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2 new DFG projects approved

1) EndOxy in Flame – Influence on Inflammatory Pathways and Immune System-Endothelial Cell-Interaction of a Biohybrid Lung

Summary: Extracorporeal membrane oxygenation (ECMO) is an adequate therapy for the treatment of acute lung failure. It could serve as a suitable option in chronic lung failure as well, if the obstacles towards an implantable lung are cleared. An example of acute lung failure is the Acute Respiratory Distress Syndrome (ARDS) in which ECMO is used for bridging to recovery while the main reason for chronic lung failure is chronic obstructive pulmonary disease (COPD). For the latter, an (implantable) lung replacement would be needed as long-term treatment option.

The long-term use of ECMO systems and their development towards an implantable lung device is mainly limited by failure of the oxygenator device. This is due to the large artificial surface of the gas exchange membranes, which is in contact with the blood. This limited hemo- & biocompatibility results in an unspecific protein binding to the gas exchange membrane which in turn leads to a significant decrease of gas transfer performance and thus a replacement of the device is required after days to some weeks. In addition, the artificial material induces a systemic inflammatory response with yet undefined consequences for the human body.

Endothelial cell lining of the gas exchange membranes seems to be a promising approach to overcome these limitations and opens the gate towards an implantable lung. The active endothelial cell layer acts as a natural biointerface for the contacting blood phase. Nevertheless, the role of the endothelial cell lining in such biohybrid systems with regard to acute and chronic inflammatory responses is currently unknown to our knowledge. Similarly, the reaction of the endothelial cell lining in the setting of low-grade inflammation in COPD and high-grade inflammation during ARDS and COPD exacerbations is unknown.

Therefore, the aim of the project is to study the effect of the endothelial cell layer on inflammation in peripheral blood and vice versa in homeostatic conditions, in low-grade and high-grade inflammatory conditions. To evaluate the inflammatory properties, we will perform (i) flow cytometric analysis of early signaling events combined with (ii) transcriptomic analyses of isolated blood cells as well as endothelial cells during ECMO in miniaturized biohybrid lung models. This will result in identification of pathways that will be (iii) verified on the protein level and can be targeted by small molecules. The combination of these methods will provide information about superiority or inferiority of endothelialized devices regarding inflammation in acute and chronic conditions and will identify possible pathways that can be targeted by pharmaceutical approaches.

2) EndoSpray – Efficient cell coating of biohybrid lungs by atomization of shear-stress resistant endothelial cells derived from induced pluripotent stem cells

Summary: Extracorporeal membrane oxygenation (ECMO) is an adequate therapy for the treatment of acute lung failure. It could serve as a suitable option in chronic lung failure as well, if the obstacles towards an implantable lung are cleared. An example of acute lung failure is the Acute Respiratory Distress Syndrome (ARDS) in which ECMO is used for bridging to recovery while the main reason for chronic lung failure is chronic obstructive pulmonary disease (COPD). For the latter, an (implantable) lung replacement would be needed as long-term treatment option.

The long-term use of ECMO systems and their development towards an implantable lung device is mainly limited by failure of the oxygenator device. This is due to the large artificial surface of the gas exchange membranes, which is in contact with the blood. This limited hemo- & biocompatibility results in an unspecific protein binding to the gas exchange membrane which in turn leads to a significant decrease of gas transfer performance and thus a replacement of the device is required after days to some weeks. In addition, the artificial material induces a systemic inflammatory response with yet undefined consequences for the human body.

Endothelial cell lining of the gas exchange membranes seems to be a promising approach to overcome these limitations and opens the gate towards an implantable lung. The active endothelial cell layer acts as a natural biointerface for the contacting blood phase. Nevertheless, the role of the endothelial cell lining in such biohybrid systems with regard to acute and chronic inflammatory responses is currently unknown to our knowledge. Similarly, the reaction of the endothelial cell lining in the setting of low-grade inflammation in COPD and high-grade inflammation during ARDS and COPD exacerbations is unknown.

Therefore, the aim of the project is to study the effect of the endothelial cell layer on inflammation in peripheral blood and vice versa in homeostatic conditions, in low-grade and high-grade inflammatory conditions. To evaluate the inflammatory properties, we will perform (i) flow cytometric analysis of early signaling events combined with (ii) transcriptomic analyses of isolated blood cells as well as endothelial cells during ECMO in miniaturized biohybrid lung models. This will result in identification of pathways that will be (iii) verified on the protein level and can be targeted by small molecules. The combination of these methods will provide information about superiority or inferiority of endothelialized devices regarding inflammation in acute and chronic conditions and will identify possible pathways that can be targeted by pharmaceutical approaches.

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