Engineering Novel Imaging Technologies for Reproductive Health: Transforming IVF outcomes

这项提案的目的是采用最先进的成像技术，并利用它们来改善辅助生殖治疗程序（也称为体外受精或IVF）的结果。虽然试管婴儿已经使用了近40年，但它仍然是一个很大程度上不成功的程序（只有26%的周期以活产结束），并且对于患者来说使用昂贵（基本周期约5000英镑，通常需要>1个周期）。在这个过程中，一个女人的卵子被取出，并在诊所里与精子受精。然后将它们孵育几天，选择最好的胚胎并返回给患者。主要的问题是胚胎学家几乎没有什么信息可以帮助他们选择，也不知道哪个胚胎是最好的。我们知道一些更常见的失败原因包括胚胎的染色体（DNA物质）数量错误，以及胚胎的代谢速度不正确-这很难在不破坏卵子的情况下确定。我们提出了两种新的成像技术来解决这些问题如下：首先，我们将使用相干拉曼显微镜（CRM）。这使我们能够通过瞄准损伤较小的激光来匹配某些类型分子的振动来成像细胞内的特定结构。在这种情况下，我们建议靶向DNA，使我们能够看到细胞内部并对染色体进行成像。因此，我们可以观察发育中的胚胎内的染色体分裂，并在分裂异常时发出警报。其次，我们将使用双光子荧光（TPF）技术。有了这个，我们可以成像的分子是细胞中代谢途径的一部分。它们发光的能力根据细胞的新陈代谢而变化，因此我们可以确定胚胎每个细胞内的代谢活动，从而可以在早期丢弃有缺陷的细胞，并选择最好的细胞。这项提议旨在将这两种成像技术结合到一个台式胚胎成像设备中。该设备将是突破性的，因为它将结合联合收割机两个有用的诊断读数，它将只使用近红外光，这是远远低于目前的可见光显微镜，它将使用光片配置。这种新颖的配置意味着胚胎被来自侧面的光平面照射，而不是传统的聚焦激光光斑。这种方法也比传统方法的破坏性小得多，而且还加快了图像捕获的速度。最终的结果是一种更健康的方式来成像胚胎。在这个建议中，我们将开发这两种新技术，并将它们联合收割机结合在新颖的光片显微镜结构中。然后，我们将测试他们区分最好和最差胚胎的能力，最初使用小鼠胚胎作为测试模型。之后，在获得必要的伦理许可后，我们将在捐赠或丢弃的人类卵子上测试该设备。我们的愿景是胚胎学家能够窥视胚胎内部，并获得丰富的信息。然后，他们只会将最好的胚胎移植给患者，大大增加了成功的机会，并减少了IVF患者目前所经历的反复失败的痛苦和经济困难。由于这是一个全球性的问题，全球对IVF的需求越来越大，因此需要改进技术解决方案。这也带来了巨大的商业机会，因为它将减少患者的痛苦，治疗负担和成本。

The aim of this proposal is to take cutting edge imaging techniques and use them to improve the outcomes of assisted reproduction treatment procedure also known as in-vitro fertilisation or IVF. Whilst IVF has been used for almost 40 years now, it remains a largely unsuccessful procedure (only 26% of cycles end with a live birth) and is expensive for patients to use (~£5000 for a basic cycle, typically >1 cycle is needed). During the procedure, a woman's eggs are taken and fertilised by sperm in the clinic. They are then incubated for several days and the best embryo is selected and returned to the patient. The main problem is that the embryologist has very little information helping them to choose, and does not know which embryo is the best.We know some of the more common causes of failure include embryos that have the wrong number of chromosomes (DNA material) and embryos that that are not metabolising at the correct rate - this is difficult to determine without destroying the eggs. We are proposing two new imaging techniques to address these problems as follows: Firstly, we will use coherent Raman microscopy (CRM). This allows us to image specific structures within cells by targeting less damaging lasers to match the vibrations of certain types of molecules. In this case we propose to target the DNA allowing us to see inside the cells and image the chromosomes. We can therefore watch the chromosome divisions inside growing embryos and be alerted if the divisions are abnormal. Secondly, we will use the technique of two-photon fluorescence (TPF). With this we can image molecules that are part of the metabolic pathway in cells. Their ability to emit light changes depending on the metabolism of the cell and so we can determine the metabolic activity within each cell of an embryo, allowing defective ones to be discarded early on and the best ones to be selected.This proposal aims to combine these two imaging techniques into a single bench-top embryo-imaging device. The device will be ground-breaking in that it will combine two useful diagnostic readings, it will only use near-infrared light, which is far less damaging than the current visible light microscopes, and it will use a light-sheet configuration. This novel configuration means the embryo is illuminated by a plane of light from the side, instead of the conventional focussed laser spot. This approach is again far less damaging than the conventional method and also speeds up image capture. The end result is a much healthier way to image an embryo. In this proposal we will develop the two new techniques, and combine them in the novel light-sheet microscope configuration. We will then test their ability to distinguish the best from the worst embryos, initially using mouse embryos as a test model. Later and with the required ethical permissions we will test the device on donated, or discarded human eggs.Our vision is that the embryologist will be able to peer inside the embryo and have a wealth of information available to them. They will then only transfer the best embryos to the patient, increasing greatly the chances of success and reducing the suffering and financial difficulties of repeated failures to conceive that are currently experienced by IVF patients. Since this is now emerging as a global issue, there is an increasing demand for IVF worldwide and consequently the need for an improved technological solution. This presents a huge business opportunity as well besides the fact that it will reduce the distress, treatment burden and costs for patients.