Engineering Novel Imaging Technologies for Reproductive Health: Transforming IVF outcomes

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.

The envisaged project will have wide ranging impacts across different areas:
1) Clinical: The most obvious outcomes will relate to improvements in healthcare for patients of IVF. Here we hope to reduce the suffering experienced by patients who repeatedly fail to conceive, whilst also accruing costs that can be crippling to lower and medium income families. Our technology will increase the chances of success during IVF, thus reducing the average number of cycles required. Since NHS funds 40% of the costs, the burden on taxpayers will also reduce. Increased success will also mean healthier babies, as embryos may need to spend less time in culture, and can spend more time in the more suitable environment of the uterus. Thus the project could result in making a real difference to the lives of the people.
2) Academic:The project will provide the tools for in-depth studies of what occurs inside the growing embryo. Currently the requirement to inject or label the embryo with damaging markers or dyes, coupled with damaging imaging protocols limit the scientific communities ability to learn more about the mammalian embryo during its early divisions. Our microscope will enable very low-invasive, long term study inside the growing embryo, without the need to inject markers or use dyes due to its ability to take advantage of natural properties of the molecules inside the cells. Thus a large number of groups engaged in embryology and development research will be benefited. We envisage initial publications from our own group demonstrating the potential of the new technology, as well as further high-impact publications exploring the early divisions of the mouse and human embryo. The knowledge generated will feed into the knowledge economy of Southampton and the UK strengthening their position as a world leaders in developmental biology and technological innovation in optics/photonics.
3) Commercial: Considering the increasing world-wide demand and especially in the Asia-Pacific region due to abolition of the one-child policy in China, fertility tourism in India and Thailand, increasing incidence of polycystic ovary syndrome in South Asian countries there is a marked ready for a technological solution for improving IVF. By protecting IP and working with industry partners either through appropriate licensing or a new venture (startup) for commercialisation of the product the project will contribute to the knowledge economy of the UK.
4) Livestock: Assistive reproductive techniques are also used to a very large extent in breeding of livestock. Technologies that improve human IVF will likely spill over into this multi-billion dollar industry too.
5) Public opinion: There will be multiple opportunities to showcase the research findings of the proposed work. Owing to the pervasiveness of sub-fertility and access to IFV, this will likely interest a large portion of the population. The advances in science and technology will be communicated to the public by press releases through the University of Southampton, which has a dedicated team for this purpose. We will also run a web-page featuring any major breakthroughs and interesting content. In the past we have had good engagement following press releases, including global media coverage. This will raise the profile of the research group, the university and the UK research sector as a whole.
6) Personnel: The proposal will benefit the career development of named postdoctoral researcher Dr. Lane by providing interdisciplinary training, working within academia but in close collaboration with industry and IVF clinics. Dr Lane intends to use the data generated to apply for fellowships to further his academic career and scientific independence. The project will also benefit PhD students in the SM lab who will acquire knowledge and skills in developmental biology in addition to their Biophotonics training.