Project Portugal 2030

Summary

The main fundamental objectives of badfAT? are to: - Advance the knowledge on diabetic wound pathophysiology by exploring the contribution of an undervalued tissue - the diabetic dermal white adipose tissue - for the abnormal diabetic wound healing and, particularly, over the migration and phenotype of circulating cells. - Replace animal testing by engineering an innovative and unique off-the-shelf easy-to-use OoC platform that mimics the interplay between the systemic circulation and the local tissue microenvironment to analyze the chemotaxis-driven migration of a specific circulating cell and the phenotype of that migrated cell type post-culture. - Advance personalized medicine by optimizing biomaterials, technologies and protocols needed to develop healthy and diseased human skin models, allowing their posterior development on-demand using patient-derived cryopreserved cells. - Accelerate drug and diagnostic tools development by uncovering potential pathophysiological biomarkers of diabetic wounds. Other specific aims of badfAT? are: - Understand whether the migration of MDM/EPC to the injury site is already impaired or if it is the diabetic wounded tissue that interferes with the chemoattraction of circulating cells. - Understand if there is a predominant factor in the diabetic signature or if it is the overall diabetic environment that affects cell recruitment. - Apply fabrication tools to develop an artificial vasculature, overcoming the struggles and demands of creating a complex tridimensional, hollowed, multilayered and multicellular biological vasculature, and the inherent variability among patients' cells and healthy/diseased cells. - Explore injection molding technology to fabricate tailor-made polystyrene well chips, laser ablation technology to customize pharmaceutical-grade silicon tubes with pores for cell permeation and chemical functionalization strategies for promoting cell adherence to the tubes. - Explore cutting edge in-house developed innovative tools, including a co-axial multi-head extrusion-based printer and bio-instructive/printable GG-based inks, to develop bioinks and bioprint skin models. - Explore different sources of primary cells from the cutaneous and subcutaneous tissues of diabetic patients to develop representative healthy/diabetic wounded skin models, including: human dermal microvascular endothelial cells (hDMECs) and human adipose-derived microvascular endothelial cells (hAMECs) as instructive and capillary-like forming cells; human dermal fibroblasts (hDFBs) as extracellular matrix producing cells; human adipose tissue-derived mesenchymal stem cells (hASCs), human preadipocytes (hpADs) and human mature adipocytes (hmADs) as precursors and mature adipocytes with dissimilar phenotypes; and type 2 diabetic patient-derived cells to create the diabetic signature. - Explore transcriptomics, proteomics and metabolomics to generate multivariate biological data on the developed healthy/diabetic wounded skin models and explanted human skin tissues. - Apply bioinformatics as a tool to integrate omics data and disclose diabetic wound pathophysiology-associated biomarkers and signaling pathways not readily perceptible.