A non-invasive metabolic sensor for improving success in IVF

摘要 在体外培养的胚胎暴露于非生理条件下，可能会损害胚胎的健康。 未来的成年人此外，培养应激降低了立即胚胎存活率和植入成功率， 促使多个胚胎移植并导致高多胎妊娠率。这些怀孕是 对胎儿和母亲有风险，并表现出高的保健费用负担。为了解决这个问题， 基于早期形态学来识别最健康的转移，但这种方法实现有限 成功与否，高度依赖于个人进行测试。准确客观的筛选 这种方法将提高植入率，减少多次移植的需要， 更健康的后代本项目的目的是开发一种新的无创体外受精胚胎技术 选择. Paolo Rinaudo博士是UCSF中心的生殖内分泌学家， 该组织每年进行超过2000例体外受精手术，并致力于研究。 通过20年的体外受精工作经验，他发现目前的筛查方法 胚胎不足，以金标准，形态学选择，达到阳性预测值 只有30%。虽然胚胎可能在形态上看起来是健康的，但它可能在分子上不健康，这可能 影响胎儿的长期发育。在他20年来对培养胚胎和体外受精的研究中， 是发现离体培养可以应激胚胎并驱动Warburg样代谢。此外，文化 压力现在已经与长期的负面健康结果相关，包括胎盘异常， 发育、代谢功能障碍、高血压和糖尿病。里瑙多医生假设新陈代谢 活跃的胚胎降低了培养液滴的pH值，类似于瓦尔堡代谢如何酸化环境 从而提供了一种简单的方法来选择最好的胚胎进行移植。他的研究 证实了这一点，但该技术不能转化为实践，因为没有有效和可靠的pH值 由于培养液滴体积微小，有了这个概念，他联系了博士。 亚当·阿巴特，加州大学旧金山分校的物理学家和工程师。Abate博士是微流体和纳米技术的领导者， 有开发和将医疗保健技术转化为实践的记录，创立了多家公司 将他的发明商业化，包括Fluent Biosciences（基因组学），使命生物（肿瘤诊断学）和 Scribe（细胞和基因治疗）。Rinaudo博士和Abate博士共同设计了一种新型水凝胶生物传感器， 作为一名IVF临床医生，Rinaudo博士了解法规和 IVF操作的实际限制，从而通过使其简单， 非侵入性的，并且具有成本效益。这笔资金将用于开发该技术并在小鼠模型中验证其有效性 为后续R01提供关键数据。因此，该项目建立在严格的科学基础之上， 数十年的临床经验，并包括一个团队能够将科学发现转化为临床。

ABSTRACT Embryos cultured external to the body are exposed to non-physiologic conditions that can impair the health of the future adult. Moreover, culture stress reduces immediate embryo viability and implantation success, motivating multiple embryo transfers and leading to high rates of multiple pregnancies. These pregnancies are risky for fetus and mother and exhibit a high healthcare cost burden. To address this, embryos are screened based on early-stage morphology to identify the healthiest for transfer, but this approach achieves limited success and is highly dependent on the individual conducting the test. An accurate and objective screening method would increase implantation rates and reduce the need for multiple transfers, in addition to yielding healthier offspring. The objective of this project is to develop a new technology for noninvasive IVF embryo selection. Dr. Paolo Rinaudo, Co-I on this grant, is a Reproductive Endocrinologist working at the UCSF Center for Reproductive Health which performs >2000 IVF procedures per year and has commitment to research. Through experience derived from two decades of work in IVF, he identified that current methods for screening embryos are inadequate, with the gold standard, morphological selection, achieving a positive predictive value of just 30%. While an embryo may appear morphologically healthy, it may not be molecularly healthy, which may affect the long-term development of the fetus. Among his two decades of research on cultured embryos and IVF is the finding that ex vivo culture can stress embryos and drive Warburg-like metabolism. In addition, culture stress has now been correlated to long-term negative health outcomes, including abnormal placental development, metabolic dysfunction, hypertension, and diabetes. Dr. Rinaudo hypothesized that metabolically active embryos lower their culture droplet pH, similar to how Warburg metabolism acidifies the environment around cancer cells, thereby affording a simple way to select the best embryos for transfer. His research has confirmed this, but the technique cannot be translated to practice because there is no effective and reliable pH measuring method for the culture droplet due to its tiny volume. Armed with this concept, he reached out to Dr. Adam Abate, a physicist and engineer at UCSF. Dr. Abate is a leader in microfluidics and nanotechnology with a record of developing and translating health care technologies to practice, having founded multiple companies commercializing his inventions, including Fluent Biosciences (genomics), Mission Bio (oncology diagnostics) and Scribe (cell & gene therapy). Together, Drs. Rinaudo and Abate have designed a novel hydrogel biosensor that non-invasively measures culture droplet pH. Being an IVF clinician, Dr. Rinaudo is aware of the regulatory and practical constraints of IVF operations and thus ensured the design is feasible for this setting by making it simple, non-invasive, and cost-effective. This grant will develop the technology and validate its efficacy in a mouse model of IVF, providing critical data for a follow-on R01. The project is thus based on a rigorous scientific foundation, decades of clinical experience, and comprises a team capable of translating science discoveries to the clinic.