Project Portugal 2030

Summary

The HuMoIR project will develop the first primary human cell-based advanced in vitro model for determining the human immune response to implantable biomaterials for cardiovascular applications. The inflammatory and immune cell response impacts biomaterial integration, and tissue repair/regeneration. Thus far, animals remain the most used models to determine the response to implantable biomaterial-based products, despite the important differences in human and animal immune systems. So, there is a pressing need to develop vitro models that encompass the cell and microenvironment complexity required to determine the human immune response to biomaterials. Our HYPOTHESIS is that the human immune response to biomaterials can be determined in vitro, using advanced models that combine human immune and stromal cells in an adequate 3D environment. To test our hypothesis we will build an advanced human model along 4 specific AIMS: AIM 1: Establish a human immune cell model of the response to biomaterials A 3D Lymph Node (LN) in vitro model encompassing myeloid and lymphoid populations, will be developed. This will go beyond current most advanced models for addressing biomaterials response and FBR (Sharifi et al., 2019). Human primary immune cells will be used, their interactions, communication and resulting activation/polarization will be analyzed in detail. Key Performance indicator (KPI): A 3D immune cell model (Task1) AIM 2. Identify the contribution of Fibroblast-like Reticular Cells to the immune response to biomaterials The impact of fibroblast-like reticular cells (FRC), crucial for immune cell activation and function (De Martin et al., 2023), on the immune response to biomaterials will be determined for the first time (Task2). KPI: The first FRC-encompassing model of immune response to biomaterials FRC (Task2). AIM 3. Characterize the Extracellular Matrix (ECM) of lymphoid tissue and its role in the immune response to biomaterials The importance of lymphoid ECM for the immune cell response to biomaterials will be determined for the first time. A decellularized ECM-based hydrogel, will be developed to culture immune cells and FRC in the LN model. The best combination to mimic the human immune response to biomaterials will be selected for the LN model. KPI: The first LN model of immune response to biomaterials encompassing stromal components and immune cells (Task3). AiIM4. Integrate the LN model in a biomaterial testing platform for cardiovascular applications. The best LN model (Tasks1-3) will be integrated with a cardiac model, developed by the team (Ergir et al., 2022) in an organ-on-a-chip (OoC) platform, developed with embedded real-time biosensing to address the human immune response to biomaterials. Clinically approved biomaterials will be used to validate the model platform. KPI: An integrated OoC prototype (Task4). The main HuMoIR BREAKTHROUGHS will include the demonstration of the impact of the stromal components of lymphoid organs in the immune response to biomaterials, and an advanced OoC platform, combining LN and cardiac tissue to determine the human immune response to implantable biomaterials. This project will develop NEW METHODOLOGIES using a “lego-like” approach, which will allow researchers to build new combinations and determine human responses in other contexts and for other tissues, with important impacts that go beyond the scope and also the duration of the current project.