Bioengenharia para o Avanço de Terapias Personalizadas em Anemia Aplásica

This project focus on the development of a co-culture device based on microfluidics as a bioengineered BM proxy for disease modeling and drug testing in the context of AA, ultimately advancing personalized medicine and targeted therapies for this condition. Importantly, a patient-tailored, personalized therapy for AA will circumvent present therapeutic limitations that AA patients face, such as ineligibility and/or treatment related toxicities, as well as incomplete hematological response (e.g. dependance on transfusions; persistent immunocompromise status) to available therapies. Specifically, BIOaptAA aims to improve therapeutic outcomes and reduce morbidity and mortality of AA patients, especially adults and elderly patients. Three levels of OBJECTIVES are targeted in BIOaptAA: ASSESSING AA AND ITS PATHOPHYSIOLOGY BY A PRACTICAL APPROACH: 1. To provide insights on the altered patterns of the niche elements, namely BM MSC and their derived cellular (i.e. osteoblasts, adipoblasts) and non-cellular (i.e. ECM) elements, in the context of AA; 2. To modulate and optimize MSC and HSPC (co-)culture conditions toward a better understanding of the role of MSC in the pathophysiology of AA in a bioengineered BM proxy of AA; ADVANCING THE ENGINEERING OF A HUMAN BONE MARROW MODEL TO FOSTER SCIENTIFIC DISCOVERY AND INNOVATIVE THERAPEUTICS 3. to develop an innovative design of a microfluidic co-culture device as a BM proxy to better mimic the in vivo BM, particularly in what concerns to HSPC-MSC cell-to-cell contact and paracrine-mediated hematopoietic regulation by MSC and MSC derived elements; 4. to design and fabricate new interdigitated electrodes (IDEs) for impedance measurements, which will be integrated into the microfluidic device allowing label-free detection of cellular responses in real-time which is particularly advantageous for studying complex cellular interactions; 5. to establish a disease modeling platform for AA by using cells from homogeneous populations of patients newly diagnosed with acquired AA; 6. to exploit a BM proxy of AA for personalized medicine aiding in the selection of the therapeutic regiments that best suit to each patient and disease characteristics. Screening and selection of drugs that could improve hematopoietic dynamics either from a direct effect on AA HSPC or by modulating hematopoiesis upon an effect on BM MSC will be performed; DRIVING KNOWLEDGE AND INNOVATION ACROSS-DISCIPLINES 7. to concretize a truly collaborative network, by exploiting complementary expertise in Stem Cell Engineering, Microfluidics and Hematology, in collaboration with specialists from medical centers of reference for the diagnostic and treatment of AA and other hematological disorders, of all ages (adult and pediatric); 8. to collaborate with associations representing AA and BM failure syndromes, to foster scientific research and advances in the study of diseases that, despite of low incidence, are still prevalent and imply significant morbidities for patients of all ages, urging efforts to improve therapeutic outcomes and life quality; 9. to provide a disease modeling and drug testing platform to be applied for clinical research and bridge with pharmaceutical manufacturing; 10. to strengthen IST-ID/iBB – INESC MN collaboration within i4HB Associate Laboratory and establish BIOaptAA as a flagship project in the field and Personalized Medicine and Targeted Therapies boosting i4HB’s Health-related thematic cell lines.