Endothelialisierung von Gasaustauschmembranen für die Entwicklung eines biohybriden Lungenunterstützungssystems
Aachen (2020) [Dissertation / PhD Thesis]
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Extracorporeal lung support can ensure the vital gas exchange in patients with respiratory failure but its application is limited by lacking hemocompatibility. In the concept of a biohybrid lung, gas exchange membranes are lined with endothelial cells (so-called endothelialization) to provide a non-thrombogenic and anti-inflammatory surface and thus, a long-term stable lung support system. However, additional design requirements are placed on a biohybrid lung to form and maintain an integral endothelial cell layer while optimizing gas exchange performance. The suitability of two different membrane materials for the use in a biohybrid lung was therefore investigated in the present studies. The first study (Menzel et al., 2017) investigated the endothelialization of a gas-permeable fluorocarbon cell culture membrane with human umbilical vein endothelial cells (HUVECs) and their influence on gas exchange performance. Short-term dynamic culture with increasing wall shear stress up to 0.15 Pa has shown a confluent and flow-resistant endothelial cell layer. Contrary to expectations, oxygen transfer rates (OTRs) of endothelialized membranes exceeded the OTRs of the blank membrane by up to 120 % and thus, even showed a gas transfer promoting effect, the underlying principles of which are not yet fully understood. In contrast to common gas exchange membranes, the cell culture membrane exhibited relatively low gas permeability. Therefore, in the second study (Klein et al., 2019), highly gas-permeable RGD-conjugated polydimethylsiloxane (RGD-PDMS) membranes were used. RGD-PDMS was endothelialized with HUVECs and their long-term stability and gas exchange performance was evaluated in a biohybrid lung model under physiological flow with a corresponding wall shear stress of 0.5 Pa. After culture periods of 3, 19 and 33 days, the gas exchange of the membranes was tested using porcine blood adjusted to venous values following ISO 7199. RGD-PDMS membranes promoted endothelialization and proved suitable for the dynamic culture of HUVECs for at least 33 days. The gas transfer tests confirmed oxygenation and decarboxylation of the blood across the endothelialized membranes and the performance was comparable to commercially available oxygenators. The cell layer was still intact after testing despite the more demanding flow conditions with an elevated wall shear stress of 2.5 Pa and the exposure to porcine blood. In the present studies, the suitability of two different membrane materials for flow-resistant endothelialization has been shown. When comparing both studies and both membrane materials, the gas exchange performance is the limiting factor for the design of a biohybrid lung. Thus, RGD-PDMS was identified as a particularly suitable membrane system for biohybrid lung support. Although aspects of hemocompatibility, especially in multimorbid patients, still need to be investigated, our results demonstrate the feasibility of RGD-PDMS for biohybrid lung applications, which might enable long-term support of patients with chronic lung failure in the future.
Cornelissen, Christian Gabriel