News
Charité Digital Clinician Scientist Pilot Program (D-CSP)
The Deutsche Forschungsgemeinschaft (DFG) will fund the Charité Digital Clinician Scientist Pilot Program (D-CSP). The ideas is to improve and safeguard the current BIH Charité Clinician Scientist Program by building an additional structure for a novel “digital science” driven career track to prepare academic clinicians for the challenges of the emerging technological transformation of medicine.
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Designated Spokesperson is Prof. Dr. Duska Dragun. Co-applicants are the NeuroCure Cluster of Excellence, Department of Experimental Neurology, Department of Pediatric Oncology and Hematology, Department of Radiology and Pediatric Radiology, Department of Surgery, Berlin Institute for Medical Systems Biology (BIMSB), Institute of Medical Biometrics and Clinical Epidemiology, Department of Neurology and Experimental Neurology, and the Department of Anesthesiology and Intensive Care Medicine.

With the changing dynamics in biomedical research having fully entered into the digital era, it is becoming increasingly clear after seven years of experience that we need more dedicated efforts to create opportunities by establishing stronger interfaces with physics, mathematics, systems biology, and computational sciences for future generations of Clinician Scientists. The newly proposed research and educational structure for integrating these new areas of expertise into the established CSP should act as a “central processing unit” to facilitate biomedical knowledge derived from a variety of clinical disciplines supported by leading technology experts to address the specific challenges of data-driven medicine in the future.

  • Precision medicine in cancer and beyond,
  • Systems biology,
  • Big data science and decision support systems,
  • Quantitative imaging,
  • Computational neuroscience and brain simulation, and
  • Augmented, mixed and virtual reality in surgery
are exemplary research topics highlight how applicants will interact with Digital Clinician Scientists to develop their skills in giving prognoses, optimizing delivery of care, and personalizing patient management and therapeutic choices.
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DFG Research Grant
In: Grant written by: Prof. Dr. Igor M. Sauer
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Priv.-Doz. Dr. Nathanael Raschzok receives a research grant from the Deutsche Forschungsgemeinschaft (DFG) for his project "Defatting of steatotic liver grafts by normothermic ex vivo machine perfusion with DNP" in collaboration with Prof. Dr. med. Andreas Birkenfeld, Universitätsklinikum Carl Gustav Carus, Dresden.

Transplantation of steatotic marginal liver grafts is associated with a certain risk of graft dysfunction, primary non-function, and biliary complications, which results in a worse outcome compared to transplantation of unimpaired livers.
We hypothesize, that normothermic machine perfusion combined with adequate pharmacological intervention can prevent the deleterious effect of ischemia-reperfusion injury on macrovesicular grafts by a) minimizing the negative effect of cold storage, and by b) actively decreasing the intracellular fat content of the graft.
Mild mitochondrial uncoupling by DNP decreases the intrahepatic fat content of steatotic liver grafts during normothermic ex vivo machine perfusion. Efficient defatting can be safely achieved ex vivo with DNP concentrations that would be toxic in vivo. Systemic side effects of DNP are prevented by exclusive hepatic exposure through machine perfusion, and by washing DNP out of the liver graft at the end of the perfusion period. The synergetic effects of normothermic perfusion and defatting with DNP will prevent ischemia-reperfusion injury and make severely steatotic liver grafts acceptable for transplantation.
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Tags: Transplantation,Organ Reconditioning,Steatosis hepatis

SFB 1365 Renoprotection
In: Grant written by: Prof. Dr. Igor M. Sauer
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The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) is establishing ten new Collaborative Research Centres (CRCs, Sonderforschungsbereich, SFB) to further support top-level research in Germany.
Chronic kidney diseases and acute kidney damage are widespread and reduce the life expectancy of those affected. The CRC “Renoprotection” therefore aims to decode specific signalling pathways for kidney damage and develop new approaches to treatment in the long term (Charité Berlin – FU Berlin and HU Berlin, Spokesperson: Prof. Dr. Pontus Börje Persson).
With the project "Renoprotective role of Lipocalin-2 in allograft rejection following kidney transplantation" Priv.-Doz. Dr. Felix Aigner and Dr. Muhammad Imtiaz Ashraf, PhD will be part of this SFB/CRC!

To provide allograft renoprotection, novel strategies are needed, including (i) prevention of renal allograft IRI and (ii) targeted immunosuppression and thus; reduction and avoidance of steroid and CNI usage in the long-run. Using a mouse model of kidney transplantation, we recently demonstrated a renoprotective role of exogenously administered recombinant Lcn2:Siderophore:Fe complex (rLcn2). The rLcn2 mediated mechanism of allograft renoprotection is still unknown; however, the mechanistic insight is essential for comprehensive translation of the rLcn2 therapy into clinical practice. In the funded project, we aim at (i) understanding the route and mechanisms of immunoregulation and/or cytoprotection, mediated by exogenously administered rLcn2 during the allograft damage; and (ii) characterizing the source and nature of endogenous Lcn2 i.e. whether it is complexed with mammalian iron binding catechols and may contribute to allograft survival in the long-run. Our ultimate goal is to pave the way for transplant renoprotection via recombinant Lcn2.

More information…
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Tags: Transplantation,Renoprotection

Comparison of AR HMDs in Visceral Surgery
In: Publication
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"Real World Usability Analysis of two Augmented Reality Headsets in Visceral Surgery" was accepted for publication in Artificial Organs. Authors are S. Moosburner, C. Remde, P. Tang, M. Queisner, N. Haep, J. Pratschke, and I.M. Sauer.

Recent developments in the field of augmented reality (AR) have enabled new use cases in surgery. Initial set-up of an appropriate infrastructure for maintaining an AR surgical workflow requires investment in appropriate hardware. We compared the usability of the Microsoft HoloLens and Meta 2 head mounted displays (HMDs). Fifteen medicine students tested each device and were questioned with a variant of the System Usability Scale (SUS). Two surgeons independently tested the devices in an intraoperative setting.
In our adapted SUS, ergonomics, ease of use and visual clarity of the display did not differ significantly between HMD groups. The field of view (FOV) was smaller in the Microsoft HoloLens than the Meta 2 and significantly more study subjects (80% vs. 13.3%; p < 0.001) felt limited through the FOV. Intraoperatively, decreased mobility due to the necessity of an AC adapter and additional computing device for the Meta 2 proved to be limiting. Object stability was rated superior in the Microsoft HoloLens than the Meta 2 by our surgeons and lead to increased use.
We examined the Meta 2 and the Microsoft HoloLens and found key advantages in the Microsoft HoloLens which provided palpable benefits in a surgical setting.
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Mathilde Feist and Paul Ritschl: Clinician Scientists
In: Grant written by: Prof. Dr. Igor M. Sauer
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Dr. Mathilde Feist and Dr. Paul Ritschl successfully applied for the BIH Charité Clinician Scientist Program. Mathilde Feist will work on "Cytokine-armed oncolytic vaccinia virus for pancreatic cancer therapy". Mentors are Prof. Bahra, Prof. Sauer and Prof. Beling.
Paul Ritschl focusses on "The Impact of Donor Derived Microparticles Following Solid Organ Transplantation". Mentors are Priv.-Doz. Dr. Schmelzle and Priv.-Doz Dr. Öllinger.
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Tags: VCA,Transplantation

Nanomolar sensing of NAD
In: Publication
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"The nanomolar sensing of nicotinamide adenine dinucleotide in human plasma using a cycling assay in albumin modified simulated body fluids." was published in Nature Scientific Reports.
Authors are P. Brunnbauer, A. Leder, C. Kamali, K. Kamali, E. Keshi, K. Splith, S. Wabitsch, P. Haber, G. Atanasov, L. Feldbrügge, I.M. Sauer, J. Pratschke, M. Schmelzle, and F. Krenzien.

Nicotinamide adenine dinucleotide (NAD), a prominent member of the pyridine nucleotide family, plays a pivotal role in cell-oxidation protection, DNA repair, cell signalling and central metabolic pathways, such as beta oxidation, glycolysis and the citric acid cycle. In particular, extracellular NAD+ has recently been demonstrated to moderate pathogenesis of multiple systemic diseases as well as aging. Herein we present an assaying method, that serves to quantify extracellular NAD+ in human heparinised plasma and exhibits a sensitivity ranging from the low micromolar into the low nanomolar domain. The assay achieves the quantification of extracellular NAD+ by means of a two-step enzymatic cycling reaction, based on alcohol dehydrogenase. An albumin modified revised simulated body fluid was employed as standard matrix in order to optimise enzymatic activity and enhance the linear behaviour and sensitivity of the method. In addition, we evaluated assay linearity, reproducibility and confirmed long-term storage stability of extracellular NAD+ in frozen human heparinised plasma. In summary, our findings pose a novel standardised method suitable for high throughput screenings of extracellular NAD+ levels in human heparinised plasma, paving the way for new clinical discovery studies.
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Normothermic ex vivo machine perfusion
In: Publication
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"Improvement of normothermic ex vivo machine perfusion of rat liver grafts by dialysis and Kupffer Cell inhibition with glycine" was accepted for publication in Liver Transplantation.
Authors are J. Gassner, M. Nösser, S. Moosburner, R. Horner, P. Tang, L. Wegener, D. Wyrwal, F. Claussen, R. Arsenic, J. Pratschke, I.M. Sauer, and N. Raschzok.

Normothermic ex vivo liver machine perfusion might be a superior preservation strategy for liver grafts from extended criteria donors. However, standardized small animal models are not available for basic research on machine perfusion of liver grafts. A laboratory-scaled perfusion system was developed consisting of a custom-made perfusion chamber, a pressure-controlled roller pump, and an oxygenator. Male Wistar rat livers were perfused via the portal vein for 6 hours using oxygenated culture medium supplemented with rat erythrocytes. A separate circuit was connected via a dialysis membrane to the main circuit for plasma volume expansion. Glycine was added to the flush solution, the perfusate, and the perfusion circuit. Portal pressure and transaminase release were stable over the perfusion period. Dialysis significantly decreased the potassium concentration of the perfusate and led to significantly higher bile and total urea production. Hematoxylin and eosin staining and immunostaining for ssDNA and activated caspase 3 showed less sinusoidal dilatation and tissue damage in livers treated with dialysis and glycine. While Kupffer cells were preserved, tumor necrosis factor α mRNA levels were significantly decreased by both treatments. For proof of concept, the optimized perfusion protocol was tested with DCD grafts, resulting in significantly lower transaminase release into the perfusate and preserved liver architecture compared to baseline perfusion.
Our laboratory-scale normothermic portovenous ex vivo liver perfusion system enables rat liver preservation for 6 hours. Both dialysis and glycine treatment were shown to be synergistic for preservation of the integrity of normal and DCD liver grafts.
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Hendrik Napierala defended his thesis summa cum laude
In: Thesis written by: Prof. Dr. Igor M. Sauer
Today, Hendrik Napierala defended his thesis "Rebesiedlung dezellularisierter Rattenpankreata mit Langerhans-Inseln" summa cum laude!

Congratulations !
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Tags: Decellularization,Transplantation,Decellularization,NeoPancreas

Tumor-stromal cross-talk in PDAC
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Hepatobiliary Pancreat Dis Int accepted the manuscript "Tumor-stromal cross-talk modulating the therapeutic response in pancreatic cancer" for publication. Authors are C.C.M. Neumann, E. von Hörschelmann, A. Reutzel-Selke, E. Seidel, I.M. Sauer, J. Pratschke, M. Bahra, and R.B.Schmuck.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor's high chemoresistance. Cancer associated fibroblasts (CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor-stromal interactions when exposed to three well-known chemotherapeutic agents.
Monocultures, indirect and direct co-cultures of two PDAC cell lines (AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretase-inhibitor (GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed.
On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma (CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor-stromal interaction more complex.
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Prof. Marcus Bahra Charité W2 professor
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Prof. Dr. Marcus Bahra was appointed as a W2 professor for Pancreato-Biliary Surgery at the Charité – Universitätsmedizin Berlin. Working with other specialists, his team provides treatment for patients with malignancies and diseases in the pancreas and bile duct and conducts research in this field.
Since 2014 he held an extraordinary professorship for Surgery at the Charité.
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Wibke Schulte: BIH Charité Clinician Scientist
In: Grant written by: Prof. Dr. Igor M. Sauer
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Dr. med. Wibke Schulte successfully applied for the BIH Charité Clinician Scientist Program with her project „Die Rolle von MIF in der humanen akuten Peritonitis | Role of MIF in human acute peritonitis“. Mentors are Priv.-Doz. Dr. med. Felix Aigner and Prof. Dr. Igor M. Sauer.
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Tags: VCA,Transplantation

Isolation of primary human hepatocytes & LiMax-test
In: Publications
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Tissue Engineering (Part C: Methods) accepted our paper entitled "The predictive value of the LiMAx-test for the isolation of primary human hepatocytes".
Authors are R.D. Major, M. Kluge, M. Jara, M. Nösser, R. Horner, J. Gassner, B. Struecker, P. Tang, S. Lippert, A. Reutzel-Selke, D. Geisel, T. Denecke, M. Stockmann, J. Pratschke, I.M. Sauer, and N. Raschzok.

The need for primary human hepatocytes is constantly growing, for basic research as well as for therapeutic applications. However, the isolation outcome strongly depends on the quality of liver tissue, and we are still lacking a preoperative test that allows the prediction of the hepatocyte isolation outcome. Here we evaluated the “maximal liver function capacity test” (LiMAx) as predictive test for the quantitative and qualitative outcome of hepatocyte isolation. This test is already used in clinical routine to measure preoperative and to predict postoperative liver function.
The patient’s preoperative mean LiMAx was obtained from the patient records and preoperative CT and MRI images were used to calculate the whole liver volume in order to adjust the mean LiMAx. The outcome parameters of the hepatocyte isolation procedures were analyzed in correlation with the adjusted mean LiMAx.
Primary human hepatocytes were isolated from partial hepatectomies (n=64).
From these 64 hepatectomies we included 48 to our study and correlated their isolation outcome parameters with volume corrected LiMAx values. From a total of 11 hepatocyte isolation procedures, metabolic parameters (albumin, urea and aspartate aminotransferase) were assessed during the hepatocyte cultivation period of 5 days. The volume adjusted mean LiMAx showed a significant positive correlation with the total cell yield (p= 0.049;r= 0.242;n= 48). The correlations of volume adjusted LiMAx values with viable cell yield and cell viability did not reach statistical significance. A sub-group analysis of isolations from patients with colorectal metastasis revealed a significant correlation between volume adjusted mean LiMAx and total cell yield (p= 0.012;r= 0.488;n= 21) and viable cell yield (p=0.034;r=0.405;n=21). Whereas a sub-group analysis of isolations of patients with carcinoma of the biliary tree showed significant correlations of volume adjusted mean LiMAx with cell viability (r= 0.387;p= 0.046;n=20) and lacked significant correlations with total cell yield (r= - 0.060;p= 0.401;n=20) and viable cell yield (r= 0.012;p= 0.480;n=20). The volume-adjusted mean LiMAx did not show a significant correlation with any of the metabolic parameters. In conclusion, the LiMAx-test might be a useful tool to predict the quantitative outcome of hepatocyte isolation, as long as underlying liver disease is taken into consideration.
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Tags: Hepatocyte Isolation,Cell Culture,Cell Isolation,Cell Transplantation,Recellularization

Barbara Kern: BIH Charité Clinician Scientist
In: Grant written by: Prof. Dr. Igor M. Sauer
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Dr. Barbara Kern successfully applied for the BIH Charité Clinician Scientist Program. With her project "Novel Treatment and Diagnostic Approaches Utilizing the Role of Dendritic Cells in Immune Responsivness" Barbara will be engaged in our Vascular Tissue Allotransplantation Initiative (Project VCA). The Clinician Scientist Program is a modern career pathway within academic medicine that allows physicians to pursue a structured residency with time set aside for clinical and basic research. At the end of the program, participants will have completed their residency and, ideally, their postdoctoral teaching qualification (Habilitation). The program is intended to produce a new generation of scientists with translational training who will help speed up the rate at which scientific findings are translated into application.
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Tags: VCA,Transplantation

Future Medicine 2017
In: Presentations written by: Prof. Dr. Igor M. Sauer
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What’s trending? What’s new in health science? To find out, please save the date for the second Future Medicine in Berlin on November 7, 2017. Tagesspiegel and Berlin Institute of Health, together with Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, will feature outstanding international scientists, great visions of the future of medicine, and an exceptional concentration of knowledge. The four sessions of Future Medicine 2017 will be: 

Digital Health and Big Data
Precision Medicine and Predictive Models
Cell and Gene Therapies
Stem Cells and Human Disease Modeling  

Simon Moosburner, a student of medicine interested in regenerative medicine and future technologies, will talk about “Virtual & Mixed Reality: The Next Milestone in Surgery?” at Future Medicine 2017.
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Tags: Mixed Reality,Virtual Reality,Image Guided Surgery

21. Chirurgischen Forschungstage
In: Meetings |Presentations written by: Prof. Dr. Igor M. Sauer
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The 21. Chirurgische Forschungstage took place in Cologne. Five of our students gave terrific presentations: S. Moosburner gave an oral presentation on „Steatotic Liver Transplantation – a Growing Problem with Severe Complications“, H. Everwien on „Different biological scaffolds as a platform for engineering an endocrine Neo-Pancreas by using decellularization and recellularization techniques“, M. Noesser on „A comprehensive description of the development of a stable closed circuit for ex vivo rat liver machine perfusion“, R. Horner on „Is Percoll purifcation necessary for isolation of primary human hepatocytes?“, and N. Seiffert on „Recellularization of Decellularized Bovine Carotid Arteries using Human Endothelial Progenitor Cells: One Step towards an Autologous Bypass Graft“.
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Tags: Decellularization,Recellularization,Steatosis Hepatis,Liver Transplantation,Organ Perfusion

ESOT The Future of Transplantation
In: Meetings |Presentations written by: Prof. Dr. Igor M. Sauer
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The ESOT YPT Workshop and its Presidential Debate gives you a chance to engage with a variety of speakers in a lively ‘town hall’ format, as well as connecting with other young transplant professionals from around the world. The session will begin with talks from three key presenters on the past, present, and future of transplantation and open Q&As with each presenter. 

09:00– 10:35 - The future of transplantation: 3 lectures on Past, Present and Future CHAIRS: Alice Koenig, Lyon, France   Thomas Resch, Innsbruck, Austria
09:05 Lecture: The future of transplantation - Historical Perspective Sir Roy Calne, Cambridge, United Kingdom 09:25 Open Q&A with Roy Calne
09:35 Lecture: The future of transplantation - Present perspective Jan Lerut, Brussels, Belgium 09:55 Open Q&A with Jan Lerut
10:05 Lecture: The future of transplantation - Future perspective  Igor Sauer, Berlin, Germany
10:25 Open Q&A with Igor Sauer
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Tags: Transplantation

Mixed Reality in Visceral Surgery
In: Publications written by: Prof. Dr. Igor M. Sauer
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Annals of Surgery accepted our manuscript "Mixed Reality in visceral surgery - Development of a suitable workflow and evaluation of intraoperative use-cases" for publication. The paper evaluates the application of a mixed reality (MR) head-mounted display (HMD) for the visualization of anatomical structures in complex visceral-surgical interventions. A workflow was developed and technical feasibility was evaluated. 
Medical images are still not seamlessly integrated into surgical interventions and thus, remain separated from the surgical procedure. Surgeons need to cognitively relate two-dimensional sectional images to the three-dimensional (3D) during the actual intervention. MR applications simulate 3D images and reduce the offset between working space and visualization allowing for improved spatial-visual approximation of patient and image. The surgeon’s field of vision was superimposed with a 3D-model of the patient’s relevant liver structures displayed on a MR-HMD. This set-up was evaluated during open hepatic surgery. A suitable workflow for segmenting image masks and texture mapping of tumors, hepatic artery, portal vein and the hepatic veins was developed. The 3D model was positioned above the surgical site. Anatomical reassurance was possible simply by looking up. Positioning in the room was stable without drift and minimal jittering. Users reported satisfactory comfort wearing the device without significant impairment of movement. MR technology has high potential to improve the surgeon’s action and perception in open visceral surgery by displaying 3D anatomical models close to the surgical site. Superimposing anatomical structures directly onto the organs within the surgical site remains challenging since the abdominal organs undergo major deformations due to manipulation, respiratory motion and the interaction with the surgical instruments during the intervention. A further application scenario would be intraoperative ultrasound examination displaying the image directly next to the transducer. Displays and sensor-technologies as well as biomechanical modeling and object-recognition algorithms will facilitate the application of MR-HMD in surgery in the near future. Authors are I.M. Sauer, M. Queisner, P. Tang, S. Moosburner, O. Hoepfner, R. Horner, R. Lohmann and J. Pratschke.
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Tags: Mixed Reality,Head Mounted Displays,Surgical Techniques

Cells isolated from diseased explanted livers
In: Publications written by: Prof. Dr. Igor M. Sauer
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The International Journal of Artificial Organs (official journal of the European Society for Artificial Organs [ESAO]) published our paper on Isolation, characterization and cold storage of cells isolated from diseased explanted livers. Authors are Belaschk E, Rohn S, Mukiibi R, Reutzel-Selke A, Tang P, Sawitzki B, Pratschke J, Sauer IM and Mogl MT.

Livers discarded after standard organ retrieval are commonly used as a cell source for hepatocyte transplantation. Due to the scarcity of organ donors, this leads to a shortage of suitable cells for transplantation. Here, the isolation of liver cells from diseased livers removed during liver transplantation is studied and compared to the isolation of cells from liver specimens obtained during partial liver resection. Hepatocytes from 20 diseased explanted livers (Ex-group) were isolated, cultured and stored at 4°C for up to 48 hours, and compared to hepatocytes isolated from the normal liver tissue of 14 liver lobe resections (Rx-group). The nonparenchymal cell fraction (NPC) was analyzed by flow cytometry to identify potential liver progenitor cells, and OptiPrep™ (Sigma-Aldrich) density gradient centrifugation was used to enrich the progenitor cells for immediate transplantation. There were no differences in viability, cell integrity and metabolic activity in cell culture and survival after cold storage when comparing the hepatocytes from the Rx-group and the Ex-group. In some cases, the latter group showed tendencies of increased resistance to isolation and storage procedures. The NPC of the Ex-group livers contained considerably more EpCAM+ and significantly more CD90+ cells than the Rx-group. Progenitor cell enrichment was not sufficient for clinical application. Hepatocytes isolated from diseased explanted livers showed the essential characteristics of being adequate for cell transplantation. Increased numbers of liver progenitor cells can be isolated from diseased explanted livers. These results support the feasibility of using diseased explanted livers as a cell source for liver cell transplantation.
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Tags: Hepatocyte Isolation,Cell Culture,Cell Tracking,Transplantation

ECRT - Advanced Scientist Grant
In: Grant written by: Prof. Dr. Igor M. Sauer
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PD Dr. Nathanael Raschzok receives one of the 2017 Einstein Center for Regenerative Therapies (ECRT) Kickbox – Advanced Scientist Grant.
Einstein Center for Regenerative Therapies Kickbox – advanced scientist grant. The project is entitled „Overcoming steatotic compromise – Reconstitution of endogenous repair in severely steatotic liver grafts by metabolic reconditioning“. The project will be conducted by Nathanael Raschzok, Angelika Kusch, Duska Dragun, and Igor M. Sauer.

In order to stimulate excellent and creative research ideas that might take regenerative therapies a vital step forward, the Einstein Center offers a special two-stage funding scheme. At first, the Kickbox seed grant provides a great framework to investigate initial ideas and to develop sound research concepts. Subsequently, the flexible funds enable the realisation of projects that evolved from the Kickbox initiation phase in order to reach the scientific goals of the Einstein Center. Congratulations!
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Tags: Liver,Liver Support Therapy,Liver Transplantation,Steatosis Hepatis,Graft Reconditioning

Magnetic field and cells labeled with IO particles
In: Publications written by: Prof. Dr. Igor M. Sauer
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Our paper entitled "The magnetic field of magnetic resonance imaging systems does not affect cells labeled with micrometer-sized iron oxide particles," has been accepted for publication in Tissue Engineering, Part C: Methods. Authors are Martin Kluge, Annekatrin Leder, Karl H. Hillebrandt, Benjamin Struecker, Dominik Geisel, Timm Denecke, Rebeka D. Major, Anja Reutzel-Selke, Peter Tang, Steffen Lippert, Christian Schmidt, Johann Pratschke, Igor M. Sauer, and Nathanael Raschzok.

Labeling using iron oxide particles enables cell tracking via magnetic resonance imaging (MRI). However, the magnetic field can affect the particle-labeled cells. Here, we investigated the effects of a clinical MRI system on primary human hepatocytes labeled using micrometer-sized iron oxide particles (MPIOs).  HuH7 tumor cells were incubated with increasing concentrations of biocompatible, silica-based, micron-sized iron oxide-containing particles (sMPIO; 40 – 160 particles/cell). Primary human hepatocytes were incubated with 100 sMPIOs/cell. The particle-labeled cells and the native cells were imaged using a clinical 3.0-T MRI system, whereas the control groups of the labeled and unlabeled cells were kept at room temperature without exposure to a magnetic field. Viability, formation of reactive oxygen species, aspartate aminotransferase leakage, and urea and albumin synthesis were assessed over a culture period of 5 days. 
The dose finding study showed no adverse effects of the sMPIO labeling on HuH7 cells. MRI had no adverse effects on the morphology of the sMPIO-labeled primary human hepatocytes. Imaging using the T1- and T2-weighted sequences did not affect the viability, transaminase leakage, formation of reactive oxygen species, or metabolic activity of the sMPIO-labeled cells or the unlabeled, primary human hepatocytes. sMPIOs did not induce adverse effects on the labeled cells under the conditions of the magnetic field of a clinical MRI system.
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Tags: Cell Tracking,Microparticles,MRI,Cell Culture,Cell Transplantation

Charité BIH Entrepreneurship Summit
In: Meetings written by: Prof. Dr. Igor M. Sauer
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The Charité BIH Entrepreneurship Summit is a preeminent international cross-disciplinary forum for sharing and exploring the most important discoveries and emerging trends influencing the future of healthcare around the world.

Every year in May over 400 global leaders in healthcare innovation, including entrepreneurs, scientists, physicians, investors, policymakers, and business leaders convene at the Charité BIH Entrepreneurship Summit in the vibrant German capital of Berlin. We offer our participants a one-of-a-kind opportunity to meet with world-class specialists working at Charité & MDC, to build relationships with prominent international partners and experts working in the healthcare industry, and to help grow businesses.

This year's 10th Charité Entrepreneurship Summit will again take place at the Berlin-Brandenburg Academy of Sciences and Humanities on May 8 - 9, 2017. The Summit is significantly supported by the Berlin Institute of Health and focusses on 'Global Challenges of Healthcare'. Israel will be the official partner country for the Summit 2017. We are looking forward to learning more about the Israeli innovation & start-up culture, funding opportunities and challenges in Healthcare.

The Summit's two-day agenda will address a wide variety of topical issues including change of innovation culture, healthy aging & degenerative diseases, virtual reality and mental health. In addition, the Summit will seek to engage participants in lively discussions about business, science and the intersection of the two. Startups and Entrepreneurs are invited to apply for the LifeSciences VentureMarket, a platform to present their companies to a pool of international angels, venture investors, and corporate funds at this year's Summit.

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BIH Paper of the Month
In: Publications written by: Prof. Dr. Igor M. Sauer
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Benjamin Strücker, Hendrik Napierala and the rest of the team were awarded with the BIH Paper of the Month for their publication on a new method for developing a transplantable endocrine Neo-Pancreas.

 The BIH Paper of the Month is awarded by the BIH Board of Directors to honor a special publication achievement from the joint research space of Charité and MDC. The Paper of the Month is sponsored by the Stiftung Charité as part of its Johanna Quandt Private Excellence Initiative. 

H. Napierala, K.-H. Hillebrandt, N. Haep, P. Tang, M. Tintemann, J. Gassner, M. Noesser, H. Everwien, N. Seiffert, M. Kluge, E. Teegen, D. Polenz, S. Lippert, D. Geisel, A. Reutzel Selke, N. Raschzok, A. Andreou, J. Pratschke, I. M. Sauer & B. Struecker. Engineering an endocrine Neo-Pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans. Scientific Reports 7. Article number: 41777 (2017) doi:10.1038/srep41777
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Tags: Decellularization,Rezellularization,Pancreas,Diabetes

ECRT Kickbox - Junior Scientist Grant
In: Grant written by: Prof. Dr. Igor M. Sauer
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Karl Hillebrandt receives one of the 2017 Einstein Center for Regenerative Therapies (ECRT) Kickbox – Junior Scientist Grant. The project is entitled "Fighting liver cirrhosis? Establishment and analysis of decellularized human cirrhotic liver slices as a 3-dimensional model to study cell matrix interactions".

Liver cirrhosis is one of the main indications for liver transplantation. Due to the organ shortage, this therapy option is limited to the minority of patients suffering from cirrhosis. Therefore, there is a need of alternative treatment options.The aim of our project is to establish a decellularization protocol for human cirrhotic livers slices, which preserves the natural extracellular matrix (ECM) of cirrhotic livers. These decellularized liver slices will serve as a 3 dimensional model to study cell matrix interactions. If we are able to establish a protocol which will preserve the ECM, we will conduct in vitro recellularization experiments to study how the cirrhotic ECM will change the genotype and phenotype of different cell types. With this knowledge we aim to modify specific cell types in vivo or vitro for example prior to cell transplantation. Our ambition is to steer the cell matrix interaction via these modified cells after their transplantation and thereby halt or even reverse the progress of liver cirrhosis. This approach may offer an alternative treatment option in the future.

Team : Karl Hillebrandt, Oliver Klein, Ben Strücker, Igor Sauer  
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Tags: Decellularization,Rezellularization,Matrix

Einstein Visiting Fellow Prof. Stefan G. Tullius
In: General written by: Prof. Dr. Igor M. Sauer
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Prof. Dr. Stefan G. Tullius, Harvard Medical School, became Einstein BIH Visiting Fellow at the Charité, Department of Surgery. 

Vascular Composite Tissue Allotransplantation (VCA) has developed from a pioneering endevour to a clinical reality during the last 15 years. More than 150 extremity, face, knee, and most recently uterus and penis transplants have been performed during the last 15 years. VCA activities have been seen around the globe. Although feasibility of the procedure has been shown, it is still emerging and far from being a standard clinical procedure. 

The Charité has been an international leader in transplantation research for decades. However, neither VCA basic clinical research programs are currently offered in Berlin or Germany in a meaningful way.The involvement of Prof. Tullius as an Einstein BIH Visiting Fellow is expected to synergize and accelerate efforts igniting both a clinical research transplant program and a basic research group of excellence. The overall objective of our integrated basic and clinical research working group Vascular Composite Tissue Transplantation has three main goals:

To establish a basic Research group of Excellence: VCAs offer unique opportunities to study novel aspects of antigenicity, immune modulation and neo-vascularization. One important aspect that distinguishes VCA from solid organ transplants is their blood supply through a vascularized arterial in- and venous outflow in addition to sprouting new vessels at the large interface of VCA with recipient tissue.

To establish a clinical bio-repository as a pre-requisite for a clinical research VCA program.

To implement a clinical VCA research program (hand, abdominal wall, uterus) as a multi- disciplinary and translational effort.

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Tags: VCA,Uterus Transplantation,Hand Transplantation,Composite Tissue Transplantation

Engineering an endocrine Neo-Pancreas
In: Publications written by: Prof. Dr. Igor M. Sauer
Stacks Image 16595
Scientific Reports accepted our latest paper on „Engineering an endocrine Neo-Pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans“. Authors are H. Napierala, K. Hillebrandt, N. Haep, P. Tang, M. Tintemann, J. Gassner, M. Noesser, H. Everwien, N. Seiffert, M. Kluge, E. Teegen, D. Polenz, S. Lippert, D. Geisel, A. Reutzel-Selke, N. Raschzok, A. Andreou, J. Pratschke, I.M. Sauer, and B. Struecker.
Decellularization of pancreata and repopulation of these non-immunogenic matrices with islets and endothelial cells could provide transplantable, endocrine Neo- Pancreata. In this study, rat pancreata were perfusion decellularized and repopulated with intact islets, comparing three perfusion routes (Artery, Portal Vein, Pancreatic Duct). Decellularization effectively removed all cellular components but conserved the pancreas specific extracellular matrix. Digital subtraction angiography of the matrices showed a conserved integrity of the decellularized vascular system but a contrast emersion into the parenchyma via the decellularized pancreatic duct. Islets infused via the pancreatic duct leaked from the ductular system into the peri-ductular decellularized space despite their magnitude. TUNEL staining and Glucose stimulated insulin secretion revealed that islets were viable and functional after the process.
We present the first available protocol for perfusion decellularization of rat pancreata via three different perfusion routes. Furthermore, we provide first proof-of-concept for the repopulation of the decellularized rat pancreata with functional islets of Langerhans. The presented technique can serve as a bioengineering platform to generate implantable and functional endocrine Neo-Pancreata.
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Tags: Decellularization,Rezellularization,NeoPancreas,Islet Cells,Pancreas

Recellularization of rat livers: morphology and function
In: Publications written by: Prof. Dr. Igor M. Sauer
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The Journal of Tissue Engineering and Regenerative Medicine accepted our paper „Evolution of graft morphology and function after recellularization of decellularized rat livers“ for publication.

Decellularization of livers is a well-established procedure. Data on different reseeding techniques or the functional evolution and re-organization processes of repopulated grafts remains limited. 

We established a proprietary, customized bioreactor to repopulate decellularized rat livers (n=21) with primary rat hepatocytes (150 x 106 cells) via the hepatic artery and to subsequently evaluate graft morphology and function during seven days of ex vivo perfusion. Grafts were analyzed at 1h, 6h, 12h, 24h, 3d, 5d and 7d after recellularization (all n=3) by immunohistologic evaluation, hepatocyte-related enzyme (AST, ALT, LDH) and albumin measurement in the perfusate. 
To the best of our knowledge, this is the first available protocol for repopulation of rat livers via the hepatic artery. Within the first 24 hours after repopulation, the hepatocytes seemed to migrate out of the vascular network and form clusters in the parenchymal space around the vessels. Graft function increased for the first 24 hours after repopulation with a significantly higher function compared to standard 2D culture after 24 hours. Thereafter, graft function constantly decreased with significantly lower values after six and seven days of perfusion, although histologically viable hepatocytes were found even after this period. Our data suggests that due to a constant loss of function, repopulated grafts should potentially be implanted as soon as cell engraftment and graft re-organization are completed. 

Authors are Antje Butter, Khalid Aliyev, Karl-Herbert Hillebrandt, Nathanael Raschzok, Martin Kluge, Nicolai Seiffert, Peter Tang, Hendrik Napierala, Muhammad Imtiaz Ashraf, Anja Reutzel-Selke, Andreas Andreou, Johann Pratschke, Igor Maximilian Sauer, and Benjamin Struecker.
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Tags: Decellularization,Rezellularization,Liver,Transplantation

Vascular anatomy of the juvenile Göttingen minipig
In: Publications written by: Prof. Dr. Igor M. Sauer
Stacks Image 16630
Lab Animal accepted our „Computed tomography-based survey of the vascular anatomy of the juvenile Göttingen minipig“ for publication.

Over the past 50 years, image-guided procedures have been established for a wide range of applications. The development and clinical translation of new treatment regimens necessitate the availability of suitable animal models. The juvenile Göttingen minipig presents a favourable profile as a model for human infants. However, no information can be found regarding the vascular system of juvenile minipigs in the literature. Such information is imperative for planning the accessibility of target structures by catheterization.

We present here a complete mapping of the arterial system of the juvenile minipig based on contrast-enhanced computed tomography. Four female animals weighing 6.13 ± 0.72 kg were used for the analyses. Imaging was performed under anaesthesia, and the measurement of the vascular structures was performed independently by four investigators. Our dataset forms a basis for future interventional studies in juvenile minipigs, and enables planning and refinement of future experiments according to the 3R (replacement, reduction and refinement) principles of animal research.


Authors are J. Siefert, K.H. Hillebrandt, M. Kluge, D. Geisel, P. Podrabsky, T. Denecke, M. Nösser, J. Gassner, A. Reutzel-Selke, B. Strücker, M.H. Morgul, S. Guel-Klein, J.K. Unger, A. Reske, J. Pratschke, I.M. Sauer, and N. Raschzok.
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Tags: Mixed Reality,Virtual Reality,Digital Surgery

Monitoring of hepatocyte transplantation by MRI
In: Publications written by: Prof. Dr. Igor M. Sauer
Stacks Image 16640
A new book on Hepatocyte Transplantation Methods and Protocols, part of the series: Methods in Molecular Biology, Vol. 1506 P. Stock, B. Christ (Eds.), Springer, will be available end of November, 2016. We contributed a chapter on Preclinical swine models for monitoring of hepatocyte transplantation by MRI (authors: Nathanael Raschzok, Ulf Teichgräber, Johann Pratschke, and Igor M. Sauer) and are proud to provide the cover image.

This volume features up-to-date protocols for the isolation, preservation, and validation of various cell sources comprising large and small animal models, examining the impact of cell transplantation on acute and chronic liver diseases. Hepatocyte Transplantation: Methods and Protocols guides readers through laboratory protocols for the generation of humanized livers for the assessment of biological actions in vivo and techniques to monitor cell engraftment after cell transplantation in vivo are described and procedures for computational analyses of hepatocyte transplantation.

Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Comprehensive and practical, Hepatocyte Transplantation: Methods and Protocols is an essential resource for researchers and clinicians to assess the biological as well as the therapeutic potential of hepatocyte transplantation.
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Tags: Cell Transplantation,MRI,Particles

HCC: miRNA profiles of the tumor-surrounding tissue
In: Publications written by: Prof. Dr. Igor M. Sauer
Stacks Image 16657
The presence of hepatocellular carcinoma (HCC) is a significant complication of cirrhosis because it changes the prognosis and the treatment of the patients. By now, contrast-enhanced CT and MR scans are the most reliable tools for the diagnosis of HCC; however, in some cases, a biopsy of the tumor is necessary for the final diagnosis. The aim of the study was to develop a diagnostic tool using the microRNA (miRNA) profiles of the tissue surrounding the HCC tumor combined with clinical parameters in statistical models. At a transplantation setting, 32 patients with HCC and cirrhosis (B) were compared to 22 patients suffering from cirrhosis only (A). The diagnosis and exclusion of HCC was confirmed following the histopathological examination of the explanted liver.

The HCC patients were significantly older than the patients with cirrhosis only (B: 60.6 and A: 49.9, p<0.001) and showed higher levels of ALT (A: 0.76μkat/l, B: 1.02μkat/, p=0.006) and AFP (A: 5.8ng/ml, B: 70.3ng/ml, p<0.001), whereas the bilirubin levels were higher in the cirrhosis only group (p=0.002). Using age (cut-off 50.23years) and AFP (cut-off 4.2ng/ml) thresholds, the levels of expression of miR-1285-3p and miR-943 differentiated between the patients with HCC and cirrhosis from those with cirrhosis only with an accuracy of 96.3%. This is the first report about the use of stepwise penalized logistic regression and decision tree analyses of miRNA expressions in the tumor-surrounding tissue combined with clinical parameters for the diagnosis of HCC.

Authors are Mehmet Haluk Morgul, Sergej Klunk, Zografia Anastasiadou, Ulrich Gauger, Corinna Dietel, Anja Reutzel-Selke, Philipp Felgendref, Hans-Michael Hau, Hans-Michael Tautenhahn, Rosa Bianca Schmuck, Nathanael Raschzok, Igor Maximillian Sauer, and Michael Bartels. Exp Mol Pathol. 2016 Aug 20;101(2):165-171. doi: 10.1016/j.yexmp.2016.07.014. [Epub ahead of print]
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Tags: miRNA

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