Development of a Multilayer Encapsulation System for the Production of Core-Shell Microcapsules Suitable for Organoid Growth

Every year, 20 million people worldwide are diagnosed with cancer, with 9.7 million succumbing to the disease (Kocarnik et al., 2021). Personalized treatment could significantly reduce the number of deaths. This thesis addresses this challenge by proposing the development of organoids derived from patient biopsies to optimize treatments.

The bioproduction of encapsulated cells in biopolymers is a rapidly growing field, with applications in personalized medicine, research, drug screening, cell therapies, and bioengineering. This thesis aims to contribute to these fields by focusing on the multilayer encapsulation of cells in biopolymers with a wide range of viscosities.

The inner layer (core) provides an optimal environment for the maturation and survival of cells or organoids, while the outer layer (shell) ensures mechanical protection and acts as a filtering barrier against pathogens.

This new thesis aims to design, develop, and study—both analytically and numerically—the architecture of a dual-compartment nozzle for the high-frequency production of monodisperse core-shell capsules. It builds upon a previous thesis completed in 2023, which focused on the detailed characterization and development of a predictive model for the generation of single-layer microcapsules using centrifugal force alone.

The formation and ejection mechanisms of multilayer capsules are complex, involving the rheological properties of biopolymers, centrifugal force, surface tension, and interfacial dynamics. The nozzle architecture must account for these properties.

The first part of this thesis will focus on understanding the multilayer formation and ejection mechanisms of microcapsules as a function of nozzle geometry. This will allow the prediction and control of capsule formation based on the rheological properties of the biopolymers. The second part will involve developing an automated system for the aseptic production of capsules. Finally, biological validation will assess the functionality and reliability of the developed technology.

To achieve the objectives of this study, the candidate will first conduct analytical and numerical studies, design the ejection nozzles, and leverage the laboratory's expertise for their fabrication. Fluidic tests on prototypes will help optimize the design, leading to the development and testing of a fully operational microcapsule production system.

The ideal candidate will have a background in physics, engineering, and fluid mechanics, with a strong inclination for experimental approaches. Prior experience in microfluidics or biology would be a valuable asset.

Development of a microfluidic bioanalytical platform to quantify the cellular bio-distribution of a drug

A drug's mode of action and efficacy are correlated not only with its ability to accumulate in the targeted pathological tissues, i.e. its tissue bio-distribution, but also with its ability to specifically reach its molecular target within cells. Non-specific accumulation of a drug in these cells can be the cause of undesired effects, such as side effects during chemotherapy. In other words, assessing a drug's efficacy, specificity and absence of toxicity requires precise, quantitative determination of its cellular bio-distribution. Antibody-drug conjugates (ADCs) have become an indispensable tool in oncology, enabling vectorized therapy to preferentially target a subset of tumor cells expressing the antigen recognized by the antibody.

These ADCs target specific tumor cells expressing a particular antigen, thus limiting toxicity to healthy tissue. Radioactive labeling of drugs (3H, 14C) is a key method for quantifying their accumulation in tumor and non-tumor cells, in order to assess targeting accuracy and avoid undesirable side effects. However, the detection of low-level tritium emissions requires new technological solutions. The project proposes the development of an innovative microfluidic platform to detect and quantify these isotopes in single cells. This approach will enable us to better document ADC distribution in heterogeneous tissues and refine therapeutic strategies.