News
Duška Dragun
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We have received the sad news that Professor Duška Dragun, Director of the Biomedical Innovation Academy (BIA) of the Berlin Institute of Health (BIH) and Head of the Charité BIH Clinician Scientist Program, succumbed to her long, severe, bravely endured illness on December 28, 2020 at the age of 51.
 
Her tireless efforts were devoted to her life's work: the Charité BIH Clinician Scientist Program. Ten years ago, she launched the first Clinician Scientist Program in Berlin and over the decade established and continuously expanded it as "best practice" for the German-speaking region. She has played a key role in developing and shaping the various programs for scientifically active physicians: from the Clinician Scientist Program, which enables aspiring specialists to spend up to 50 percent of their working time on research, to the Junior Clinician Scientist Program with 20 percent working time on research, which begins in the first year of specialist training, to the Advanced Clinician Scientist Program for specialists with postdoctoral qualifications. Two years ago, she successfully applied to the German Research Foundation (DFG) for the first and only Digital Clinician Scientist Program in Germany. This enables young physicians and scientists to conduct research and work in the field of digitalization in medicine and healthcare. Thus, within a few years, Duška Dragun made a significant contribution to building a new generation of young professionals for medicine – the impact of her programs will last for a long time, via promising individual careers as well as via the programmatic strengthening of a patient-oriented science.  
 
As a physician herself, Professor Duška Dragun has always been committed to research: As acting senior physician and deputy to the acting director of the Department of Nephrology and Intensive Care Medicine at the Charité Campus Virchow-Klinikum, as well as head of the nephrology research laboratory, she made highly regarded, internationally distinguished contributions to transplantation research with the goal of improving graft approach and long-term survival, preventing cardiovascular comorbidity, and thus improving the quality of life and life expectancy of transplanted patients.  She pursued her great goals with tremendous energy and passion, impressive perseverance and clear determination. She devoted her full attention to her employees, colleagues, and students, being equally attentive, understanding, and demanding.
 
The death of Duška Dragun is a great and painful loss. We will miss her greatly as director of the Charité BIH Clinician Scientist Program, as a physician, university professor and scientist. To us she was an inspiration, a mentor and an ever driving force.

Above all, however, we will greatly miss Duška as a friend.  
Karl Hillebrandt | Charité 3R Tandem project for early career researchers
In: Grant
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Together with Dr. Björn Papke (Molecular tumour pathology), Dr. Karl Hillebrandt was able to acquire funding for a "Tandem project for early career researchers" from the Charité 3R. The project is entitled "A personalised therapy approach implementing individually matched matrix-based in vitro colorectal liver metastases to reduce metastatic mouse models".
Although modern multimodal therapy strategies have improved the clinical outcome of patients with colorectal liver metastases (CRLM), the overall prognosis is still poor. To further improve treatment options for patients, it is necessary to develop and test new targeted therapeutic approaches. To date, mouse models have often been used to study metastatic colorectal cancer. However, the rate of successful translation of animal models into clinical trials is less than 8%, highlighting the urgent need for alternative models to study the biology of metastatic cancer. This project aims to develop a novel personalised extracellular matrix-based in vitro model of human CRLM. This model will be validated against existing data from patient-derived organoids and xenografts (histology, single cell RNA sequencing and targeted gene sequencing). After internal comparison of our in vitro CRLM with the original CRLM, we will translate it into a personalised drug screening platform to test drug response from standard therapy to novel inhibitor combinations.

Tags: Oncology,Tissue Engineering

Dr. Moritz Queisner
In: Thesis
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Dr. rer. medic. Moritz Queisner received his doctorate certificate today (magna cum laude)! This is in recognition of his work in the field of extended reality technology in visceral surgery. His thesis is entitled XR in surgery – spatial end embodied computing in digital surgery: technology, application, design.

CONGRATULATIONS !

Tags: Digital Surgery,Extended Reality

CLOUZ | spinoff from the Charité
In: Spinoff company
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Dr. Panagiotis Fikatas invented a surgical device using a knot technology for minimally invasive surgery. Early prototyping and development work was significantly supported by the SPARK-BIH program with the Validation Fund and funds from the Stiftung Charité.

The startup Clouz GmbH, a spinoff from the Charité – Universitätsmedizin Berlin, has developed a novel surgical knot-tying device for use in restrictive access surgery. Clouz GmbH has signed a purchasing agreement for the knot patent with the Charité Technology Transfer Office. The medical device startup was founded by Dr. Panagiotis Fikatas, Marco Climaco and Anne-Mette Jensen.

The novel surgical closure device allows surgical knots to be tied easily, quickly, and most importantly, safely, even in surgeries with severely limited access (e.g. minimally invasive procedures). The products are based on a patented knotting technology that can be used in a range of device types: from manual application by the surgeon to devices for robotic surgery. CLOUZ OneKnot ensures consistent closure for the surgeon and saves valuable time in the operating room.

Tags: Surgical Devices

Two new (Junior) Clinician Scientitsts
In: Grant
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Dr. Simon Moosburner and Dr. Tomasz Dziodzio successfully applied for the BIH Charité (Junior) Clinician Scientist Program.

Dr. Dziodzio is studying pathomechanisms of obesity in the context of kidney transplantation and investigates the impact of obesity on the immune response in the kidney transplant recipient. In addition, a clinical trial will investigate whether surgical weight reduction in obese patients prior to kidney transplantation leads to improved graft function.

Dr. Moosburner is working on the extracorporeal evaluation of liver grafts from older donors. The aim is to characterise old liver grafts during normothermic machine perfusion. For this purpose, a model for normothermic ex vivo machine perfusion of small animal livers as well as liver transplantation in the rat model was established.

Tags: Transplantation,Organ Recovery

CASSANDRA | Clinical ASSist AND aleRt Algorithms
In: Grant
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The Innovationsausschuss beim Gemeinsamen Bundesausschuss (G-BA) is funding 33 new projects in healthcare research. A total of 186 project applications were received in response to the funding announcements of December 2019. Nine project proposals from the open topic area and 24 project proposals from the topic-specific area received a positive funding decision.

Our project CASSANDRA (Clinical ASSist AND aleRt Algorithms – Early detection of postoperative complications with machine learning algorithms) is one of the projects funded for three years.

The aim of the project is to evaluate Machine Learning (ML) in the detection of postoperative complications after major abdominal surgery. By means of digital records and ML-driven analysis of perioperative risk factors, postoperative parameters as well as telemedical vital parameter monitoring, it is to be examined whether complications requiring treatment – in particular infections of the abdominal cavity after liver, pancreas, stomach and intestinal surgery – can be automatically detected and predicted, in order to develop the basis for an autonomous real-time monitoring system on normal wards.
CASSANDRA is a collaboration of Axel Winter, Dr. Max Maurer, Prof. Dr. Igor M. Sauer (Charité – Universitätsmedizin Berlin) and Prof. Dr. Bert Arnrich, Head of the Chair, Professor for Digital Health - Connected Healthcare, Hasso Plattner Institut.

Tags: Machine Learning,Digital Surgery

DICOM_XR | XR4ALL 2nd Open Call: Project Selected for Phase 1
In: Grant
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XR4ALL is an initiative by the European Commission to strengthen the European XR industry.

After 140 applications, 18 projects have been selected for Phase 1 of the 2nd Cut-off date of the XR4ALL Open Call. In this phase, projects need to expand upon and validate their concept from a business and a technical perspective during two months.
Based on an evaluation at the end of the first phase, only the best-rated projects will be admitted to Phase 2 and therefore be able to develop the proposed solution.

Our project DICOM_XR (PI: Christoph Rüger) is one of them (and one of three from Germany)!

One of the most common use-cases for XR in medicine is the visualization of medical imaging data like computed tomography (CT) scans. The well-established standard for storing and transferring such data is DICOM (Digital Imaging and Communications in Medicine). It is used in all major hospitals in the European Union – XR applications that involve medical images need to be built upon this standard. Existing open-source DICOM frameworks offer data interoperability and are compatible with 3D engines, like Unity. However, while DICOM is well-established and very feature rich, it is also a complex standard to work with as a developer. In addition to data interoperability provided by DICOM, most medical XR applications also require: 1) Data transfer from a machine with access to the hospital’s image network to mobile XR devices such as HMDs, 2) performant visualization, particularly for stereographic displays, and 3) view manipulation with 3D input (e.g. hand tracking) instead of mouse input. These requirements are, at best, additional workloads for technically skilled teams and, at worst, insurmountable hurdles for projects lacking programmers.
DICOM_XR is a framework aiming to solve all three of these requirements: data transfer, performant visualization and utilization of three-dimensional input. Building upon an existing open-source DICOM solution, DICOM_XR will offer a ‘plug and play’ solution for XR developers. It will significantly decrease technical hurdles for e.g. medical studies evaluating XR, which are still sorely needed. It can also streamline the development of commercial XR applications: Medical open-source projects such as SlicerIGT have been successfully used as a foundation for certified medical products. In short, DICOM_XR will allow medical XR developers to focus on features that their users want, rather than technical infrastructure.

Tags: Extended Reality,Digital Surgery

Engineering an endothelialized, endocrine NeoPancreas
In: Publication
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Acta Biomaterialia accepted our latest paper on "Engineering an endothelialized, endocrine Neo-Pancreas: evaluation of islet functionality in an ex vivo model".

Islet-based recellularization of decellularized, repurposed rat livers may form a transplantable Neo-Pancreas. The aim of this study is the establishment of the necessary protocols, the evaluation of the organ structure and the analysis of the islet functionality ex vivo.
After perfusion-based decellularization of rat livers, matrices were repopulated with endothelial cells and mesenchymal stromal cells, incubated for 8 days in a perfusion chamber and finally repopulated on day 9 with intact rodent islets. Integrity and quality of re-endothelialization was assessed by histology and FITC-dextran perfusion assay. Functionality of the islets of Langerhans was determined on day 10 and day 12 via glucose stimulated insulin secretion.
Blood gas analysis variables confirmed the stability of the perfusion cultivation. Histological staining showed that cells formed a monolayer inside the intact vascular structure. These findings were confirmed by electron microscopy. Islets infused via the bile duct could histologically be found in the parenchymal space. Adequate insulin secretion after glucose stimulation after 1-day and 3-day cultivation verified islet viability and functionality after the repopulation process.
We provide the first proof-of-concept for the functionality of islets of Langerhans engrafted in a decellularized rat liver. Furthermore, a re-endothelialization step was implemented to provide implantability. This technique can serve as a bioengineered platform to generate implantable and functional endocrine Neo-Pancreases.

Authors are Hannah Everwien, Eriselda Keshi, Karl H. Hillebrandt, Barbara Ludwig, Marie Weinhart, Peter Tang, Anika S. Beierle, Hendrik Napierala, Joseph MGV Gassner, Nicolai Seiffert, Simon Moosburner, Dominik Geisel, Anja Reutzel-Selke, Benjamin Strücker, Johann Pratschke, Nils Haep, and Igor M. Sauer.
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Tags: Tissue Engineering,Extracellular Matrix,NeoPancreas,Recellularization

Best Poster prize for Anna Pfefferkorn
In: Prize
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Anna Pfefferkorn won the Best Poster prize for our work on "Molecular and cellular mechanisms of Lipocalin-2 mediated renoprotection in kidney transplantation" at the Kongress für Nephrologie 2020, held in Berlin 1.-4. October, 2020!

Lipocalin-2 (Lcn2) is distinctly upregulated in kidney transplants and serves as an early marker of AKI, DGF and acute rejection. However, the functional role and mechanisms underlying Lcn2 upregulation remain largely unknown. Using a mouse model of kidney transplantation we recently demonstrated a renoprotective role of recombinant Lcn2:Siderophore:Fe (rLcn2). However, the molecular and cellular events underlying the renoprotective effects of rLcn2 in kidney allografts remain unclear. Elucidating these events forms the primary focus of the current study.
rLcn2 significantly lowered CD8+ T cells in the allograft, LN and blood at POD 7, whereas their number remained unaffected in spleen. Nevertheless, the number of CD4+ T Lymphocytes was reduced only in lymph nodes. NKG2D+CD8+T cells and CD27+CD11b+NKp46+NK cells were the most prominent subpopulations of the cytotoxic lymphocytes whose frequencies were significantly reduced in graft, spleen and blood with the treatment of rLcn2. Besides, a significantly reduced infiltration of monocytes/macrophages was also observed at POD-7 with the said treatment. Importantly, degranulation capacity and IFNg production of intragraft and splenic CD4+ and CD8+ T cells were impaired in the treated animals. Besides, rLcn2 lowered hypoxia and reoxygenation induced cytotoxicity of the primary RTECs, associated with reduced caspase-3 cleavage and activation of Erk and AKt signaling.

rLcn2 treatments differentially affects the relative frequencies and activation of various immune cell. Besides, rLcn2 depicts cytoprotective effect on murine primary RTECs during H/R, possibly via activation of Erk and Akt signaling.

CONGRATULATIONS !

Tags: Transplantation,Renoprotection,Kidney

Declined Liver Grafts – Analysis of the German Donor Population from 2010 to 2018
In: Publication
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"Declined Liver Grafts – Analysis of the German Donor Population from 2010 to 2018" was published in the Zeitschrift für Gastroenterologie.
The lack of suitable allografts limits the availability of liver transplantation in Germany. The quality of potentially available German donor livers has to date not been analyzed.
Analysis of all donors for potential liver transplantations reported to the Eurotransplant by the German Organ Transplantation Foundation from 2010 to 2018. Categorization of transplanted and discarded organs utilizing available histopathological reports and predefined extended criteria for organ donation.
A total of 8594 livers were offered for transplantation, of which 15.2 % were discarded. During the analysis period the proportion of donor livers from extended criteria donors increased from 65 % to 70 % (p = 0.005). In 2018, 21.3 % of offered donor livers were discarded, more than half (56.4 %) of these organs came from donors meeting multiple extended criteria. Livers were significantly more likely to be not transplanted, when from donors of older age (> 65 years; 41 vs. 28 %), BMI > 30 kg/m2 (29 vs. 14 %) or elevated transaminase levels (all p < 0.001).
Despite the consistent organ scarcity in Germany, a relevant amount of livers cannot be transplanted due to a multitude of organ quality limitations. This should stimulate the search for concepts such as normothermic ex vivo machine perfusion to evaluate, protect and potentially improve organ quality.

Authors are Simon Moosburner, Nathanael Raschzok, Christina Schleicher, Detlef Bösebeck, Joseph M.G.V. Gaßner, Paul V. Ritschl, Axel Rahmel, Igor M. Sauer, and Johann Pratschke.
Z Gastroenterol. 2020 Aug 24. doi: 10.1055/a-1199-7432. Online ahead of print.

Tags: Organ recovery,Liver transplantation,organ reconditioning

Felix Krenzien received Ferdinand-Sauerbruch Prize 2020
In: Publication |Prize
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Priv.-Doz. Dr. Felix Krenzien received the Ferdinand-Sauerbruch Prize 2020 for his project and publication „The ILLS Laparoscopic Liver Surgery Fellow Skills Curriculum“ published in Annals of Surgery (online ahead of print).

Congratulations!

Laparoscopy is becoming the standard approach in liver surgery. As the degree of difficulty varies greatly from core skills to advanced procedures, strategies for teaching young surgeons need to be reconsidered. We here aimed to design a skills curriculum for LLR. Using the nominal group technique, 22 substeps of LLR were identified by 61 hepatobiliary surgeons. The raters were asked to rate (1) the difficulty of substeps and (2) the minimum number of times that the substep must be performed for mastery of the technique. According to the frequency of defined substeps, being estimated on the basis of high volume center experiences (n = 222 LLR; 1/2017-12/2018), the center's training capacity and defined goals for a 2-year fellowship were calculated.
Ten surgical substeps (45%) are routinely performed and can thus be taught sufficiently at centers carrying out ≥50 LLR in 2 years. As the mobilization of the right liver lobe and the dissection of the hepatic artery or portal vein is performed in only 27% and 28% of all LLR, respectively, sufficient training can only be provided at centers with ≥100 LLRs in 2 years. Mastery of complex parenchymal dissection (19%) and hilar lymphadenectomy (8%) can only be achieved in center performing ≥200 LLR in 2 years.
The authors suggest a stepwise approach for training of hepatobiliary fellows in LLR. Based on the estimated complexity of the substeps and the size of the center, not every substep can be learned within 2 years.

Authors are Felix Krenzien, Wenzel Schöning, Philipp Brunnbauer, Christian Benzing, Robert Öllinger, Matthias Biebl, Marcus Bahra, Nathanael Raschzok, Daniel Cherqui, David Geller, Ho-Seong Han, Go Wakabayashi, Moritz Schmelzle, Johann Pratschke, and the study group of the International Laparoscopic Liver Society (ILLS).

Tags: Felix Krenzien

EKFS grant | Metabolic reconditioning of steatotic rat liver grafts by normothermic ex vivo machine perfusion
In: Grant
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The Else Kröner Fresenius Stiftung will fund the project "Metabolic reconditioning of steatotic rat liver grafts by normothermic ex vivo machine perfusion" (PI: Priv.-Doz. Dr. Nathanael Raschzok) for two years.

Liver transplantation is the treatment of choice for end-stage liver disease, yet the number of transplant candidates constantly exceeds the organ supply. The imbalance between demand and supply of liver grafts is dramatically exacerbated by the rising prevalence of obesity and the metabolic syndrome, which both show a strong correlation with steatosis hepatis. Liver grafts with macrovesicular steatosis above 30% are associated with delayed graft function and lower graft and patient survival, and livers with >60% steatosis are generally discarded from transplantation. Within the next 10 years, the overall liver graft utilization could potentially be halved due to the rising prevalence of steatosis, emphasizing the urgent clinical need to find solutions to make steatotic livers acceptable for transplantation.

In this project the hypothesis is tested whether metabolic reprogramming of steatotic liver grafts will 1) restore hepatocyte function, 2) activate lipid catabolism, 3) increase resistance to ischemia reperfusion damage, and 4) alleviate overwhelming inflammatory processes in the early phase of post-transplant regeneration with beneficial long-term impact for graft function and recipient survival.

Tags: Organ recovery,Liver transplantation,organ reconditioning

The Human Liver Matrisome
In: Publication
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Biomaterials accepted our latest paper on „The Human Liver Matrisome – Proteomic Analysis of Native and Fibrotic Human Liver Extracellular Matrices for Organ Engineering Approaches“.

The production of biomaterials that endow significant morphogenic and microenvironmental cues for the constitution of cell integration and regeneration remains a key challenge in the successful implementation of functional organ replacements. Despite the vast development in the production of biological and architecturally native matrices, the complex compositions and pivotal figures by which the human matrisome mediates many of its essential functions are yet to be defined. Here we present a thorough analysis of the native human liver proteomic landscape using decellularization and defatting protocols to extract create extracellular matrix scaffolds of natural origin that can further be used in both bottom-up and top-down approaches in tissue engineering based organ replacements. Furthermore, by analyzing human liver extracellular matrices in different stages of fibrosis and cirrhosis, we have identified distinct attributes of these tissues that could potentially be exploited therapeutically and thus require further investigation. The general experimental pipeline presented in this study is applicable to any type of tissue and can be widely used for different approaches in regenerative medicine and in the construction of novel biomaterials for organ engineering approaches.

Authors are A. Daneshgar, O. Klein, G. Nebrich, M. Weinhart, P. Tang, A. Arnold, I. Ullah, J. Pohl, S. Moosburner, N. Raschzok, B. Strücker, M. Bahra, J. Pratschke, I.M. Sauer, and K.H. Hillebrandt. The authors acknowledge the support of the Cluster of Excellence Matters of Activity. Image Space Material funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany´s Excellence Strategy – EXC 2025.
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Tags: Tissue Engineering,Extracellular Matrix

Ex vivo machine perfusion: current applications and future directions in liver transplantation
In: Publication
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Langenbeck's Archives of Surgery accepted the manuscript „Ex vivo machine perfusion: current applications and future directions in liver transplantation“ for publication.

Liver transplantation is the only curative treatment option for end-stage liver disease, however, its use remains limited due to a shortage of suitable organs. In recent years, ex vivo liver machine perfusion has been introduced to liver transplantation, as a means to expand the donor organ pool.
To present a narrative review of prospective clinical studies on ex vivo liver machine perfusion, in order to assess current applications and highlight future directions.
Methods: A systematic literature search of both PubMed and ISI web of science databases as well as the ClinicalTrials.gov registry was performed.
Twenty articles on prospective clinical trials on ex vivo liver machine perfusion were identified. Out of these, eight reported on hypothermic, nine on normothermic, and two on sequential perfusion. These trials have demonstrated the safety and feasibility of ex vivo liver machine perfusion in both standard and expanded criteria donors. Currently, there are 12 studies enrolled in the clinicaltrials.gov registrar, and these focus on use of ex vivo perfusion in extended criteria donors as well as declined organs.
Ex vivo liver machine perfusion seems to be a suitable strategy to expand the donor pool for liver transplantation and holds promise as a platform for reconditioning diseased organs.

Authors are Julian Michelotto, Joseph MGV Gaßner, Simon Moosburner, Vanessa Muth, Madhukar S Patel, Markus Selzner, Johann Pratschke, Igor M. Sauer, and Nathanael Raschzok.

Tags: Organ recovery,Liver transplantation

SiM | Der Simulierte Mensch
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„Der Simulierte Mensch“ ("The Simulated Human", Si-M) is a new research building which is currently under construction and is expected to be finished in 2023. The building site is directly adjacent to the Charité Campus Virchow-Klinikum of the Charité - Universitätsmedizin in Berlin-Wedding and is also the birthplace of biotechnology at the TU Berlin.

The initiators of Si-M are Roland Lauster (Head of the Department of Medical Biotechnology at TU Berlin) and Andreas Thiel (Head of the research group Regenerative Immunology and Aging at Charité – Universitätsmedizin Berlin). They applied for the research building in 2018 (GG §91b) and successfully defended it before the German Science Council.

In the building, scientists from both institutions will work together to simulate the functions of human cells and tissues with new technologies of 3D cultivation, multi-organ chips or 3D bioprinting. In contrast to already existing collaborative projects, the building will be used to practice the joint development of models "side by side" in the same laboratory environment. In this way, both the development of organ models and technological developments can be adapted and optimized at the same time.

More information via https://www.si-m.org .

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Ultrasound in augmented reality: a mixed-methods evaluation of head-mounted displays in image-guided interventions
In: Publication
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The International Journal of Computer Assisted Radiology and Surgery accepted Christoph Rüger's paper on "Ultrasound in augmented reality: a mixed-methods evaluation of head-mounted displays in image-guided interventions" for publication.

Augmented reality (AR) and head-mounted displays (HMD) are current subjects of investigation in medical practice. A commonly proposed use-case of AR-HMDs is to display data in image-guided interventions. Although technical feasibility has been thoroughly shown, effects of AR-HMDs on interventions are not yet well researched, hampering clinical applicability. Therefore, the goal of this study is to better understand the benefits and limitations of this technology in ultrasound-guided interventions.
We used an AR-HMD system (based on Hololens, Microsoft Corp.) which overlays live ultrasound images spatially correctly at the location of the ultrasound transducer. We chose ultrasound-guided needle placements as a representative task for image-guided interventions. To examine the effects of the AR-HMD, we used mixed methods and conducted two studies in a lab setting: (1) in an experimental study, we asked participants to place needles into a training model and evaluated task duration and accuracy with the AR- HMD as compared to the standard procedure without visual overlay and (2) in a qualitative study, we analysed the user experience with AR-HMD using think-aloud protocols during ultrasound examinations and semi-structured interviews after the task.
Participants (n=20) placed needles more accurately (mean error of 7.4 mm vs. 4.9 mm, p=0.022) but not significantly faster (mean task duration of 74.4 s vs. 66.4 s, p=0.211) with the AR-HMD. All participants in the qualitative study (n=6) reported limitations of and unfamiliarity with the AR-HMD, yet all but one also clearly noted benefits and/or that they would like to test the technology in practice.
We present additional, though still preliminary, evidence that AR-HMDs provide benefits in image-guided procedures. Our data also contribute insights into potential causes underlying the benefits, such as improved spatial perception. Still, more comprehensive studies are needed to ascertain benefits for clinical applications and to clarify underlying mechanisms.

Authors are Christoph Rüger, Markus A. Feufel, Simon Moosburner, Christopher Özbek, Johann Pratschke, and Igor M. Sauer.

Tags: Digital Surgery

Brigitta Globke: Digital Clinician Scientist
In: Grant
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Dr. Brigitta Globke successfully applied for participation in the BIH Charite Digital Clinician Scientist Program.

The aim of the project is the development and evaluation of an augmented reality assist system for intraoperative photoplethysmographic control of perfusion. The project is carried out in collaboration with Benjamin Kossack, Fraunhofer | Heinrich Hertz Institute Computer Vision and Graphics.

Charité and BIH are jointly organizing the new "Digital Clinician Scientist Program" (D-CSP). The program is primarily aimed at physicians who are already working on innovative research projects to meet the technological challenges of data-driven medicine during their specialist training. The German Research Foundation (DFG) is funding the project for an initial period of three years.

The BIH Charité Digital Clinician Scientist Program will provide a new career path for the creators of digital change in medicine and will expand the successful Germany-wide model of the BIH Charité Clinician Scientist Program. In addition to the three-year individual funding, which is based on protected time for research, the focus is on modules for the acquisition of scientific skills (Big Data, bioinformatics or artificial intelligence) as well as mandatory mentoring. For the new program, various experts* from the Charité, the BIH, the Max Delbrück Center for Molecular Medicine (MDC), the Berlin Institute for Medical Systems Biology (BIMSB), the Einstein Center for Digital Future, and the Bernstein Center for Computational Neuroscience will be involved in the design of the D-CSP and in the recruitment and supervision of program participants.

Tags: Extended Reality,Digital Surgery

Dual versus single vessel normothermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation
In: Publication
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F. Claussen, J.M.G.V. Gassner, S. Moosburner, D. Wyrwal, M. Nösser, P. Tang, L. Wegener, J. Pohl, A. Reutzel-Selke, R. Arsenic, J. Pratschke, I.M. Sauer, and N. Raschzok published their trecent work on "Dual versus single vessel normothermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation" in PLoS One 2020;15(7): e0235635.

Normothermic ex vivo liver perfusion (NEVLP) is a promising strategy to increase the donor pool in liver transplantation. Small animal models are essential to further investigate questions regarding organ preservation and reconditioning by NEVLP. A dual vessel small animal NEVLP (dNEVLP) model was developed using metamizole as a vasodilator and compared to conventional portovenous single vessel NEVLP (sNEVLP).

Livers of male Wistar rats were perfused with erythrocyte-supplemented culture medium for six hours by either dNEVLP via hepatic artery and portal vein or portovenous sNEVLP. dNEVLP was performed either with or without metamizole treatment. Perfusion pressure and flow rates were constantly monitored. Transaminase levels were determined in the perfusate at the start and after three and six hours of perfusion. Bile secretion was monitored and bile LDH and GGT levels were measured hourly. Histopathological analysis was performed using liver and bile duct tissue samples after perfusion.

Hepatic artery pressure was significantly lower in dNEVLP with metamizole administration. Compared to sNEVLP, dNEVLP with metamizole treatment showed higher bile production, lower levels of transaminases during and after perfusion as well as significantly lower necrosis in liver and bile duct tissue. Biochemical markers of bile duct injury showed the same trend.

Our miniaturized dNEVLP system enables normothermic dual vessel rat liver perfusion. The administration of metamizole effectively ameliorates arterial vasospasm allowing for six hours of dNEVLP, with superior outcome compared to sNEVLP.

Tags: Transplantation,Tissue Engineering,Orgen Recovery

Development of GelMA/PCL and dECM/PCL resins for 3D printing of acellular in vitro tissue scaffolds by stereolithography
In: Publication
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Gelatin methacryloyl (GelMA) is a chemically modified extracellular matrix (ECM)-derived biopolymer that is widely used for 3D fabrication of tissue engineering scaffolds. However, its tendency for physical gelation limits its use in aqueous 3D printing resins to low concentrations, yielding a poor printing resolution in stereolithography (SLA).
To obtain a GelMA-based resin that can be printed into high-resolution tissue scaffolds, we formulated resins of fish and porcine-derived GelMA in formamide using GelMA alone or mixed with star-shaped poly(ε-caprolactone) methacrylate (PCL-MA). We identified GelMA resins and GelMA/PCL-MA hybrid resins with a ratio of 70/30 wt-% to yield a suitable viscosity for SLA at 32 °C and demonstrated the resolution of the new resins in SLA by 3D printing acellular human small intestine-mimicking tissue scaffolds. The presence of PCL-MA in the hybrid resins improved the 3D printing fidelity compared to the neat GelMA resins, while GelMA provided the hybrid materials with enhanced swelling and proliferation of seeded cells. We further demonstrated the transferability of our resin formulation to native organ-derived materials by successfully replacing GelMA in the hybrid resin with solubilized, methacryloyl-functionalized decellularized liver ECM (dECM-MA) and by 3D printing multi-layer dECM/PCL-MA hydrogels.

"Development of GelMA/PCL and dECM/PCL resins for 3D printing of acellular in vitro tissue scaffolds by stereolithography" was published in Mater Sci Eng C Mater Biol Appl. 2020 Jul;112:110958. Authors are L. Elomaa, E. Keshi, I.M. Sauer, and M. Weinhart.

Tags: 3D Tissue Printing,Tissue Engineering

Extended reality technologies for support of surgical workflows
In: Publication
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Current developments in the field of extended reality (XR) could prove useful in the optimization of surgical workflows, time effectiveness and postoperative outcome. Although still primarily a subject of research, the state of XR technologies is rapidly improving and approaching feasibility for a broad clinical application. Surgical fields of application of XR technologies are currently primarily training, preoperative planning and intraoperative assistance. For all three areas, products already exist (some clinically approved) and technical feasibility studies have been conducted. In teaching, the use of XR can already be assessed as fundamentally practical and meaningful but still needs to be evaluated in large multicenter studies. In preoperative planning XR can also offer advantages, although technical limitations often impede routine use; however, for cases of intraoperative use informative evaluation studies are mostly lacking, so that an assessment is not yet possible in a meaningful way. Furthermore, there is a lack of assessments regarding cost-effectiveness in all three areas. The XR technologies enable proven advantages in surgical workflows despite the lack of high-quality evaluation with respect to the practical and clinical use of XR. New concepts for effective interaction with XR media also need to be developed. In the future, further research progress and technical developments in the field can be expected.

Authors are Christoph Rüger, Simon Moosburner and Igor M. Sauer (Chirurg 2020; 91(7): 544-552).

Tags: Digital Surgery

Junior Professorship for Digital Surgery and Interdisciplinary Technology Research
In: Open Position
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The Department of Surgery of the Charité (Director: Prof. Dr. Johann Pratschke) at the Charité Center 8 (CharitéCenter for Surgery) invites applications for the position of the Junior Professorship for Digital Surgery and interdisciplinary Technology Research (Salary Group: W1 BBesG-ÜfBE, non-tenured) with the reference number: Prof. 546/2020.

The initial appointment is for three years with the optional extension for another three years follow-ing successful evaluation. It is aimed to turn the Junior Professorship into a W2-Professorship (Salary Group: W2 BBesG-ÜfBE) after six years.The successful candidate has to fulfill the appointment requirements in accordance with § 102a of the Berlin Higher Education Act (Berliner Hochschulgesetz, Gem. § 102a BerlHG) and needs to credibly demonstrate through his/her previous scientific work that he/she is able to fulfill the expectations of the junior professorship.

One of the tasks of this Junior Professorship is the appropriate representation of the research area mentioned above. Within the framework of the Cluster of Excellence Matters of Activity – Image Space Material, he/she is expected to evaluate, accompany and advance the digital transformation in surgery and related disciplines as well as expand the repertoire of methods and initiate innovations. In cooperation with the research areas Cutting and Material Form Function of the Cluster of Excellence, new surgical cutting techniques are to be investigated and developed. It is planned to be linked to the currently being established institutions, The Simulated Human Being (Si-M) and the Berlin Simulation and Training Centre (BeST). In addition to the tasks mentioned, the following three fields of activity are to be covered:

Interdisciplinary Knowledge Transfer

  • Implementation of new applications from areas such as deep learning, extended reality (mixed and virtual reality) or robotics in surgical practice requires an intensification of interdisciplinary cooperation
  • Continuous exchange between industry and practice as well as with adjacent disciplines (e.g. Radiology)
  • Integration of a growing number of applications and competencies from areas outside established medical technology, e.g.game design, computer science or human factor studies

Technology Assessment

  • Sustainable implementation of digital technologies through opportunity and risk assessment
  • Advising the Department of Surgery on investment decisions through appropriate risk and media competency

Innovation

  • Identification of concrete application locations and practices of digital surgery within the clinic and experimental research (e.g. use of technologies in the context of biomedical research approaches to organ replacement as well as oncological models) for future Living Labs and to demonstrate these to the public
  • Integration of users, research projects and start-ups also outside the Clinic

The successful candidate will be engaged in teaching activities of the medical education curriculum at Charité, supervise Master and Doctoral candidates, and participate in academic self-organization. In addition, the candidate should present concepts for a good supervision of doctoral students as well as for the integration of his/her research activities into the teaching of the Charité. Appointment requirements are governed by article 102a of the Berlin Higher Education Act (Berliner Hochschulgesetz:§ 102a BerlHG). Completed university degree in Natural Sciences, Humanities and/or Life Sciences or any other related field of Medicine or non-medicine is required. In addition, a Doctorate (Ph.D and/or M.D.) and significant post-doctoral experience are required. Basic medical knowledge is desired.

The Charité is an equal opportunity employer committed to excellence through diversity. As women are under-represented in academics, we explicitly encourage women to send in their application. Women will be given preference over equally qualified men (within the framework of the legal possibilities). We value diversity and therefore welcome all applications – regardless of gender, nationality, social background, religion or age. Equally qualified applicants with disabilities will be given preference.

Written applications according to the format specified on https://career.charite.de/am/calls/application_notes.pdf should be submittedby June 19th, 2020 under https://career.charite.de. For further questions on details, please contact Prof. Dr. Igor Maximilian Sauer.

Tags: Digital Surgery,Tissue Engineering

Magnetic resonance elastography quantification of decellularized liver tissue
In: Publication
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"Magnetic resonance elastography quantification of the solid-to-fluid transition of liver tissue due to decellularization" was published in the latest issue of the Journal of the Mechanical Behavior of Biomedical Materials.

Maintenance of tissue extracellular matrix (ECM) and its biomechanical properties for tissue engineering is one of the substantial challenges in the field of decellularization and recellularization. Preservation of the organ-specific biomatrix is crucial for successful recellularization to support cell survival, proliferation, and functionality. However, understanding ECM properties with and without its inhabiting cells as well as the transition between the two states lacks appropriate test methods capable of quantifying bulk viscoelastic parameters in soft tissues.
We used compact magnetic resonance elastography (MRE) with 400, 500, and 600 Hz driving frequency to investigate rat liver specimens for quantification of viscoelastic property changes resulting from decellularization. Tissue structures in native and decellularized livers were characterized by collagen and elastin quantification, histological analysis, and scanning electron microscopy.
Decellularization did not affect the integrity of microanatomy and structural composition of liver ECM but was found to be associated with increases in the relative amounts of collagen by 83-fold (37.4 ± 17.5 vs. 0.5 ± 0.01 μg/mg, p = 0.0002) and elastin by approx. 3-fold (404.1 ± 139.6 vs. 151.0 ± 132.3 μg/mg, p = 0.0046). Decellularization reduced storage modulus by approx. 9-fold (from 4.9 ± 0.8 kPa to 0.5 ± 0.5 kPa, p < 0.0001) and loss modulus by approx. 7-fold (3.6 kPa to 0.5 kPa, p < 0.0001), indicating a marked loss of global tissue rigidity as well as a property shift from solid towards more fluid tissue behavior (p = 0.0097).
Our results suggest that the rigidity of liver tissue is largely determined by cellular components, which are replaced by fluid-filled spaces when cells are removed. This leads to an overall increase in tissue fluidity and a viscous drag within the relatively sparse remaining ECM. Compact MRE is an excellent tool for quantifying the mechanical properties of decellularized biological tissue and a promising candidate for useful applications in tissue engineering.

Authors are Hannah Everwien, Angela Ariza de Schellenberger, Nils Haep, Heiko Tzschätzsch, Johann Pratschke, Igor M. Sauer, Jürgen Braun, Karl H. Hillebrandt and Ingolf Sack.

J Mech Behav Biomed Mater. 2020 Apr;104:103640. doi: 10.1016/j.jmbbm.2020.103640. Epub 2020 Jan 14.

Tags: Decellularization,Recellularization,Extracellular Matrix

Characterization of pancreatic and biliary cancer stem cells in patient-derived tissue
In: Publication
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Pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangio-carcinoma (eCC) represent two cancer entities with devastating prognoses. Despite recent progress in research and treatment, therapy remains challenging. Cancer stem cells (CSCs) have been shown to play an important role in metastasis and chemoresistance. Therefore, CSCs may play a promising role as a potential therapeutic target.
A total of 31 patients (23 PDAC, 8 eCC) were included in the study. CSCs were analyzed in a single-cell suspension of tumor samples via fluorescence-activated cell scanning (FACS) with a functional Hoechst 33342 staining as well as a cell surface marker staining of the CSC-panel (CD24, CD44 and EpCAM) and markers to identify fibroblasts, leukocytes and components of the notch signaling pathway. Furthermore, the potential presence of CSCs among primary cancer-associated fibroblasts (CAFs) was assessed using the same FACS-panel.
We showed that CSCs are present in patient-derived dissociated tumor tissue. The functional and surface marker profile of CSC-detection did in fact correlate. The amount of CSCs was significantly correlated with tumor characteristics such as a higher UICC stadium and nodal invasion. CSCs were not restricted to the epithelial cell fraction in tumor tissues, which has been verified in independent analysis of primary cell cultures of CAFs.
Our study confirms the in vivo presence of CSCs in PDAC and eCC, stating a clinical significance thereof and thus their plausibility as therapeutic targets. In addition, stem-like cells also seem to constitute a part of the CAFs.

"Characterization of Pancreatic and Biliary Cancer Stem Cells in Patient-derived Tissue" was published in Anticancer Research. Authors are J. Gogolok, E. Seidel, A. Strönisch, A. Reutzel-Selke, I.M. Sauer, J. Pratschke, M. Bahra, and R.B. Schmuck.

Tags: pancreas,oncology,stem cells

Hepatocyte transplantation to the liver via the splenic artery
In: Publication
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Hepatocyte transplantation (HcTx) is a promising approach for the treatment of metabolic diseases in newborns and children. The most common application route is the portal vein, which is difficult to access in the newborn. Transfemoral access to the splenic artery for HcTx has been evaluated in adults, with trials suggesting hepatocyte translocation from the spleen to the liver with a reduced risk for thromboembolic complications. Using juvenile Göttingen minipigs, we aimed to evaluate feasibility of hepatocyte transplantation by transfemoral splenic artery catheterization, while providing insight on engraftment, translocation, viability, and thromboembolic complications. Four Göttingen Minipigs weighing 5.6 kg to 12.6 kg were infused with human hepatocytes (two infusions per cycle, 1.00E08 cells per kg body weight). Immunosuppression consisted of tacrolimus and prednisolone. The animals were sacrificed directly after cell infusion (n=2), 2 days (n=1), or 14 days after infusion (n=1). The splenic and portal venous blood flow was controlled via color-coded Doppler sonography. Computed tomography was performed on days 6 and 18 after the first infusion. Tissue samples were stained in search of human hepatocytes. Catheter placement was feasible in all cases without procedure-associated complications. Repetitive cell transplantations were possible without serious adverse effects associated with hepatocyte transplantation. Immunohistochemical staining has proven cell relocation to the portal venous system and liver parenchyma. However, cells were neither present in the liver nor the spleen 18 days after HcTx. Immunological analyses showed a response of the adaptive immune system to the human cells. We show that interventional cell application via the femoral artery is feasible in a juvenile large animal model of HcTx. Moreover, cells are able to pass through the spleen to relocate in the liver after splenic artery infusion. Further studies are necessary to compare this approach with umbilical or transhepatic hepatocyte administration.

"Hepatocyte Transplantation to the Liver via the Splenic Artery in a Juvenile Large Animal Model" was published in Cell Transplantation.
Authors are J. Siefert, K.H. Hillebrandt, S. Moosburner, P. Podrabsky, D. Geisel, T. Denecke, J.K. Unger, B. Sawitzki, S. Gül-Klein, S. Lippert, P. Tang, A. Reutzel-Selke, M.H. Morgul, A.W. Reske, S. Kafert-Kasting, W. Rüdinger, J. Oetvoes, J. Pratschke, I.M. Sauer, and N. Raschzok.

Tags: Cell transplantation,Tissue engineering

New book: Decellularized Extracellular Matrix: Characterization, Fabrication and Applications
In: Publication |Book
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The extracellular matrix (ECM) supports cells and regulates various cellular functions in our body. The native ECM promises to provide an excellent scaffold for regenerative medicine. In order to use the ECM as a scaffold in medicine, its cellular fractions need to be removed while retaining its structural and compositional properties. This process is called decellularization, and the resulting product is known as the decellularized extracellular matrix (dECM).
The book Decellularized Extracellular Matrix: Characterization, Fabrication and Applications (Editors: Tetsuji Yamaoka, Takashi Hoshiba) focuses on the sources of dECM and its preparation, characterization techniques, fabrication, and applications in regenerative medicine and biological studies. Using this book, the reader will gain a good foundation in the field of ECM decellularization complemented with a broad overview of dECM characterization, ranging from structural observation and compositional assessment to immune responses against dECM and applications, ranging from microfabrication and 3D-printing to the application of tissue-derived dECM in vascular grafts and corneal tissue engineering etc. The book closes with a section dedicated to cultured cell dECM, a complementary technique of tissue-derived dECM preparation, for application in tissue engineering and regenerative medicine, addressing its use in stem cell differentiation and how it can help in the study of the tumor microenvironment as well as in clinical trials of peripheral nerve regeneration.

E. Keshi, I.M. Sauer and K.H. Hillebrandt contributed the chapter "Engineering an endocrine Neo-Pancreas".

The print version of this book (Royal Society of Chemistry, ISBN 978-1-78801-467-0) is planned for release on 11 December 2019.

Tags: Decellularization,Recellularization,Extracellular Matrix

Simon Moosburner defended thesis summa cum laude
In: Thesis
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Today, Simon Moosburner successfully defended his doctoral thesis entitled "Erweiterung der Spenderpopulation bei Lebertransplantation: Klinischer Bedarf und Entwicklung eines Kleintier-Lebermaschinenperfusionssystems (Expanding the donor pool for liver transplantation: clinical need and development of small animal liver perfusion system)" summa cum laude !

Congratulations!

Tags: Transplantation,VCA

Einstein BIH Visiting Fellow project, funded by Stiftung Charité
In: Grant
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The Stiftung Charité will fund our project “Vascular Composite Tissue Allotransplantation (VCA): An integrated, multidisciplinary basic and clinical research program for hand and uterus transplantation” (Einstein BIH Visiting Fellowship) within the framework of the Private Excellence Initiative Johanna Quandt for two more years!

The Charité has a long tradition as an international leader in transplantation. Prior to starting our Einstein BIH funded project in February 2017, Vascular Composite Tissue Allotransplantation (VCA) was neither object of scientific investigations, nor offered to patients. As an Einstein BIH Visiting Fellow Prof. Stefan G. Tullius, Harvard Medical School, ignited both: a basic research group in this field and a clinical research transplant program. During the first three years of our multidisciplinary basic and clinical research program, we have been able to implement complex small animal models (mouse hindlimb, heart, skin transplant models); a rat uterus transplant model is currently established. Those models offer unique opportunities to address basic research questions of translational relevance including: organ-specific alloimmune responses, immunogenicity, and the maternal-fetal interface in uterus transplantation.
An enthusiast clinical, multi-disciplinary has been established, led and mentored by Prof. Tullius that has brought preparatory surgical exercises and clinical algorithms for VCA at the Charité on the way.

Stiftung Charité is an independent charitable foundation. It was endowed in 2005 by entrepreneur Johanna Quandt, who entrusted it with the mission of supporting the innovative potential and excellence of Berlin’s university medicine, which can look back on a rich tradition in medical research and patient care. Thereby, the foundation is active in two focal areas: promoting technology transfer between the laboratory and the clinic as well as improving the framework conditions for innovation and entrepreneurship in medicine. Since 2014, Stiftung Charité is also funding the life sciences in Berlin by its Private Excellence Initiative Johanna Quandt.

Tags: Transplantation,VCA

Development of a rat liver machine perfusion system for normothermic and subnormothermic conditions
In: Publication
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Tissue Engineering Part A accepted our paper on the "Development of a rat liver machine perfusion system for normothermic and subnormothermic conditions" (Tissue Eng Part A. 2019 Jul 31. doi: 10.1089/ten.TEA.2019.0152. [Epub ahead of print[) !
Ex vivo liver machine perfusion is a promising alternative for preservation of liver grafts from extended criteria donors. Small animal models can be used to evaluate different perfusion conditions. We here describe the development of a miniaturized ex vivo machine perfusion system for rat liver grafts, evaluating cell-free and erythrocyte-based perfusion solutions, subnormothermic and normothermic temperatures and dialysis. A perfusion chamber was designed after a suitable liver position was identified. Normothermic ex vivo liver perfusion (NEVLP) required supplementation of erythrocytes to reduce cell damage. Perfusion with erythrocytes led to rising potassium levels after 12 hours (NEVLP, 16.2mmol/l, interquartile range (IQR) 5.7 and subnormothermic ex vivo liver perfusion (SNEVLP), 12.8 mmol/l, IQR 3.5), which were normalized by dialysis using a laboratory dialysis membrane (NEVLP, 6.2 mmol/l, IQR 0.5 and SNEVLP, 5.3 mmol/l, IQR 0.1; p=0.004). Livers treated with NEVLP conditions showed higher bile production (18.52mg/h/g, IQR 8.2) compared to livers perfused under SNEVLP conditions (0.4 mg/h/g, IQR 1.2, p=0.01). Reducing the perfusion volume from 100ml to 50ml allowed for higher erythrocytes concentrations, leading to significantly lower transaminases (15.75 U/l/ml, IQR 2.29 vs. 5.97 U/l/ml, IQR 18.07, p=0.002). In conclusion, a well-designed perfusion system, appropriate oxygen carriers, dialysis, and miniaturization of the perfusion volume are critical features for successful miniaturized ex vivo liver machine perfusion.

Authors are M. Nösser, J.M.G.V. Gassner, S. Moosburner, D. Wyrwal, F. Claussen, K.H. Hillebrandt, R. Horner, P. Tang, A. Reutzel-Selke, D. Polenz, R. Arsenic, J. Pratschke, I.M. Sauer, and N. Raschzok.

Tags: Liver Transplantation,Liver Support,Liver Surgery

TEBURU – our latest bioreactor system
In: Publication
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Three‐dimensional tissue cultures are important models for the study of cell‐cell and cell‐matrix interactions, as well as, to investigate tissue repair and reconstruction pathways. Therefore, we designed a reproducible and easy to handle printable bioreactor system (Teburu), that is applicable for different approaches of pathway investigation and targeted tissue repair using human tissue slices as a three‐dimensional cell culture model. Here, we definitively describe Teburu as a controlled environment to reseed a 500‐µm thick decellularized human liver slice using human mesenchymal stroma cells. During a cultivation period of eight days, Teburu, as a semi‐open and low consumption system, was capable to maintain steady pH and oxygenation levels. Its combination with additional modules delivers an applicability for a wide range of tissue engineering approaches under optimal culture conditions.

"Teburu—Open source 3D printable bioreactor for tissue slices as dynamic three‐dimensional cell culture models" was published in Artif Organs. 2019 Jun 18. doi: 10.1111/aor.13518. [Epub ahead of print]. Authors are A. Daneshgar, P. Tang, C. Remde, M. Lommel, S. Moosburner, U. Kertzscher, O. Klein, M. Weinhart, J. Pratschke, I.M. Sauer, and K.H. Hillebrandt.

Tags: Bioreactor,Tissue engineering,Tissue culture

EUROSTARS project
In: Grant
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Within the Eurostars project „Comprehensive qualitative/quantitative multi-pathogen IVD workflow for immunocompromised patients (Im-compr-IVD)“ an IVD workflow covering sample preparation up to clinical relevant diagnosis of infection in immunocompromised patients will be developed. Deliverables are:
  • Design, development and preclinical validation of QIC-Finder assay with novel primers and probes for qualitative and quantitative screening of 23 pathogens (bacterial, viral, fungal and parasitic);
  • Detection instrumentation and interpretation software optimized for assay performance;
  • Instructions for high quality DNA/RNA extraction from plasma.
Partners are Pathofinder (Netherlands, Coordinator), Ella Biotech (Germany), IT-IS International Ltd. (United Kingdom) and Charité - Universitätsmedizin Berlin.

Eurostars projects are co-funded by EUREKA member countries and the European Union Horizon 2020 Framework program.

Tags: Transplantation

DFG Research Grant for PD Dr. Moritz Schmelzle
In: Grant
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Priv.-Doz. Dr. Moritz Schmelzle receives additional financial support for his project "CD39-dependent regulation of innate immune responses and modulation of exacerbated sterile inflammation in acute-on-chronic liver failure" (DFG Research Grant 299534341, SCHM2661/3-2).
Acute on chronic liver failure (ACLF) is defined as an acute hepatic insult in patients with chronic liver disease and is characterized by high death rates. Systemic inflammation is considered a hallmark of ACLF and can be linked to progression of liver failure and clinical deterioration. Criteria for ACLF and the systemic inflammatory response syndrome (SIRS) substantially overlap and support the assumption of mechanistic similarities between both syndromes. Thus, modulating inflammation and the linked immune responses in ACLF might help to restore homeostasis and improve of regenerative capacities of the injured liver.We hypothesize that the catalyzed hydrolysis of purinergic damage-associated molecular patterns (DAMPS), such as extracellular ATP, by the ectonucleotidase CD39 is crucially involved in the regulation of innate immune responses and the modulation of exacerbated sterile inflammation in ACLF. We here aim to describe characteristics and functions of monocyte subsets in ACLF and to investigate implications of purinergic signaling. We further plan to investigate the therapeutical relevance of non-classical monocytes and the immune-type ectonucleotidase CD39 in experimental ACLF. Finally, we will evaluate the clinical significance of cellular and non-cellular immune responses in ACLF patients enrolled in the GRAFT Trial.

Tags: Liver Failure,Liver Surgery

Priv.-Doz. Dr. Felix Krenzien & Priv.-Doz. Dr. Christian Benzing
In: Habilitation
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Today Dr. Felix Krenzien and Dr. Christian Benzing received they post-doctoral lecturing qualification (Habilitation) at Charité – Universitätsmedizin Berlin.
The title of Felix Krenzien's Habilitationsschrift is "Der differenzierte Einfluss der Seneszenz auf die Organtransplantation und Leberteilresektion", Christian Benzing focussed on the "Untersuchung der gesundheitsbezogenen Lebensqualität und der psychischen Gesundheit nach Lebertransplantation".

Congratulations !

Tags: Liver Transplantation,Liver Support,Liver Surgery

Two new BIH Charité Junior Clinician Scientists
In: Grants
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Dr. Karl Hillebrandt and Dr. Matthäus Felsenstein successfully applied for the BIH Charité Junior Clinician Scientist Program. Karl Hillebrandt will continue his work on human decellularized liver slices as 3D platform for in vitro models of cholangiocellular carcinoma. Matthäus Felsenstein focusses on derivation of normal pancreatic duct cells from human primary tissue and their stepwise genetic modification in vitro using CRISPR/Cas9 .

Congratulations!

Tags: Decellularisation,Recellularisation,Tissue Engineering,Oncology

Strategies based on organ decellularization and recellularization
In: Publication
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Transplantation is the only curative treatment option available for patients suffering from end-stage organ failure, improving their quality of life and long-term survival. However, because of organ scarcity, only a small number of these patients actually benefit from transplantation. Alternative treatment options are needed to address this problem. The technique of whole-organ decellularization and recellularization has attracted increasing attention in the last decade. Decellularization includes the removal of all cellular components from an organ, while simultaneously preserving the micro and macro anatomy of the extracellular matrix. These bioscaffolds are subsequently repopulated with patient-derived cells, thus constructing a personalized neo-organ and ideally eliminating the need for immunosuppression. However, crucial problems have not yet been satisfyingly addressed and remain to be resolved, such as organ and cell sources.

In this paper "Strategies based on organ decellularization and recellularization" (Transpl Int. 2019; 32(6):571-585), we focus on the actual state of organ de- and recellularization, as well as the problems and future challenges. Authors are K.H. Hillebrandt, H. Everwien, N. Haep, E. Keshi, J. Pratschke, and I.M. Sauer.

Tags: Decellularisation,Recellularisation,Tissue Engineering

Impact of Percoll purification on isolation of primary human hepatocytes
In: Publication
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Scientific Reports published our paper "Impact of Percoll purification on isolation of primary human hepatocytes" (Sci Rep. 2019 Apr 25;9(1):6542). Authors are R. Horner, J.G.M.V. Gassner, M. Kluge, P. Tang, S. Lippert, K.H. Hillebrandt, S. Moosburner, A. Reutzel-Selke, J. Pratschke, I.M. Sauer, and N. Raschzok.

Research and therapeutic applications create a high demand for primary human hepatocytes. The limiting factor for their utilization is the availability of metabolically active hepatocytes in large quantities. Centrifugation through Percoll, which is commonly performed during hepatocyte isolation, has so far not been systematically evaluated in the scientific literature. 27 hepatocyte isolations were performed using a two-step perfusion technique on tissue obtained from partial liver resections. Cells were seeded with or without having undergone the centrifugation step through 25% Percoll. Cell yield, function, purity, viability and rate of bacterial contamination were assessed over a period of 6 days. Viable yield without Percoll purification was 42.4 × 106 (SEM ± 4.6 × 106) cells/g tissue. An average of 59% of cells were recovered after Percoll treatment. There were neither significant differences in the functional performance of cells, nor regarding presence of non-parenchymal liver cells. In five cases with initial viability of <80%, viability was significantly increased by Percoll purification (71.6 to 87.7%, p = 0.03). Considering our data and the massive cell loss due to Percoll purification, we suggest that this step can be omitted if the initial viability is high, whereas low viabilities can be improved by Percoll centrifugation.

Tags: Hepatocyte isolation,Liver support,Liver Surgery

Immunologic cellular characteristics of the tumour microenvironment of HCC
In: Publication
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"Immunologic cellular characteristics of the tumour microenvironment of hepatocellular carcinoma drive patient outcomes" is available via World J Surg Oncol. 2019; 17(1):97

Anti-tumour immune competence has an impact in hepatocarcinogenesis and success of anti-cancer therapies. Tumour-infiltrating lymphocytes (TILs) and monocytes/macrophages (TAMs) are proposed to have significance in cancer. However, there is only limited data concerning their impact on patient outcome and survival in hepatocellular carcinoma (HCC).
Frequencies of CD68+, CD163+ M2-polarized TAMs and TILs were measured in de novo HCC tumours in non-cirrhosis (n = 58) using immunohistology and correlated to patients' clinicopathological characteristics and survival rates.
Patients with tumours marked by appearance of TILs and CD68+ TAMs showed an improved 1-, 3- and 5-year recurrence-free survival (all p ≤ 0.05). CD68+ TAMs were associated with reduced incidence of recurrent and multifocal disease. Conversely, CD163+ TAMs were associated with multifocal HCC and lymphangiosis carcinomatosa (all p ≤ 0.05).
TILs and CD68+ TAMs are associated with multiple tumour characteristics and patient survival in HCC. However, there is only scarce data about the biology underlying their mechanistic involvement in human tumour progression. Thus, experimental data on functional links might help develop novel immunologic checkpoint inhibitor targets for liver cancer.

Authors are G. Atanasov, K. Dino, K. Schierle, C. Dietel, G. Aust, J. Pratschke, D. Seehofer, M. Schmelzle, H.M. Hau.

Tags: Hepatocellular carcinoma,Liver,Liver Surgery

Dr. med. Martin Kluge
In: Thesis
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Martin Kluge is wearing excellent suits and successfully defended his doctoral thesis magna cum laude! He examined the effects of the magnetic field of magnetic resonance imaging (MRI) systems on cells labeled with micrometer-sized iron oxide particles.

Congratulations!

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Cytokine production of human CD4+ memory T cells
In: Publication written by: Prof. Dr. Igor M. Sauer
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Nature Communication accepted the manuscript "Progressive expression of killer-like receptors and GPR56 defines the cytokine production of human CD4+ memory T cells" for publication. Authors are Kim-Long Truong, Stephan Schlickeiser, Katrin Vogt, David Boës, Katarina Stanko, Christine Appelt, Mathias Streitz, Gerald Grütz, Nadja Stobutzki, Christian Meisel, Christina Iwert, Stefan Tomiuk, Julia Polansky, Andreas Pascher, Nina Babel, Ulrik Stervbo, Igor Sauer, Undine Gerlach, and Birgit Sawitzki.

All memory T cells mount an accelerated response on antigen reencouter, but significant functional heterogeneity is present within the respective memory T cell subsets as defined by CCR7 and CD45RA expression, thereby warranting further stratification. Here we show that several surface markers, KLRB1, KLRG1, GPR56 and KLRF1, help define “low”, “high” or “exhausted” cytokine producers within human peripheral and intra-hepatic CD4+ memory T cells. Highest simultaneous production of TNF and IFN-γ is observed in KLRB1+KLRG1+GPR56+ CD4 T cells. By contrast, KLRF1 expression is associated with reduced TNF/IFN-γ production and T cell exhaustion. Lastly, TCRbeta repertoire analysis and in vitro differentiation support a regulated, successive expression for these markers during CD4+ memory T cell differentiation. Our results thus help refine the classification of human memory T cells to provide insights on inflammatory disease progression and immunotherapy development.
Read More

Tags: cytokine production ,CD4+ memory T cells

Critical Care for Potential Liver Transplant Candidates
In: Publication |Book written by: Prof. Dr. Igor M. Sauer
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The book Critical Care for Potential Liver Transplant Candidates
(D. Bezinover and F. Saner [Eds.]) focuses on patients with end-stage-liver disease (ESLD) who could possibly qualify for liver transplant. This patient cohort raises many problems: who should be treated and also, when is it too late for transplant? The authors are all dedicated experts in the field of ESLD/liver transplantation, but from different disciplines with different views of the problem.
In the past 15 years many things have changed in the treatment for these patients: cardiac assessment, treatment of porto-pulmonary hypertension, hemodynamics, coagulation assessment and management, diagnosis of kidney failure, and the timing of dialysis. These issues are comprehensively discussed in this book, in order to provide physicians starting in the field of transplantation an overview of different areas of concern.
This book is aimed at specialists and trainees in critical care, hepatology, anesthesia, surgery, and nephrology.

N. Raschzok, K.H. Hillebrandt and I.M. Sauer contributed with the chapter "Liver Assist Systems for Bridging to Transplantation: Devices and Concepts".

More information via this link.
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Tags: Liver Transplantation,Liver Support

DFG grant for Linda Feldbrügge
In: Grant |Regeneration
Dr. Linda Feldbrügge receives a research grant from the Deutsche Forschungsgemeinschaft (DFG) for her project "Purinergic regulation of inflammation in liver fibrosis by ectonucleoside triphosphate diphosphohydrolase-3 (ENTPD3)“.

ENTPD3, expressed by macrophages and various other cell types, modulates inflammation and tissue regeneration by scavenging extracellular ATP and ADP. As demonstrated by her preliminary work, ENTPD3 appears to play a deleterious role in liver fibrosis. Her new project aims to define the mechanisms of ENTPD3 mediated modulation of macrophage function and regulation of liver fibrosis, and test their relevance in human liver fibrosis.

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Dr. med. Antje Butter
In: Thesis written by: Prof. Dr. Igor M. Sauer
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Today, Antje Butter successfully defended her doctoral thesis magna cum laude!
Congratulations!

Antje was involved in basic research with respect to liver decellularization and recellularization. A proprietary, customized bioreactor was established to repopulate decellularized rat livers with primary rat hepatocytes via the hepatic artery and to subsequently evaluate graft morphology and function during 7 days of ex vivo perfusion. More information via this link.
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Percoll purification after isolation of Primary Human Hepatocytes
In: Publication written by: Prof. Dr. Igor M. Sauer
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The manuscript "Isolation of Primary Human Hepatocytes: Is Percoll Purification Really Necessary?" was accepted for publication in Scientific Reports.
Authors are Rosa Horner, Jospeh G.M.V. Gassner, Martin Kluge M, Peter Tang, Steffen Lippert, Karl H. Hillebrandt, Simon Moosburner, Anja Reutzel-Selke, Johann Pratschke, Igor M. Sauer and Nathanael Raschzok.

Research and therapeutic applications create a high demand for primary human hepatocytes. The limiting factor for their utilization is the availability of metabolically active hepatocytes in large quantities. Centrifugation through Percoll, which is commonly performed during hepatocyte isolation, has so far not been systematically evaluated in the scientific literature. 27 hepatocyte isolations were performed using a two-step perfusion technique on tissue obtained from partial liver resections. Cells were seeded with or without having undergone the centrifugation step through 25% Percoll. Cell yield, function, purity, viability and rate of bacterial contamination were assessed over a period of 6 days. Viable yield without Percoll purification was 42.4 x 106 (SEM ± 4.6 x 106) cells/g tissue. An average of 59% of cells were recovered after Percoll treatment. There were neither significant differences in the functional performance of cells, nor regarding presence of non-parenchymal liver cells. In five cases with initial viability of <80%, viability was significantly increased by Percoll purification (71.6 to 87.7%, p=0.03). Considering our data and the massive cell loss due to Percoll purification, we suggest that this step can be omitted if the initial viability is high, whereas low viabilities can be improved by Percoll centrifugation.
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Tags: Hepatocytes,Cell isolation

Critical Care for Potential Liver Transplant Candidates
In: Publication |Book written by: Prof. Dr. Igor M. Sauer
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The book Critical Care for Potential Liver Transplant Candidates
(D. Bezinover and F. Saner [Eds.]) focuses on patients with end-stage-liver disease (ESLD) who could possibly qualify for liver transplant. This patient cohort raises many problems: who should be treated and also, when is it too late for transplant? The authors are all dedicated experts in the field of ESLD/liver transplantation, but from different disciplines with different views of the problem.
In the past 15 years many things have changed in the treatment for these patients: cardiac assessment, treatment of porto-pulmonary hypertension, hemodynamics, coagulation assessment and management, diagnosis of kidney failure, and the timing of dialysis. These issues are comprehensively discussed in this book, in order to provide physicians starting in the field of transplantation an overview of different areas of concern.
This book is aimed at specialists and trainees in critical care, hepatology, anesthesia, surgery, and nephrology.

N. Raschzok, K.H. Hillebrandt and I.M. Sauer contributed with the chapter "Liver Assist Systems for Bridging to Transplantation: Devices and Concepts".

More information via this link.
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Tags: Liver Transplantation,Liver Support

Matters of Activity. Image Space Material
In: Cluster of Excellence written by: Prof. Dr. Igor M. Sauer
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Prof. I.M. Sauer and Prof. J. Pratschke became principal investigators in the new Cluster of Exzellence Matters of Activity. Image Space Material. This Cluster will explore materials’ own inner activity, which can be discovered as a new source of innovative strategies and mechanisms for rethinking the relationship between the analog and the digital and for designing more sustainable and energy-efficient technologies.
The project’s central vision is to develop images, spaces, and materials as active structures of a new physical and symbolic reality, in which nature and culture intertwine in a novel way. In this context, interdisciplinary research and development of sustainable processes and structures is a key priority in all areas of visual-material character, such as wearables, materials technology, medical technology, logistics, architecture, and robotics. More than 40 disciplines are systematically investigating design strategies for materials and structures that adapt to specific requirements and the environment. The cluster relies on a new role for design within the context of growing diversity and the continuous improvement of materials and forms of visualization in all disciplines.
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Tags: Tissue Engineering,Extended Reality

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