Biohybrid Lung

The aim of the WG is the development of the implantable biohybrid lung as an equivalent bridging or alternative to lung transplantation. In addition to the development and integration of novel implantable oxygenator prototypes, blood pumps and intracorporeal cannulation strategies, the focus lies on the biologization of all surfaces in contact with blood. For the evaluation of the biological and technical system components, the group also develops various circulation simulations and in-vivo models.

Research

Development of a customized implantable biohybrid lung

The aim of the research group is the development of an individually adapted, implantable biohybrid lung as a bridge or alternative to lung transplantation, which permanently supports or completely takes over the blood gas exchange of patients with terminal lung disease. This development is based on the technology of extracorporeal membrane oxygenation (ECMO), which is already used clinically and involves the exchange of blood gases with the aid of artificial hollow fibers. However, ECMO can only be used for a limited period of time (days to weeks) due to the incomplete blood compatibility of the individual artificial components. In addition, patients must be strictly anticoagulated and given primary prophylactic antibiotics during ECMO therapy, among other things, so they must therefore be monitored intensively. To ensure complete and long-term blood compatibility of the biohybrid lung and to guarantee permanent functionality, all blood-contacting device components are seeded with endothelial cells, which physiologically line our inner vascular walls. In addition, computer-aided simulations are used to adjust the device geometry to achieve optimal blood flow dynamics that neither promote blood clot formation nor result in the destruction (hemolysis) of blood cells.

1. For this purpose, we are developing surface modifications and coatings that allow endothelial cells to settle on the different artificial materials of the various device components, such as the gas exchange membranes, the blood pump and the tubing.

2. Several million endothelial cells are required for effective colonization of all device components. Since these cells cannot be isolated in this large number from each patient, we are exploring the use of alternative (genetically modified) endothelial cell sources that can be generated in large numbers in advance of application and are not recognized as foreign by the patient's immune system and rejected.

3. By means of computer-aided models and taking into account the conditions of different degrees and characteristics of pulmonary diseases of the potential patient groups (e.g. cystic fibrosis, COPD), which are candidates for the application of a biohybrid lung, we develop and test prototypes of the biohybrid lung, among others with regard to their blood flow dynamics and their gas exchange capacity.

4. The prototypes will be analyzed both in so-called phantom circuits, but also in large and small animal experiments, especially with regard to their biological compatibility, gas exchange capacity and flow dynamic aspects.

GROUP LEADER

PD Dr.

Bettina Wiegmann

Clinic for Cardiac, Thoracic, Transplantation and Vascular Surgery

Publications

1 Wiegmann B, Hess C, Haverich A, Fischer S. Development of a biohybrid lung - permanent "lung assist device" or even future alternative to lung transplantation? Journal of cardiothoracic and vascular surgery. State of the science, issue 5/2009.

2. Hess, C.; Wiegmann, B.; Maurer, A.N.; Fischer, P.; Möller, L.; Martin, U.; Hilfiker, A.; Haverich, A.; Fischer, S. Reduced Thrombocyte Adhesion to Endothelialized Poly 4-Methyl-1-Pentene Gas Exchange Membranes-A First Step Toward Bioartificial Lung Development. Tissue Eng Pt A 2010, 16, 3043-3053, doi:10.1089/ten.tea.2010.0131.

3. Möller, L.; Hess, C.; Paleček, J.; Su, Y.; Haverich, A.; Kirschning, A.; Draeger, G. Towards a Biocompatible Artificial Lung: Covalent Functionalization of Poly(4-Methylpent-1-Ene) (TPX) with CRGD Pentapeptide. Beilstein J Org Chem 2013, 9, 270-277, doi:10.3762/bjoc.9.33.

4. Wiegmann, B.; Maurer, A.; Zhang, R.; Zardo, P.; Haverich, A.; Fischer, S. Combined Pulmonary and Renal Support in a Single Extracorporeal Device. Asaio J 2013, 59, 433-438, doi:10.1097/mat.0b013e318292e887.

5. Hess C, Schwenke A, Wagener P, Franzka S, Laszlo Sajti C, Pflaum M, Wiegmann B, Haverich A, Barcikowski S. Dose-dependent surface endothelialization and biocompatibility of polyurethane noble metal nanocomposites. J Biomed Mater Res A. 2014 Jun;102(6):1909-20. doi: 10.1002/jbm.a.34860. epub 2013 Jul 30.

6 Wiegmann B, Figueiredo C, Gras C, Pflaum M, Schmeckebier S, Korossis S, Haverich A, Blasczyk R. Prevention of rejection of allogeneic endothelial cells in a biohybrid lung by silencing HLA-class I expression. Biomaterials. 2014 Sep;35(28):8123-33. doi: 10.1016/j.biomaterials.2014.06.007. Epub 2014 Jun 21.

7. Wiegmann, B.; Seggern, H. von; Höffler, K.; Korossis, S.; Dipresa, D.; Pflaum, M.; Schmeckebier, S.; Seume, J.; Haverich, A. Developing a Biohybrid Lung-Sufficient Endothelialization of Poly-4-Methly-1-Pentene Gas Exchange Hollow-Fiber Membranes. J Mech Behav Biomed 2016, 60, 301-311, doi:10.1016/j.jmbbm.2016.01.032.

8. Lau S, Eicke D, Carvalho Oliveira M, Wiegmann B, Schrimpf C, Haverich A, Blasczyk R, Wilhelmi M, Figueiredo C, Böer U. Low immunogenic endothelial cells maintain morphofunctional properties needed for tissue engineering. Tissue Eng Part A. 2017 Oct 5. doi: 10.1089/ten.TEA.2016.0541.

9. Pflaum, M.; Kühn-Kauffeldt, M.; Schmeckebier, S.; Dipresa, D.; Chauhan, K.; Wiegmann, B.; Haug, R.J.; Schein, J.; Haverich, A.; Korossis, S. Endothelialization and Characterization of Titanium Dioxide-Coated Gas-Exchange Membranes for Application in the Bioartificial Lung. Acta Biomater 2017, 50, 510-521, doi:10.1016/j.actbio.2016.12.017.

10. Zwirner, U.; Höffler, K.; Pflaum, M.; Korossis, S.; Haverich, A.; Wiegmann, B. Identifying an Optimal Seeding Protocol and Endothelial Cell Substrate for Biohybrid Lung Development. J Tissue Eng Regen M 2018, 12, 2319-2330, doi:10.1002/term.2764.

11. Schumer, E.; Höffler, K.; Kuehn, C.; Slaughter, M.; Haverich, A.; Wiegmann, B. In-Vitro Evaluation of Limitations and Possibilities for the Future Use of Intracorporeal Gas Exchangers Placed in the Upper Lobe Position. J Artif Organs 2018, 21, 68-75, doi:10.1007/s10047-017-0987-0.

12. Figueiredo, C.; Eicke, D.; Yuzefovych, Y.; Avsar, M.; Hanke, J.S.; Pflaum, M.; Schmitto, J.-D.; Blasczyk, R.; Haverich, A.; Wiegmann, B. Low Immunogenic Endothelial Cells Endothelialize the Left Ventricular Assist Device. Scientific reports 2019, 9, 11318-13.

13. Pflaum, M.; Merhej, H.; Peredo, A.; De, A.; Dipresa, D.; Wiegmann, B.; Wolkers, W.; Haverich, A.; Korossis, S. Hypothermic Preservation of Endothelialized Gas-exchange Membranes. Artif Organs 2020, 44, e552-e565, doi:10.1111/aor.13776.

14. Dipresa, D.; Kalozoumis, P.; Pflaum, M.; Peredo, A.; Wiegmann, B.; Haverich, A.; Korossis, S. Hemodynamic Assessment of Hollow-Fiber Membrane Oxygenators Using Computational Fluid Dynamics in Heterogeneous Membrane Models. J Biomechanical Eng 2021, 143, 1-14, doi:10.1115/1.4049808.

15. Pflaum, M.; Jurmann, S.; Katsirntaki, K.; Mälzer, M.; Haverich, A.; Wiegmann, B. Towards Biohybrid Lung Development-Fibronectin-Coating Bestows Hemocompatibility of Gas Exchange Hollow Fiber Membranes by Improving Flow-Resistant Endothelialization. Membr 2021, 12, 35, doi:10.3390/membranes12010035.

16. Pflaum, M.; Dahlmann, J.; Engels, L.; Naghilouy-Hidaji, H.; Adam, D.; Zöllner, J.; Otto, A.; Schmeckebier, S.; Martin, U.; Haverich, A.; et al. Towards Biohybrid Lung: Induced Pluripotent Stem Cell Derived Endothelial Cells as Clinically Relevant Cell Source for Biologization. Micromachines 2021, 981, doi:https://doi.org/10.3390/ mi12080981.

Keywords

artificial lung, artificial lung, biohybrid lung, lung support, endothelial cells, endothelialization, anti-thrombogenic surface, hemocompatibility, membrane oxygenation, ECMO, blood gas exchange, intracorporeal, implantable

Contact

PD Dr. Bettina Wiegmann

+49 511 532 1408

wiegmann(at)mh-hannover.de

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