Patient-specific induced pluripotent stem (iPS) cells for endothelialisation of membrane surfaces of implantable biohybrid lung devices

• Applicant: Professor Dr. Ulrich Martin
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology ; Pneumology, Thoracic Surgery
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 347326394

One strategy to overcome the limited durability of current lung assist devices due to clotting and thrombus formation is the functionalization of synthetic membrane surfaces. Chemical modification or coating with biological substances such as heparin have been applied to reduce thrombocyte adhesion. Although such strategies can improve the hemocompatibility to a certain extent, long-term functionality of the gas exchange membranes has not been achieved yet. It has been hypothesized that stable endothelialization of blood contacting materials may create a natural non-thrombogenic surface, which could allow for long-term use of membrane oxygenators without thrombus formation.While first studies aiming at the endothelialization of gas exchange membranes show encouraging results, an endothelial cell (EC) source suitable for clinical scale up and application is not yet identified. For seeding of a typical membrane oxygenator with a membrane surface of about 1.3 to 4 sqm, a cell source with high expansion potential will be necessary, that can provide genetically stable ECs with all typical functional properties of cells in the natural EC layer. It is noteworthy that recent developments towards an endothelialized implantable membrane oxygenator did neglect these needs as well as recent reports that demonstrated frequent chromosomal aberrations in cultured primary ECs. Due to the lack of sufficient expandability of adult primary ECs (e.g. from saphena veins), most experimental studies used ECs isolated from human cord blood or umbilical veins.Based on our previous results we hypothesize that patient-specific iPSC-derived ECs represent the most suitable cell source for endothelialization of membrane oxygenators. Here we propose to conduct a systematic study that analyses expandability, genetic integrity as well as functionality of ECs from different cell sources (late outgrowth ECs from cord and adult peripheral blood, ECs from umbilical veins and adult saphena veins, microvascular ECs from adipose tissue as well as endothelial cells differentiated from human iPSCs). In particular, we will investigate senescence-related changes in cell function and secretory characteristics after extended culture expansion that would be required to provide the necessary cell numbers of about 1 to 2 billion cells per device. This project will thus critically contribute to clinical translation of biofunctionalized membrane oxygenators and other EC-based cellular therapies.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2014: Towards an Implantable Lung