In vitro fertilization technology: microfluidic platform for non-invasive embryo reception and characterization

Infertility affects 17.5% of couples of childbearing age. Assisted reproductive technologies (ART), such as in vitro fertilization (IVF), are costly and complex procedures requiring advanced equipments and a highly skilled workforce. Successive embryo manipulations are a source of stress that can impact on embryo quality and viability. But developmental abnormalities and miscarriages are mainly caused by chromosomal number anomalies or aneuploidies. These can be detected by pre-implantation diagnosis of aneuploidies (PGD-A) followed by high-throughput sequencing (NGS). However, PGD-A remains complex and invasive, with embryo biopsy potentially having implications for embryo development.
The question the PhD student will have to answer is: can we design a technological alternative that enables both automated culture of in vitro fertilization (IVF) embryos and their selection by non-invasive methods? The project will focus on automating embryo handling, while minimizing mechanical stress, and on extracting the extra-embryonic medium for circulating DNA analysis.
Expected results include an automated microfluidic platform for handling embryos without human intervention, extraction of extra-embryonic medium for aneuploidy analysis by sequencing, and building the program basis for microfluidic technologies applied to IVF.

Transcutaneous sampling of gaseous biomarkers

The development of wearable medical devices is a fundamental and essential in order to promote ambulatory medicine. Exhaled gases as transcutaneous gases (gases that diffuse through the skin) are known to carry molecules ("biomarkers") representative of pathologies or degradation of the physiological state, the ambulatory monitoring of which would be a real diagnostic and monitoring tool. However, the personal equipment associated to the continuous monitoring of exhaled gases is inappropriate for intensive sports activities, unlike the transcutaneous gases monitoring which could be carried out without losing mobility and discreetly (social impact), for example with a device placed on the forearm. Apart from oxygen and carbon dioxide, most of the biomarkers present are in very low concentrations and are therefore difficult to detect. One way of getting around this low concentration is to carry out a pre-concentration step, i.e. to accumulate over time, and therefore to concentrate enough molecules so that they are more easily detectable and measurable.
The objective of this thesis is therefore to develop and optimise a transcutaneous gas collector and pre-concentrator. The work will consist in particular in modelling the gas exchanges between the skin and the device in order to optimize the efficiency of the pre-concentration. The model will be compared with experimental results on a gas test bench for validation with two biomarkers of interest.
This subject requires a highly motivated person with skills in modelling and instrumentation. Skills in mechanical design of medical devices would be a plus.

Hollow microneedle and capillary microfluidic system for InterStitial Fluide (ISF) monitoring

Interstitial fluid (ISF) is the fluid that occupies the space between blood capillaries and cells. ISF consists mainly of water, salts, sugars, hormones, neurotransmitters, CO2 and fatty acids. It is particularly interesting as it is described as a filtrate of plasma, but more accessible than blood for continuous monitoring. Continuous monitoring of ISF is targeted, for example, for cortisol (a marker of stress, whose circadian rhythm makes continuous monitoring very interesting), sex hormones (PMA) and other biomarkers for monitoring a patient's state of health. The aim of this thesis is to develop a wearable device for ISF sampling, which co-integrates biocompatible or even resorbable hollow microneedles and a capillary microfluidic part. Eventually, this type of system will be combinable with various types of sensors at the fluidic outlet for various applications such as circadian cortisol monitoring for stress and post-traumatic stress. Three main issues will need to be addressed in this thesis: (a) One is the management of very low flow rates in passive microfluidics (flow rates in the nL/min range). (b) Technologically, the manufacturing process for resorbable hollow microneedles with fine management of the surface finish of the channel interior (to promote capillarity) will also be an important focus of the study. (c) Finally, the process will be evaluated and improved in terms of eco-circularity.

Multi-target capture strategy for micro total analysis systems

The concentration of biomarkers and pathogens in biological samples is generally limited by the preparation of these samples after their collection. In addition, their detection, when based on an antibody-antigen capture reaction, can be difficult to optimize within biosensors. If the approach which consists of functionalizing a wall to capture molecules or particles flowing in a micro channel seems simple at first glance, the results are often below expectations. On the one hand, the capture of molecules is a convection-diffusion problem; on the other hand, capturing particles must also take into account the pressure distributions on them. Thus the proposed thesis subject is part of a project to optimize the capture and concentration of all types of biological and biochemical targets within fluidic microsystems.

The thesis project will begin by the exploration of models dedicated to the capture of biochemical and biological targets within a microchannel. The objective of this task is to specify the optimal and common conditions for capturing all targets of interest. Among all possible configurations, maintaining functionalized beads dispersed in volume by an adequate field will be favored because it is expected to be optimal. This configuration will be a subject of particular attention, especially as it offers an original microfluidic implementation, particularly in the study of organoids on chips to capture, concentrate and monitor their secretions.

For this project, the laboratory is looking for a student motivated by experimental work in microfluidics with a detailed understanding of the involved physical phenomena. In addition, knowledge of classic molecular biology tests will be appreciated. Skills in numerical simulation are also an asset when applying for the proposed thesis.

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