Microfluïdische oplossingen voor intradermale vaccinatie: van hoge-doorvoer selectie tot autonome toediening

Vaccines are among the most powerful and cost-effective tools of modern medicine, yet vaccine-preventable diseases still cause an estimated 1.5 million deaths each year in low- and middle-income countries. One of the main contributing factors to this high number is limited vaccine accessibility, in part constrained by the current gold standard route for vaccine delivery. The intramuscular route requires hypodermic needle-based injection, which needs to be administered by often scarce trained healthcare personnel. The intradermal route offers a potent alternative as the skin is rich in immune cells and efficiently drains to the lymphatic system, thereby allowing dose sparing. In addition, intradermal delivery can be performed using minimally invasive delivery tools, which reduce dependence on trained personnel, lower injection-associated pain and needle-phobia-related-hesitancy while opening the possibility for self-administration. Despite these advantages, global adoption of intradermal vaccination remains limited. This is, in part, a consequence of most existing vaccine formulations being optimized for muscle tissue, while a lack of viable commercially available minimally invasive vaccine handling and delivery tools results in a lasting need for skilled personnel for vaccine handling and injection. To contribute to the challenges this field faces, in this dissertation the general objective was to develop and advance microfluidic platforms to overcome challenges in both intradermal vaccinology and administration, toward more accessible and efficient vaccination. This work consists of two parts, each building on a different microfluidic technology. In the first part, we developed a novel droplet microfluidic platform for high-throughput manipulation of single cells. The platform enabled highly accurate multiway droplet sorting. It was successfully validated for diverse model systems, including human cells transfected with a novel vaccine formulation. By showing successful coupling to a serial picoinjection module, we demonstrated its potential towards high-throughput screening of vaccine formulations to study and optimize immunization in a miniaturized and automated manner. In the second part we focused on a self-powered intradermal delivery device using the iSIMPLE (infusion Self-powered Imbibing Microfluidic Pump by Liquid Encapsulation) technology. Injection into rat skin was studied and a library of capillary pump materials was characterized in terms of pressure generation, injection volume, and flow rate, showing the capability of this technology to deliver liquid formulations to the skin. This pumping principle was further refined into a capillary pump battery for reliable and user-independent pumping action through the integration of a container, designed for off-chip liquid reagent storage, with a specialized microfluidic unit, designed for autonomous liquid handling. An in-depth study on the pump characteristics was performed, unraveling the principles governing capillary pump battery-mediated pumping. This enabled efficient selection of an optimal pump configuration for the integrated with a microfluidic network for autonomous on-patch vaccine reconstitution, allowing the handling of freeze-dried vaccine formulations without external power or manual mixing and exhibiting long-term storage capabilities. The resulting patch demonstrated reliable intradermal delivery and effective immunization in animal models while supporting user-friendly handling. We believe that these advances in the field of microfluidics might lead to new insights and next-generation microfluidic platforms for both the study of vaccine formulations and the development of novel vaccine patches, toward more accessible and efficient vaccination.