viscoelastic properties of proteoglycans in the native extracellular matrix will be used to assess sex differences in cell response to controlled changes in matrix properties. Theme 2: How does estrogen presentation to the cell affect downstream transcription and behavior? While estrogen is known to play a role on cell processes, these results are dependent on the concentration and the temporal presentation of estrogen to the cell. To address this limitation, we will use concentration gradient generator microchips to quickly and accurately determine the effect of estrogen concentration and timing on cell transcriptional activity. Theme 3: Can we engineer biomaterial systems to control release and presentation of estrogen to the cells? Release rates in a range of hours to months will be controlled by modulating diffusion out of the biomaterials via material chemistry and architecture. The ability to control the rate of release and localize to a specific tissue in the body is critical to promote the estrogen effects at the site while reducing the negative and potentially deadly off-target effects. Results from these studies will provide future avenues of study to understand how estrogen and the cell microenvironment drive sex differences in stem cell behavior which is critical for tissue repair and homeostasis in both women and men.