BIOHYBRID LUNG
PD Dr. Bettina Wiegmann
The aim of the working group is to develop an implantable biohybrid lung as an alternative to lung transplantation, which can permanently support or completely take over the blood gas exchange of patients suffering from severe lung and/or heart disease. This development is based on the technology of extracorporeal membrane oxygenation (ECMO), which is already used clinically and in which artificial hollow fibers are used to exchange blood gas. However, due to the low blood compatibility of the individual artificial components, ECMO can only be used for a limited period of time (days to weeks), and patients undergoing ECMO therapy must be strictly anticoagulated and receive primary prophylactic antibiotic treatment, meaning that they must be monitored in intensive care. In order to ensure the complete and long-term blood compatibility of the biohybrid lung and to guarantee its permanent functionality, all blood-contacting device components will be colonized with endothelial cells (cells of the inner walls of blood vessels). In addition, computer-aided adaptation of the device geometry is carried out for optimal blood flow dynamics, which prevents so-called "low flow" areas in the system and thus prevents the formation of blood clots on the one hand and hemolysis of the blood components on the other.
1. for this purpose, we are developing surface modifications and coatings that allow endothelial cells to colonize the different artificial materials of the various device components, such as the gas exchange membranes, the blood pump and the tubes.
2. more than 5 x 108 endothelial cells are required for the effective colonization of all device components, which cannot be isolated from the vascular system of the patient who has to use the biohybrid lung. Therefore, we are investigating alternatives (genetically modified cells) to these autologous (patient's own) endothelial cells, comparing their cellular behavior under the conditions prevailing in the biohybrid lung with the behavior of native endothelial cells.
3. using computer-aided models and taking into account the conditions of different degrees and manifestations of pulmonary/cardiac diseases of potential patient groups (e.g. cystic fibrosis, COPD) that are eligible for the application of a biohybrid lung, we develop and test prototypes of the biohybrid lung with regard to their blood flow dynamics and their gas exchange capacity.
4. the prototypes are analyzed in so-called phantom circuits as well as in large and small animal experiments with regard to their biological compatibility, their gas exchange capacity and the flow-dynamic aspects.
1.
Calabrese F, Schiavon M, Perissinotto E, Lunardi F, Marulli G, Di Gregorio G, Pezzuto F, Vuljan S, Forin E, Wiegmann
B, Jonigk D, MD, Warnecke G, Rea F; Organ Care System Lung resulted In Lower Apoptosis and INOS Expression
in Donor Lungs; Am J Transplant. 2020 Jul 11. doi: 10.1111/ajt.16187.
2.
Blockus S, Wiechert S, Wetzke M, Grethe C, Frenz T, Pils M, Prochnow H, Rox K, Wiegmann B, Dijkman
R, Rameix-Welti MA, Eléouët JF, Duprex P, Thiel V, Hansen G, Stadler M, Brönstrup M, Haid S, and Pietschmann
T; Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry; Antiviral Res. 2020 May;177:104774.
doi: 10.1016/j.antiviral.2020.104774. Epub 2020 Mar 18. PMID: 32197980
3.
Warnecke G, Van Raemdonck D, Smith MA, Massard G, Kukreja J, Rea F, Loor G, De Robertis F, Nagendran J,
Dhital KK, Moradiellos Díez FJ, Knosalla C, Bermudez CA, Tsui S, McCurry K, Wang IW, Deuse T, Lesèche G, Thomas
P, Tudorache I, Kühn C, Avsar M, Wiegmann B, Sommer W, Neyrinck A, Schiavon M, Calabrese F, Santelmo N,
Olland A, Falcoz PE, Simon AR, Varela A, Madsen JC, Hertz M, Haverich A, Ardehali A. Normothermic ex-vivo
preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE):
a randomized, open-label, non-inferiority, phase 3 study. Lancet Respir Med. 2018 May;6(5):357-367. doi: 10.1016/
S2213-2600(18)30136-X. Epub 2018 Apr 9.
4.
Figueiredo C, Carvalho Oliveira M, Chen-Wacker C, Jansson K, Höffler K, Yuzefovych Y, Pogozhykh O, Jin Z,
Kühnel M, Jonigk D, Wiegmann B, Sommer W, Haverich A, Warnecke G, Blasczyk R. Immunoengineering of the
Vascular Endothelium to Silence MHC Expression During Normothermic Ex Vivo Lung Perfusion. Hum Gene
Ther. 2018 Nov 20. doi: 10.1089/hum.2018.117.
5.
Sander J, Schmidt S, Cirovic B, McGovern N, Papantonopoulou O, Hardt A, Aschenbrenner A, Kreer C, Quast T,
Xu A, Schmidleithner L, Theis H, Do T, Sumatoh H, Lauterbach M, Schulte-Schrepping J, Günther P, Xue J, Baßler
K, Ulas T, Klee K, Katzmarski N, Herresthal S, Krebs W, Martin B, Latz E, Händler K, Kraut M, Kolanus W, Beyer
M, Falk C, Wiegmann B, Burgdorf S, Melosh N, Newell E, Ginhoux F, Schlitzer A, Schultze J. Cellular differentiation
of human monocytes is regulated by time dependent IL4 signaling and NCOR2. Immunity. 2017 Dec 19;47(6):1051-
1066.e12. doi: 10.1016/j.immuni.2017.11.024.
6.
Pflaum M, Kühn-Kauffeldt M, Schmeckebier S, Dipresa D, Chauhan K, Wiegmann B, Haug RJ, 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 Mar 1;50:510-521. doi: 10.1016/j.actbio.2016.12.017.
Epub 2016 Dec 9.
7.
Sommer W, Ius F, Salman J, Avsar M, Tudorache I, Kühn C, Wiegmann B, Marsch G, Kaufeld T, Zinne N, Fuehner T,
Greer M, Gottlieb J, Boethig D, Haverich A, Welte T, Warnecke G. Survival and spirometry outcomes after lung
transplantation from donors aged 70 years and older. J Heart Lung Transplant. 2015 Oct;34(10):1325-33. doi:
10.1016/j.healun.2015.06.002. Epub 2015 Jun 10.
8.
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.
9.
Birschmann I, Dittrich M, Eller T, Wiegmann B, Reininger AJ, Budde U, Strüber M. Ambient hemolysis and
activation of coagulation is different between HeartMate II and HeartWare left ventricular assist devices. J Heart
Lung Transplant. 2014 Jan;33(1):80-7. doi: 10.1016/j.healun.2013.11.010. Epub 2013 Dec 1.
10.
Warnecke G, Moradiellos J, Tudorache I, Kühn C, Avsar M, Wiegmann B, Sommer W, Ius F, Kunze C, Gottlieb
J, Varela A, Haverich A. Normothermic perfusion of donor lungs for preservation and assessment with the Organ
Care System Lung before bilateral transplantation: a pilot study of 12 patients. Lancet. 2012 Nov 24;380(9856):1851-
8. doi: 10.1016/S0140-6736(12)61344-0. Epub 2012 Oct 10.
AG Biohybrid Lung
Dr. Bettina Wiegmann
Phone: +49 (0) 511 - 532 1408
Mail: wiegmann.bettina@mh-hannover.de