Clot-in-a-Chip and Innovative Programmable Materials

Abstract

[eng] Stroke is a medical condition in which vessel or artery obstruction leads to tissue damage due to a lack of nutrients and oxygen in the affected area. In the past decade, stroke has become the most common circulatory disease in the European Union (EU) and one of the leading causes of death and disability globally, ranking second and third in 2019 and 2020, respectively. The research presented in this thesis was conducted as part of the European-funded ANGIE project (magnetically steerable wireless nanodevices for targeted delivery of therapeutic agents in any vascular region of the body, HORIZON 2020). This thesis contributes to ANGIE by developing novel technologies for producing submillimeter-sized blood clots and investigating innovative materials for programming micrometer-sized robotics to dissolve blood clots. We propose technical approaches for creating blood clots within microfluidic devices that will support future research on magnetically guided entities that promote lytic processes in complex environments. This thesis comprises multiple chapters that contain experimental results. Initially, we developed a microfluidic device with five inlets for controlled generation of blood clots containing tissue factor. The device flow conditions facilitated precise manipulation of the straight blood clot dimensions by adjusting the flow rates of the side streams. This experimental setup enabled the production of both heterogeneous and homogeneous blood clots, which were used to investigate the variation in thrombolytic agent efficacy based on the clot composition. Quake valve systems were employed as a secondary approach for the formation of free interface diffusion between whole blood and tissue factors. The reaction under diffusive mass transport facilitated the formation of homogeneous blood clots with volumes on the order of nanoliter. The latter acquired a semi-hemispherical shape as determined by the channel contour. Dissolution studies revealed a correlation between blood clot size and the injected volume of the thrombolytic agent. As a third approach, the mass transport phenomena through an in situ produced PDMS membrane was investigated. Blood clots were generated within the control chambers, separated by a thin membrane from the fluidic channel carrying thrombogenic agents. The blood clots assumed complex morphologies determined by chamber geometry, and structural alterations were contingent on the concentration of the thrombogenic agent. The generated blood clots were used to develop a high-throughput printing system for drug testing in future research. This study introduces a novel method for creating programmable robots using polymeric meshes for dissolution treatments. This process integrates Liquid Crystal Elastomers and hydrogels via sequential photopolymerization. A tailored photopolymerization setup was devised to control hydrogel alignment via Lyotropic Chromonic Liquid-Crystal templating regulated by a permanent magnetic field during polymerization. High-temperature water applications have demonstrated composite actuation. In addition, the setup allows the printing of complex designs.

[cat] La manca de nutrients i oxigen com a conseqüència d'una obstrucció d'un vas sanguini o artèria és una condició mèdica anomenada accident cerebrovascular. Aquesta tesi es va desenvolupar dins del marc del projecte europeu ANGIE (magnetically Steerable wireless nanodevices per a targeted delivery of therapeutic agents in any vascular region of the body, HORIZON 2020), i contribueix en aquest projecte mitjançant el desenvolupament de noves tecnologies per a la producció de coàguls sanguinis de mida submil·limètrica; abordant el control de paràmetres estructurals i morfològics. A més, s'ha investigat l'ús de nous materials per a la programació de robots amb fins trombolítics. La tesi s'ha dividit en diversos capítols experimentals. El primer dispositiu desenvolupat consisteix en un canal de cinc entrades on es produeix la barreja controlada de sang i factor tisular que va facilitar la manipulació de les dimensions i microestructura dels coàguls produïts. Aquest disseny va permetre la producció de coàguls heterogenis i homogenis, que es van utilitzar per a estudis on variacions en l'eficàcia d'agents trombolítics. El segon dispositiu consisteix en la implementació de vàlvules mecàniques per a la formació d'una interfase lliure de difusió, capaç de controlar la barreja de sang i factor tissular. La reacció sota el transport de massa difusiu va facilitar la formació de coàguls homogenis amb volums de l'ordre de nL. L'últim dispositiu desenvolupat s'ha utilitzat en l'estudi de fenòmens de transport de massa a través d'una membrana de PDMS. Els coàguls sanguinis van adquirir morfologies complexes determinades per la geometria de la cambra. Els coàguls de sang generats es van utilitzar per desenvolupar un sistema d'impressió que podrà ser utilitzat per a testar fàrmacs en investigacions futures. A banda del desenvolupament de coàguls de sang, en aquesta tesi, també es presenta un nou mètode per crear robots programables utilitzant sistemes polimèrics per a tractaments de dissolució. Aquest procés integra elastòmers de cristalls líquids i hidrogels mitjançant fotopolimerització seqüencial. S’ha demostrat la bona actuació del sistema integrat i la impressió de dissenys complexos.