Cells isolated from diseased explanted livers

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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.

Int J Artif Organs. 2017 May 23:0. doi: 10.5301/ijao.5000594. [Epub ahead of print]

Magnetic field and cells labeled with IO particles

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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.

BIH Paper of the Month...

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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

You may download the publication here.

Engineering an endocrine Neo-Pancreas

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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.

Recellularization of rat livers: morphology and function

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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 liversfor 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.

Vascular anatomy of the juvenile Göttingen minipig

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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.
Update: Now available via Lab Anim. 2016 Dec 8. pii: 0023677216680238. [Epub ahead of print]

Monitoring of hepatocyte transplantation by MRI

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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.

HCC: miRNA profiles of the tumor-surrounding tissue

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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]

Bile: miRNA Pattern post OLT

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BIOMARKERS accepted our latest paper on "Bile: miRNA Pattern and Protein Based Biomarkers May Predict Acute Cellular Rejection after Liver Transplantation" for publication. Authors are Rosa Bianca Schmuck, Anja Reutzel-Selke, Nathanael Raschzok, Mehmet Haluk Morgul, Benjamin Struecker, Steffen Lippert, Cynthia de Carvalho Fischer, Moritz Schmelzle, Sabine Boas-Knoop, Marcus Bahra, Andreas Pascher, Johann Pratschke, and Igor M. Sauer.

Bile rather than blood depicts the local inflammation in the liver and may improve prediction and diagnosis of acute cellular rejection (ACR) after liver transplantation (OLT). Secretome and miRNAs were analyzed during the first two weeks and on clinical suspicion of ACR in the bile of 45 OLT recipients. Levels of CD44, CXCL9, miR-122, miR-133a, miR-148a and miR-194 were significantly higher in bile of patients who developed ACR within the first 6 months after OLT and during ACR. Analysis of secretome and miRNA in bile could further our understanding of the local inflammatory process during rejection.

Biomarkers. 2016 Aug 5:1-9. [Epub ahead of print]

Hepatocyte isolation after laparoscopic liver resection

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Tissue Engineering, Part C: Methods accepted our paper entitled "Hepatocyte isolation after laparoscopic liver resection" for publication. Authors are Horner R*, Kluge M*, Gassner J, Nösser M, Major RD, Reutzel-Selke A, Leder AK, Struecker B, Morgul MH, Pratschke J, Sauer IM, Raschzok N (*contributed equally).

Liver tissue obtained from partial hepatectomy is a common source for isolation of primary human hepatocytes. Until now, liver resections were most commonly performed by conventional open surgery. Although the laparoscopic approach is currently emerging in liver surgery, data on the outcome of hepatocyte isolation from laparoscopically resected liver tissue is not available.
A total of 22 hepatocyte isolations were performed using the two-step collagenase perfusion technique from October 2015 until March 2016. Liver tissue was obtained from n=15 open liver resections (OLR) and n=7 laparoscopic liver resections (LLR). Isolation parameters (cell yield, viability, percoll survival) were assessed and hepatocyte function (plating efficiency, urea, albumin, and aspartate aminotransferase) was measured over a culture period of 6 days (OLR: n=13; LLR: n=3).
Total cell yield (OLR: 36.81 ± 6.77 x106 cells/g vs. LLR 16.84 ± 10.66 x106 cells/g, p=0.0318) as well as viable yield (OLR 31.70 ± 6.05 x106 cells/g vs. LLL 14.70 ± 9.89 x106 cells/g, p=0.0260) were significantly higher in the OLR group. Subgroup analysis revealed that the worse outcome of isolation of laparoscopically resected liver tissue was associated with right-lateral laparoscopic liver resections, while hepatocyte isolation from left-lateral laparoscopic liver resections was as effective as from open surgery. Hepatocyte function did not differ between hepatocytes from openly resected versus left-lateral laparoscopically resected liver tissue.
We here present the first data on hepatocyte isolation from laparoscopic liver surgery. While the overall outcome is worse compared to open surgery, our data suggest that liver tissue from laparoscopic resection of the left lobe is an excellent source for primary human hepatocytes.

NeoHybrid liver graft – proof of concept

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Cells Tissues Organs accepted our latest paper on "Allogeneic liver transplantation and subsequent syngeneic hepatocyte transplantation in a rat model – proof of concept for in vivo tissue engineering" for publication.
Authors are Susanne Rohn, Jan Schroeder, Henriette Riedel, Dietrich Polenz, Katarina Stanko, Anja Reutzel-Selke, Peter Tang, Lydia Brusendorf, Nathanael Raschzok, Peter Neuhaus, Johann Pratschke, Birgit Sawitzki, Igor M. Sauer, and Martina T. Mogl.

Aim of the project was the evaluation of a new concept for in vivo tissue engineering using autologous primary human hepatocytes and hepatic progenitor cells isolated from diseased livers explanted during orthotopic liver transplantation (LTx). Cells will be isolated and infused into the spleen for repopulation of the allogeneic liver graft. The latter is serving as biological matrix for the engraftment of autologous cells. Once these cells have engrafted, it is assumed that autologous cells will repopulate the allogeneic liver, since they should have a selective advantage due to their autologous origin. It is postulated that this will lead to a neo-hybrid liver graft, reducing immunogenicity and inducing immunoregulation thus minimizing the need for extensive immunosuppression and eventually inducing operational tolerance.
We therefore developed a new rat model for combined liver and liver cell transplantation under stable immunosuppression. Immunohistochemistry demonstrated the engraftment of transplanted cells, as confirmed by fluorescence in-situ hybridization, showing repopulation of the liver graft with 15.6 % male cells (± 1.8 SEM) at day 90. The quantitative PCR revealed 14.15 % (mean ± 5.09 SEM) male DNA at day 90. Engraftment of transplanted autologous cells after combined liver and cell transplantation was achieved for up to 90 days under immunosuppression. Immunohistochemistry indicated cell proliferation, and the fluorescence in-situ hybridization results were partly confirmed by quantitative RT-PCR. This new protocol in rats appears feasible to address long-term function and eventually induction of operational tolerance in the future.

LTx – microRNA signatures in peripheral blood ?

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BIOMARKERS accepted our latest paper on „microRNA signatures in peripheral blood fail to detect acute cellular rejection after liver transplantation“ for publication. Authors are N. Raschzok, A. Reutzel-Selke, R. Schmuck, L. Tannus, M. Morgul, C. Dietel, A. Leder, B. Struecker, S. Lippert, H. Sallmon, M. Schmelzle, M. Bartels, S. Jonas, J. Pratschke, and I.M. Sauer.

We investigated whether microRNA signatures in whole blood samples are associated with acute cellular rejection (ACR) after liver transplantation. Blood samples were collected using Paxgene technology and analyzed by microarrays and qRT-PCR.
microRNA signatures failed to distinguish between 19 patients with ACR and 16 controls. Let-7b-5p and let-7c were up-regulated in a subgroup of patients with ACR during the 6th and 7th postoperative day but failed in an independent validation of 20 patients.
microRNA signatures in whole blood processed by Paxgene technology are not suited for detection of ACR after liver transplantation.

Single Pass Albumin Dialysis – Dose finding study

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Artificial Organs accepted our paper „Single Pass Albumin Dialysis (SPAD) – A dose finding study to define optimal albumin concentration and dialysate flowfor publication.
Authors are R.B. Schmuck, G.-H. Nawrot, P. Fikatas, A. Reutzel-Selke, J. Pratschke, and I.M. Sauer.

Aim of these studies was to define the optimal conditions for SPAD in a standardized experimental set-up. Albumin concentration was adjusted to either 1%, 2%, 3%, or 4%, while the flow rate of the dialysate was kept constant at a speed of 700 ml/h. The flow rate of the dialysate was altered between 350, 500, 700, and 1000 ml/h, whereas the albumin concentration was continuously kept at 3%.
This study revealed that the detoxification of albumin bound substances could be improved by increasing the concentration of albumin in the dialysate with an optimum at 3%. A further increase of the albumin concentration to 4% did not lead to a significant increase in detoxification. Furthermore, we observed a gradual increase of the detoxification efficiency for albumin bound substances, from 350 ml/h to 700 ml/h (for bilirubin) or 1000 ml/h (for bile acids) of dialysate flow. Water-soluble toxins (ammonia, creatinine, urea, uric acid) were removed almost completely, regardless of albumin concentration or flow rate.

Implantation of a Neo Bile Duct in domestic pigs

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European Surgical Research accepted our latest paper entitled "Implantation of a tissue engineered Neo Bile Duct in domestic pigs" for publication. Authors are B. Struecker, K. Hillebrandt, N. Raschzok, K. Jöhrens, A. Butter, P. Tang, A. Andreou, H. Napierala, D. Polenz, A. Reutzel-Selke, T. Denecke, J. Pratschke, and I.M Sauer.

Extrahepatic bile duct injuries remain severe complications during cholecystectomy and often require reconstruction by bilioenteric anastomosis (i.e. hepatico-jejunostomy), which comes along with further long-term complications (e.g. recurring ascending cholangitis, secondary biliary cirrhosis). Furthermore, in case of inherent extrahepatic biliary atresia or during liver transplant artificial or engineered bile ducts could enable novel surgical strategies without the need for hepatico-jejunostomy. We present data on the implantation of in vitro generated Neo Bile Ducts in five domestic pigs. Neo Bile Ducts were engineered through decellularization of allogeneic blood vessels and recellularization with autologous cholangiocytes.On postoperative days 0, 1, 7 and 14 blood samples were taken and analyzed (AST, ALT, Bilirubin, Alkaline Phosphatase, Creatinine and Leukocytes). An magnetic resonance cholangiography was performed on postoperative day 14 with one pig. 14 days after implantation pigs were sacrificed and bile ducts were explanted. All pigs survived the complete study period without severe complications. None of the pigs showed signs of biliary leakage or peritonitis. Neo Bile Ducts were infiltrated by neutrophils and neo-angiogenesis was observed around and into the implanted tissue. Whether the presented technique enables the long-term replacement of native bile ducts has to be further evaluated.

Human hepatocyte isolation – new paper

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Tissue Engineering, Part C: Methods accepted our paper „Human hepatocyte isolation: Does portal vein embolization affect the outcome?“ Authors are Martin Kluge, Anja Reutzel-Selke, Hendrik Napierala, Karl H. Hillebrandt, Rebeka D. Major, Benjamin Struecker, Annekatrin Leder, Jeffrey Siefert, Peter Tang, Steffen Lippert, Daniel Seehofer, Johann Pratschke, Igor M. Sauer und Nathanael Raschzok.

Primary human hepatocytes are widely used for basic research, pharmaceutical testing, and therapeutic concepts in regenerative medicine. Human hepatocytes can be isolated from resected liver tissue. Preoperative portal vein embolization (PVE) is increasingly used to decrease the risk of delayed postoperative liver regeneration by induction of selective hypertrophy of the future remnant liver tissue. The aim of this study was to investigate the effect of PVE on the outcome of hepatocyte isolation. Primary human hepatocytes were isolated from liver tissue obtained from partial hepatectomies (n=190) using the two-step collagenase perfusion technique followed by Percoll purification. Of these hepatectomies, 27 isolations (14.2%) were performed using liver tissue obtained from patients undergoing PVE prior to surgery. All isolations were characterized using parameters that had been described in the literature as relevant for the outcome of hepatocyte isolation. The PVE and non-PVE groups were similar in regard to donor parameters (sex, age, indication for surgery), isolation parameters (liver weight, cold ischemic time), and the quality of the liver tissue. The mean initial viable cell yield did not differ between the PVE and non-PVE groups (10.16±2.03x106 cells/g vs. 9.70±0.73 x106 cells/g, p=0.499). The initial viability was slightly better in the PVE-group (77.8 ±2.03% vs. 74.4 ±1.06%). The mean viable cell yield (p=0.819) and the mean viability (p=0.141) after Percoll purification did not differ between the groups. PVE had no effect on enzyme leakage and metabolic activity of cultured hepatocytes.
Although PVE leads to drastic metabolic alterations and changes in hepatic blood flow, embolized liver tissue is a suitable source for the isolation of primary human hepatocytes and is equivalent to untreated liver tissue in regard to cell yield and viability.

The Morning After

Referring to our paper „CD44 and CXCL9 serum protein levels predict the risk of clinically significant allograft rejection after liver transplantation“ Geoffrey W. McCaughan, Patrick Bertolino and David G. Bowen wrote an interesting editorial entitled „Could The Morning After liver transplant be immunologically interesting?“

They conclude, „that our study urges us to study the immune system response in liver allograft recipients during the very early phases after liver transplantation and to explore how events in immune organs and the allograft are reflected within the serum. Whether the patterns observed truly represent early detection of ACR versus tolerance, or a combination of both, requires further study and experimentation, including the identification of the cellular sources of these and other potential markers of immune outcome. It seems that despite significant levels of immunosuppressive drugs, immune activation and engagement occurs very early after human liver transplant, within the first 24 hours, in a manner that may have similarities with experimental animal models. Thus, the morning after effect could be an exciting window to longer-term immune outcomes, rather than just being preoccupied with observing important routine outcomes and detecting early complications.“ See Liver Transplantation, Volume 21, Issue 9, pages 1120–1122, September 2015

Publication in Jove

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„Procedure for Decellularization of Rat Livers in an Oscillating-pressure Perfusion Device“ is available in J Vis Exp. 2015 Aug 10;(102). doi: 10.3791/53029 – accessible via the JOVE servers. Authors are K. Hillebrandt, D. Polenz, A. Butter, P. Tang, A. Reutzel-Selke, A. Andreou, H. Napierala, N. Raschzok, J. Pratschke, I.M. Sauer, and B. Struecker . The presented techniques for liver harvesting, cannulation and perfusion using our proprietary device enable sophisticated perfusion set-ups to improve decellularization and recellularization experiments in rat livers.

microRNAs in liver tissue engineering

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Our paper "microRNAs in liver tissue engineering - New promises for failing organs" was accepted for publication in Advanced Drug Delivery Reviews (IF: 15.038). Authors are Nathanael Raschzok, Hannes Sallmon, Johann Pratschke and Igor M. Sauer.

miRNA-based technologies provide attractive tools for several liver tissue engineering approaches. Herein, we review the current state of miRNA applications in liver tissue engineering. Several miRNAs have been implicated in hepatic disease and proper hepatocyte function. However, the clinical translation of these findings into tissue engineering has just begun. miRNAs have been successfully used to induce proliferation of mature hepatocytes and improve the differentiation of hepatic precursor cells. Nonetheless, miRNA-based approaches beyond cell generation have not yet entered preclinical or clinical investigations. Moreover, miRNA-based concepts for the biliary tree have yet to be developed. Further research on miRNA based modifications, however, holds the promise of enabling significant improvements to liver tissue engineering approaches due to their ability to regulate and fine-tune all biological processes relevant to hepatic tissue engineering, such as proliferation, differentiation, growth, and cell function.

CD44 and CXCL9 predicting rejection after LTx

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Based on a fruitful collaboration with the department of Visceral, Transplantation, Thoracic, and Vascular Surgery at the University of Leipzig our paper on CD44 and CXCL9 serum protein levels predict the risk of clinically significant allograft rejection after liver transplantationhas been accepted for publication in Liver Transplantation.
Authors are Nathanael Raschzok, Anja Reutzel-Selke, Rosa Bianca Schmuck, Mehmet Haluk Morgul, Ulrich Gauger, Kukuh Aji Prabowo, Laura-Marie Tannus, Annekatrin Leder, Benjamin Struecker, Sabine Boas-Knoop, Michael Bartels, Sven Jonas, Christian Lojewski, Gero Puhl, Daniel Seehofer, Marcus Bahra, Andreas Pascher, Johann Pratschke, and Igor Maximilian Sauer.

The diagnosis of acute cellular rejection (ACR) after liver transplantation is based on histological analysis of biopsies because non-invasive biomarkers for allograft rejection are not yet established for clinical routines. CD31, CD44, and CXCL9 have previously been described as biomarkers for cross-organ allograft rejection. Here, we assessed the predictive and diagnostic value of these proteins as serum biomarkers for clinically significant ACR in the first six months after liver transplantation in a prospective study. The protein levels were measured in 94 patients immediately prior to transplantation, at postoperative days (POD) 1, 3, 7, and 14, and when biopsies were performed during episodes of biochemical graft dysfunction. Our results suggest that CD44 and CXCL9 may serve as predictive biomarkers to identify liver allograft recipients at risk for clinically significant ACR.

Cover – march issue of Tissue Engineering

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One of the figures of our paper „Porcine liver decellularization under oscillating pressure conditions – A technical refinement to improve the homogeneity of the decellularization process“ made it to the cover of the march issue of Tissue Engineering, Part C : Methods.

Congratulations to Dietrich Polenz, who made the corrosion cast of a decellularized pig liver matrix: red, hepatic artery; blue, portal vein; yellow, bile duct and gallbladder.

Particles for microRNA-targeted manipulation

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Biomaterials accepted our paper on „Micron-sized iron oxide-containing particles for microRNA-targeted manipulation and MRI-based tracking of transplanted cells“. Authors are Annekatrin Leder, Nathanael Raschzok, Christian Schmidt, Duygu Arabacioglu, Antje Butter, Susanne Kolano, Luisa S. de Sousa Lisboa, Wiebke Werner, Dietrich Polenz, Anja Reutzel-Selke, Johann Pratschke, and Igor M. Sauer.

Particle-based delivery systems for therapeutic manipulation and tracking of transplanted cells by magnetic resonance imaging (MRI) are commonly based on nanometer-sized superparamagnetic iron oxide particles (SPIOs). Here, we present a proof of concept for multifunctional, silica based micron-sized iron oxide-containing particles (sMPIO) that combine fluorescence imaging, MRI tracking, and on-the-spot targeting of specific microRNAs on a particle surface for therapeutic manipulation by RNA interference. Antisense locked nucle-LNA) were covalently bound to the surface of silica-based, DAPI-integrated, micron-sized iron oxide particles (sMPIO--LNA). In vitro studies using primary human hepatocytes showed rapid particle uptake (4 hours) that was accompanied by significant depletion of the targeted microRNA Let7g (80%), up- regulation of the target proteins Cyclin D1 and c-Myc, and specific proteome changes. sMPIO--LNA- labeled cells were successfully detected by fluorescence imaging and could be visualized by MRI after intrasplenic transplantation in rats. This new theranostic particle provides a promising tool for cell transplantation where cellular imaging and microRNA-based manipulation is needed.

Biomaterials is the leading journal in its field. Impact factors released by ISI in July 2014 showed Biomaterials with an impact factor of 8.312!

UPDATE: The paper is available online here!

Sham Laparotomy and microRNA Expression in Rats

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BMC Research Notes accepted our latest paper on „Independent Effects of Sham Laparotomy and Anesthesia on Hepatic microRNA Expression in Rats“ for publication.

Studies on liver regeneration following partial hepatectomy (PH) have identified several microRNAs (miRNAs) that show a regulated expression pattern. These studies involve major surgery to access the liver, which is known to have intrinsic effects on hepatic gene expression and may also affect miRNA screening results. We performed two-third PH or sham laparotomy (SL) in Wistar rats to investigate the effect of both procedures on miRNA expression in liver tissue and corresponding plasma samples by microarray and qRT-PCR analyses. As control groups, non-treated rats and rats undergoing anesthesia only were used. We found that 49 out of 323 miRNAs (15%) were significantly deregulated after PH in liver tissue 12 to 48 hours postoperatively (>20% change), while 45 miRNAs (14%) were deregulated following SL. Out of these miRNAs, 10 miRNAs were similarly deregulated after PH and SL, while one miRNA showed opposite regulation. In plasma, miRNA upregulation was observed for miR-133a and miR-133b following PH and SL, whereas miR-100 and miR-466c were similarly down-regulated following anesthesia and surgery. We show that miRNAs are indeed regulated by sham laparotomy and anesthesia in rats. These findings illustrate the critical need for finding appropriate control groups in experimental surgery.

Authors are W. Werner, H. Sallmon, A. Leder, S. Lippert, A. Reutzel-Selke, M.H. Morgül, S. Jonas, S. Dame, P. Neuhaus, J. Iacomini, S.G. Tullius, I.M. Sauer and N. Raschzok.

Textbook of Organ Transplantation Set

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Brought to you by the world’s leading transplant clinicians, Textbook of Organ Transplantation provides a complete and comprehensive overview of modern transplantation in all its complexity, from basic science to gold-standard surgical techniques to post-operative care, and from likely outcomes to considerations for transplant program administration, bioethics and health policy.
Beautifully produced in full color throughout, and with over 600 high-quality illustrations, it successfully
- Provides a solid overview of what transplant clinicians/surgeons do, and with topics presented in an order that a clinician will encounter them.
- Presents a holistic look at transplantation, foregrounding the interrelationships between transplant team members and non-surgical clinicians in the subspecialties relevant to pre- and post-operative patient care, such as gastroenterology, nephrology, and cardiology.
- Offers a focused look at pediatric transplantation, and identifies the ways in which it significantly differs from transplantation in adults.
- Includes coverage of essential non-clinical topics such as transplant program management and administration; research design and data collection; transplant policy and bioethical issues.

Editors are Allan D. Kirk, Stuart J. Knechtle, Christian P. Larsen, Joren C. Madsen, Thomas C. Pearson, and Steven A. Webber.
I.M. Sauer, N. Raschzok und P. Neuhaus contributed chapter 47: „Artificial Liver, In Vivo Tissue Engineering, and Organ Printing – Solutions for Organ Scarcity“

The Wiley-Blackwell book (ISBN: 978-1-118-87014-3, 1880 pages) is available here.

Decellularization of porcine livers

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Ben Strücker’s paper entitled „Porcine liver decellularization under oscillating pressure conditions – A technical refinement to improve the homogeneity of the decellularization process“ has been accepted for publication in Tissue Engineering, Part C: Methods.
Co-authors are K. Hillebrandt, R. Voitl, A. Butter, R.B. Schmuck, A. Reutzel-Selke, D. Geisel, K. Joehrens, P.A. Pickerodt, N. Raschzok, G. Puhl, P. Neuhaus, J. Pratschke, and I.M. Sauer.

Decellularization and recellularization of parenchymal organs may facilitate the generation of autologous functional liver organoids by repopulation of decellularized porcine liver matrices with induced liver cells. We present an accelerated (7 h overall perfusion time) and effective protocol for human scale liver decellularization by pressure-controlled perfusion with 1% Triton X-100 and 1% SDS via the hepatic artery (120 mmHg) and portal vein (60 mmHg). In addition, we analyzed the effect of oscillating pressure conditions on pig liver decellularization (n=12). The proprietary perfusion device used to generate these pressure conditions mimics intra-abdominal conditions during respiration to optimize microperfusion within livers and thus optimize the homogeneity of the decellularization process. The efficiency of perfusion decellularization was analyzed by macroscopic observation, histological staining (H&E, Sirius red, Alcian blue), immunohistochemical staining (collagen IV, laminin, fibronectin) and biochemical assessment (DNA, collagen, glycosaminoglycans) of decellularized liver matrices. The integrity of the extracellular matrix post-decellularization was visualized by corrosion casting and three-dimensional CT scanning. We found that livers perfused under oscillating pressure conditions (P+) showed a more homogenous course of decellularization and contained less DNA compared to livers perfused without oscillating pressure conditions (P-). Microscopically, livers from the (P-) group showed remnant cell clusters, while no cells were found in livers from the (P+) group. The grade of disruption of the ECM was higher in livers from the (P-) group, although the perfusion rates and pressure did not significantly differ. Immunohistochemical staining revealed that important matrix components were still present after decellularization. Corrosion casting showed an intact vascular (portal vein and hepatic artery) and biliary framework. In summary, the presented protocol for pig liver decellularization is quick (7 h) and effective. The application of oscillating pressure conditions improves the homogeneity of perfusion and thus the outcome of the decellularization process.

N. Raschzok Guest Editor – Call for Papers

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Pluripotent stem cells have been an important tool for researches in hepatology, starting with mouse embryonic stem cells and transgenesis. Together, with other animal models, they largely contributed to our current knowledge in hepatic cells development and disease modeling. Therefore, with the possibility to manipulate human embryonic stem cells and more recently human induced pluripotent stem cells, there was an existing substratum to study these processes in a human environment, which contributed to the tremendous explosion of the emerging Liver Regenerative Medicine field. The use of such cells in the last few years has been already at the origin of numerous breakthroughs in disease modeling, host-pathogen interactions studies, or liver bioengineering and many are to come.

Investigators are invited to participate in a special issue on „Human Pluripotent Stem Cells in Hepatic Development, Liver Reconstruction and Disease Modeling“ through original research articles at the forefront of this fast pace moving field as well as reviews describing current and forthcoming challenges.

Lead Guest Editor is Karim Si-Tayeb (Institute of the Thorax, Nantes). Guest Editors are Gareth Sullivan (Institute of Basic Medical Sciences, University of Oslo), Robert Schwartz (Weill Cornell Medical College, Cornell University, New York), Nathanael Raschzok (Charité – Universitaetsmedizin Berlin), and Tamir Rashid (King's College London).

Manuscript Due: Friday, 23 January 2015
First Round of Reviews: Friday, 17 April 2015
Publication Date: Friday, 12 June 2015


More information ...

Decellularization and oscillating pressure conditions

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The Journal of Tissue Engineering and Regenerative Medicine accepted our latest paper on „Improved rat liver decellularization by arterial perfusion under oscillating pressure conditions“ for publication. Authors are B. Struecker, A. Butter, K. Hillebrandt, D. Polenz , A. Reutzel-Selke, P. Tang, S. Lippert, A. Leder, S. Rohn, D. Geisel, T. Denecke, K. Aliyev, K. Jöhrens, N. Raschzok, P. Neuhaus, J. Pratschke and I.M. Sauer.

One approach of regenerative medicine to generate functional hepatic tissue in vitro is de- and recellularization and several protocols for the decellularization of different species have been published. To the best of our knowledge this is the first report on rat liver decellularization by perfusion via the hepatic artery under oscillating pressure conditions, intending to optimize microperfusion and minimize damage to the ECM. Four decellularization protocols were compared: perfusion via the portal vein (PV) or the hepatic artery (HA), with (+P) or without (-P) oscillating pressure conditions. All rat livers (n=24) were perfused with 1% Triton X-100 and 1% SDS, each for 90 minutes with a perfusion rate of 5ml/min. Perfusion decellularization was observed macroscopically and the decellularized liver matrices (DLMs) were analyzed by histology and biochemical analyses (e.g., levels of DNA, glycosaminoglycans (GAG), and hepatocyte growth factor (HGF). Livers decellularized via the hepatic artery and under oscillating pressure showed a more homogenous decellularization and less remaining DNA, compared to livers of the other experimental groups. The novel decellularization method described is effective, quick (3 hours) and gentle to the ECM and thus represents an improvement of existing methodology. 

Nature Reviews Gastroenterology and Hepatology

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Nature Reviews Gastroenterology and Hepatology invited us to provide a review on liver support strategies.

The treatment of end-stage liver disease and acute liver failure remains a clinically relevant issue. Although orthotopic liver transplantation is a well-established procedure, whole-organ transplantation is invasive and increasingly limited by the unavailability of suitable donor organs. Artificial and bioartificial liver support systems have been developed to provide an alternative to whole organ transplantation, but despite three decades of scientific efforts, the results are still not convincing with respect to clinical outcome. In this Review, conceptual limitations of clinically available liver support therapy systems are discussed. Furthermore, alternative concepts, such as hepatocyte transplantation, and cutting-edge developments in the field of liver support strategies, including the repopulation of decellularized organs and the biofabrication of entirely new organs by printing techniques or induced organogenesis are analysed with respect to clinical relevance. Whereas hepatocyte transplantation shows promising clinical results, at least for the temporary treatment of inborn metabolic diseases, so far data regarding implantation of engineered hepatic tissue have only emerged from preclinical experiments. However, the evolving techniques presented here raise hope for bioengineered liver support therapies in the future.


Update: The review „Liver support strategies: cutting-edge technologies“ (authors: Benjamin Struecker, Nathanael Raschzok & Igor M. Sauer) is now available here.

Functionalizable silica-based MPIO for cellular MRI

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Our latest manuscript entitled "Functionalizable silica-based micron-sized iron oxide particles for cellular Magnetic Resonance Imaging" was accepted for publication in the journal "Cell Transplantation".

Cellular therapies require methods for non-invasive visualization of transplanted cells. Micron-sized iron oxide particles (MPIOs) generate strong contrast in
Magnetic Resonance Imaging (MRI) and are therefore ideally suited as an intracellular contrast agent to image cells under clinical conditions. However,
MPIOs were previously not applicable for clinical use. Here, we present the development and evaluation of silica-based micron-sized iron oxide particles
(sMPIOs) with a functionalizable particle surface.


UPDATE: The paper is now available (Cell Transplant. 2013; 22(11): 1959-1570)

Noninvasive monitoring of liver cell transplantation

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Our latest review on „Noninvasive monitoring of liver cell transplantation“ (authors are N. Raschzok, H.M. Morgül, L. Stelter & I.M. Sauer) is available in Imaging in Medicine, 2013; 5: 47-61:
Liver cell transplantation was developed as a therapeutic alternative to solid liver transplantation in the management of liver-based metabolic disorders and may be useful for the treatment of acute or chronic liver failure. While clinical studies have demonstrated temporal amelioration of the symptoms of metabolic liver disorders by transplanted liver cells, the long-term outcome of liver cell transplantation is still insufficient. A major limitation for improving liver cell transplantation is the inability to track the fate of cells once they have been infused. Radionuclide-based imaging, MRI and optical methods have been investigated as methods for noninvasive monitoring of liver cell transplantation. This article summarizes and critically discusses these approaches, with a special focus on MRI-based tracking of transplanted liver cells and provides an outlook on possible clinical applications for the near future.

Einladung zur öffentlichen Abschlußpräsentation

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Sehr geehrte Damen und Herren,
Dear ladies and gentlemen,

Sie sind herzlich eingeladen, unserer öffentlichen Abschlusspräsentation unseres EU/EFRE-Projekts am 20.03.2013 um 15:00 Uhr beizuwohnen. Zusammen mit unseren Partnern der Firma microparticles GmbH werden wir den aktuellen Stand zur „Entwicklung von Partikel zur Detektion und ultralokoregionären Stimulation transplantierter Leberzellen“ darlegen.
You are cordially invited to attend our public presentation of our EU/EFRE project. Together with our partners of microparticles GmbH we will present our latest results concerning the „Development of particles for detection and ultralocoregional stimulation of transplanted liver cells“.

Wann/When?
20.03.2013 um/at 15:00

Wo/Where?
Experimentelle Chirurgie und Regenerative Medizin
Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
Charité, Campus Virchow-Klinikum
Forschungshaus/BMFZ
Pilzraum, 1.OG

Wir wären dankbar, wenn Sie Ihr Kommen via email (anja.selke@charite.de)bestätigen könnten.
RSVP via email (anja.selke@charite.de).

MRI and ectopic liver cell transplantation – new paper

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Nathanael Raschzok’s latest paper on „Feasibility of fast dynamic MRI for noninvasive monitoring during ectopic liver cell transplantation to the spleen in a porcine model“ is now available in AJR Am J Roentgenol. 2012 Jun;198(6):1417-23.
Liver cell transplantation is a promising approach for the treatment of metabolic liver disorders. However, a method for noninvasive monitoring during liver cell transplantation is not available clinically. The aim of this study was to investigate the feasibility of fast dynamic MRI monitoring during liver cell infusion to the spleen, which is considered an ectopic implantation site for liver cell transplantation. Porcine liver cells were labeled with micron-sized iron oxide particles and infused to the spleens of pigs (n = 5) via the lineal artery. MRI was performed using a 3-T MR scanner. Initially, T1- and T2-weighted pulse sequences were tested. Thereafter, fast dynamic MRI was performed during cell infusion. MR findings were verified by immunohistological examinations.

Images from static MRI (TR/TE, 2500/105.2) showed significantly lower signal intensity and signal-to-noise ratio after cell infusion compared with pretransplant images. T2-weighted fast dynamic MRI enabled visualization of signal decrease of the spleen during cell infusion. When cells were infused systemically, no signal changes in the spleen were observed. This study shows that fast dynamic MRI can enable noninvasive monitoring during liver cell transplantation to the spleen. This approach could be useful for preclinical studies and for quality control of clinical liver cell transplantation.

SlideObserver in Journal of Biotechnology

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The combined meeting of World Apheresis Association (WAA) 11 th Congress and 6 th World Congress of the International Society for Apheresis (ISFA) will take place in Pacifico Yokohama Yokohama, Japan, from March 2―4, 2007. WAA federates many national, continental and international societies for hemapheresis and transfusion science, and ISFA is a representative international society for therapeutic apheresis. They have contributed to the development of these scientific fields for many years.
These two societies serve a regular meeting every two years. This is the first combined congress of the two Societies. It is really an anniversary congress. Many lecture, symposium, workshop and seminars are planned in the congress. Highly scientific papers will be presented at free communications and poster sessions. Several supports will be provided to the participants from developing countries. At the same period, 27 th Annual Meeting of Japanese Society for Apheresis (JSFA) will be held in the adjacent venue. I expect the full communication between foreign guests and Japanese participants.
All scientists, researchers, clinicians and co-medicals of are encouraged to submit abstracts and join this anniversary congress.
More information via
the official webpage.

CARS microscopy of MPIO

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Following a successful project sponsored by the BMBF G. Pless, I.M. Sauer and U. Rauen report on the "Improvement of the cold storage of isolated human hepatocytes" (Cell Transplant. 2011 Jun 7. [Epub ahead of print]).
Increasing amounts of human hepatocytes are needed for clinical applications and different fields of research, such as cell transplantation, bioartificial liver support and pharmacological testing. This demand calls for adequate storage options for isolated human liver cells. As cryopreservation results in severe cryoinjury, short term storage is currently performed at 2-8º C in preservation solutions developed for the storage of solid organs. However, besides slowing down cell metabolism, cold also induces cell injury, which is, in many cell types, iron-dependent and not counteracted by current storage solutions. In this study, we aimed to characterize storage injury to human hepatocytes and develop a customized solution for cold storage of these cells. Human hepatocytes were isolated from material obtained from partial liver resections, seeded in monolayer cultures and, after a pre-culture period, stored in the cold in classical and new solutions followed by rewarming in cell culture medium.Human hepatocytes displayed cold-induced injury, resulting in > 80% cell death (LDH release) after one week of cold storage in University of Wisconsin solution or cell culture medium and 3 h of rewarming. Cold-induced injury could be significantly reduced by the addition of the iron chelators deferoxamine and LK 614. Experiments with modified solutions based on the new organ preservation solution Custodiol-N showed that ion-rich variants were better than ion-poor variants, chloride-rich solutions better than chloride-poor solutions, potassium as main cation superior to sodium and pH 7.0 superior to pH 7.4. LDH release after two weeks of cold storage in the thus optimized solution was below 20%, greatly improving cold storage of human hepatocytes. The results were confirmed by the assessment of hepatocellular mitochondrial membrane potential and functional parameters (resazurin reduction, glucacon-stimulated glucose liberation) and thus suggest the use of a customized hepatocyte storage solution for the cold storage of these cells.

Fast dynamic MRI for during liver cell Tx

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Micrometer-sized iron oxide particles (MPIOs) attract increasing interest as contrast agents for cellular tracking by clinical Magnetic Resonance Imaging (MRI). Despite the great potential of MPIOs for in vivo imaging of labeled cells, little is known on the intracellular localization of these particles following uptake due to the lack of techniques with the ability to monitor the particle uptake in vivo at single-cell level. Here, we show that coherent anti-Stokes Raman scattering (CARS) microscopy enables non-invasive, label-free imaging of MPIOs in living cells with sub-micron resolution in three dimensions. CARS allows simultaneous visualization of the cell framework and the MPIOs, where the particles can be readily distinguished from other cellular components of comparable dimensions, and localized inside the cell.
The fruitful cooperation with the FOM Institute AMOLF in Masterdam resulted in the paper "CARS microscopy for the visualization of micrometer-sized iron oxide MRI contrast agents in living cells" (Rago G, Langer CM, Brackman C, Day JP, Domke KF, Raschzok N, Schmidt C, Sauer IM, Enejder A, Mogl MT, Bonn M.) published in Biomed Opt Express. 2011 Sep 1;2(9):2470-83.

Improved cold storage of human hepatocytes

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As a first result of our latest projects concerning the role of miRNA in liver regeneration the American Journal of Physiology - Regulatory, Integrative and Comparative Physiology has accepted our paper "Temporal expression profiles indicate a primary function for microRNA during the peak of DNA replication after rat partial hepatectomy": The liver has the unique capacity to regenerate after surgical resection. However, the regulation of liver regeneration is not completely understood. Recent reports indicate an essential role for small non-coding microRNAs (miRNAs) in the regulation of hepatic development, carcinogenesis, and early regeneration. We hypothesized that miRNAs are critically involved in all phases of liver regeneration after partial hepatectomy. We performed miRNA microarray analyses after 70% partial hepatectomy in rats under isoflurane anesthesia at different time points (0 hours - 5 days) and after sham laparotomy. Putative targets of differentially expressed miRNAs were determined using a bioinformatic approach. 2D-PAGE proteomic analyses and protein identification were performed on specimens at 0 and 24 hours after resection. The temporal dynamics of liver regeneration were characterized by BrdU, PCNA, IL-6, and HGF. We demonstrate that miRNA expression patterns changed during liver regeneration and that these changes were most evident during the peak of DNA replication at 24 hours after resection. Expression of thirteen miRNAs was significantly reduced 12-48 hours after resection (> 25% change), ouf of which downreguation was confirmed in isolated hepatocytes for 6 miRNAs at 24 hours, whereas three miRNAs were significantly upregulated. Proteomic analysis revealed 65 upregulated proteins; among them 23 represent putative targets of the differentially expressed miRNAs. We provide a temporal miRNA expression and proteomic dataset of the regenerating rat liver, which indicates a primary function for miRNA during the peak of DNA replication. These data will assist further functional studies on the role of miRNAs during liver regeneration. Authors are N. Raschzok, W. Werner, H. Sallmon, N. Billecke, C. Dame, P. Neuhaus and I.M. Sauer.

Profiles of microRNA after rat partial hepatectomy

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The website of the  24th International Congress of The Transplantation Society is online! Please go to www.transplantation2012.org for more information.
Following the exceptionally successful meetings in Boston, Sydney and Vancouver, we would like to welcome you to a city which twenty years after reunification has evolved into one of the most important capitals of Europe. Once the capital of Prussia and leading cultural centre of the 1920s, today the new capital of Germany is characterized by its dazzling modernity and breathtaking architecture. Berlin is young, dynamic and bursting with joie de vivre. Few cities has been shaped to such an extent by history and undergone as much major transformation as Berlin. “Berlin is always in the process of becoming”, remarked historian Karl Scheffler. Even in the 21st century transplantation still is in a process  of becoming, too.  Therefore, the 24th International Congress of The Transplantation Society will promote the dialogue of experts from around the world. An attractive scientific program will be developed together with the Deutsche Transplantationsgesellschaft (DTG).
The 24th Congress is designed for physicians, surgeons, scientists and organ procurement personnel, who are interested in clinical and research aspects of solid organ, cell and tissue transplantation. The program is developed to encourage the exchange of new scientific and clinical information, and and support an interchange of opinions regarding care and management issues, as well as socioeconomic, ethical and regulatory issues relevant to transplantation.
In addition to the classical types of scientific sessions including plenary sessions, symposia, workshops and poster presentations, we will also offer new types of scientific sessions within the
Forum Futurum focusing on Tailored Pharmacotherapy, Imaging and Regenerative Medicine. All of this is designed to develop a highly interactive forum to discuss cutting-edge science in our field.
We therefore cordially invite you and your colleagues together with your friends and family to come to Berlin. Your active participation in the scientific program will be the fundament for a successful event in 2012.

Labelling of hepatocytes in suspension culture

A multicompartment SlideReactor is shown at the exhibition “WeltWissen – World Knowledge”.
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This year, Berlin celebrates 200 years of the Humboldt University, 300 years of the Charité, 300 years since the first statute and first publication by the Academy of the Sciences and, one year later, 100 years of the Max Planck and Kaiser Wilhelm Society and the 350th birthday of the Berlin State Library. The exhibition “WeltWissen – World Knowledge” is the high point of the Berlin Year of Science. The Humboldt University, the Charité, the Berlin-Brandenburg Academy of the Sciences and Humanities and the Max Planck Society have organised the exhibition as a unique joint project. The Technical University, the Berlin State Museums and the Deutsches Museum, Munich are involved as partners. From 24 September 2010 to 9 January 2011, Martin-Gropius-Bau will be host   ing its “WeltWissen“ (World Knowledge) exhibition which takes a look at 300 years of the science in Berlin from an all-embracing perspective that crosses institutions, disciplines and epochs. The exhibition is the high point of the Berlin Year of Science. On an exhibition space of more than 3,200 square metres, visitors are presented with over 1,500 original exhibits, installations and media stations. The Humboldt University, the Charité, the Berlin-Brandenburg Academy of the Sciences and Humanities and the Max Planck Society have organised the exhibition as a unique joint project.
The exhibition correlates sciences in Berlin to the world: only the dynamic interplay of local imprinting and worldwide networking has allowed Berlin since 300 years to generate knowledge and share it with the world. Concrete and highly vivid stories and biographies of objects, researchers and institutions offer exciting insights into the scientific environment. “WeltWissen – World Knowledge” shows how scientists in Berlin work, how they network internationally, how they break down the boundaries of their departments and how they transformed Berlin into a scientific metropolis. 

WeltWissen. 300 Years of Science in Berlin 24 September 2010 – 9 January 2011  Martin-Gropius-Bau, Niederkirchnerstrasse 7, 10963 Berlin
Opening times: Wed - Mo: 10.00 am – 8.00 pm, closed on Tuesdays
Admission: 6 €, reduced 4€ . Free admission for children and adolescents up to an including 16 years of age, two escorts each per kindergarten group or school class as well as recipients of unemployment benefit level II 
Public transport: Underground line 2 (Potsdamer Platz), city train lines 1, 2, 25 (Potsdamer Platz or Anhalter Bahnhof), Buses: M29 (Anhalter Bahnhof) / M41 (Abgeordnetenhaus)
Please find more information at: www.weltwissen-berlin.de, www.gropiusbau.de

Copyright of upper,  large picture:
Roman März

Monitoring cell transplantation in swine model via MRI

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Nora Kammer's paper in Artificial Organs on "Labelling of primary human hepatocytes with micron-sized iron oxide particles in suspension culture suitable for large-scale preparation" is available pre-print. Co-authors are Nils Billecke, Mehmet H. Morgul, Michaela K. Adonopoulou, Martina Mogl, Mao D. Huang, Stefan Florek, Katharina R. L. Schmitt, Nathanael Raschzok and Igor M. Sauer.
Protocols for labelling of hepatocytes with micron-sized iron oxide particles (MPIO) in adhesion culture enable cell detection using clinical Magnetic Resonance equipment. For clinical applications, large numbers of cells must be labelled in a simple and rapid manner, which requires new labelling protocols. The aim of this study was to investigate the feasibility of preparing MPIO-labelled primary human hepatocytes in a temporary suspension culture. Human hepatocytes were isolated from 16 donors and labelled with MPIO in suspension, using the Rotary Cell Culture System. Particle incorporation was investigated by light and electron microscopy. Cells were compared to adhesion culture-labelled and subsequently enzymatically resuspended cells. During a five-day culture period, hepatocyte-specific parameters of cell damage (aspartate aminotransferase and alanine aminotransferase) and metabolic activity (urea and albumin) were analysed. Suspension cultures showed a higher outcome in cell recovery compared to the conventional labelling method. When incubated with 180 particles/cell for four hours, the mean particle uptake was 28.8 particles/cell at a labelling efficiency of 95.1%. Labelling in suspension had no adverse effects on cell integrity or metabolic activity. In conclusion, labelling in suspension is a practicable method for fast and efficient preparation of large numbers of labelled cells that are suitable for clinical applications.

SPAD in children with acute liver failure

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Our latest paper on "Monitoring of liver cell transplantation in a preclinical swine model using magnetic resonance imaging" has been accepted for publication in CELL Medicine (Part B of CELL TRANSPLANTATION). Authors are Nathanael Raschzok, Ulf Teichgräber, Nils Billecke, Anja Zielinski, Kirsten Steinz, Nora N. Kammer, Mehmet H. Morgul, Sarah Schmeisser, Michaela K. Adonopoulou, Lars Morawietz, Bernhard Hiebl, Ruth Schwartlander, Wolfgang Rüdinger, Bernd Hamm, Peter Neuhaus and Igor M. Sauer. The study was based on the excellent colaboration with the department of Radiology and the Institute of Pathology, both Charité - Campus Mitte, Universitätsmedizin Berlin, Berlin, Germany, the Centre for Biomaterial Development and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Institute for Polymer Research, GKSS Research Centre Geesthacht GmbH, Teltow, Germany, the Department of Materials, ETH Zurich, Zurich, C Switzerland, and Cytonet GmbH, Weinheim, Germany.
Liver cell transplantation (LCT) is a promising treatment approach for certain liver diseases, but clinical implementation requires methods for non-invasive follow-up. Labeling with superparamagnetic iron oxide particles can enable the detection of cells with magnetic resonance imaging (MRI). We investigated the feasibility of monitoring transplanted liver cells by MRI in a preclinical swine model and used this approach to evaluate different routes for cell application. Liver cells were isolated from landrace piglets and labeled with micron-sized iron oxide particles (MPIO) in adhesion. Labeled cells (n = 10), native cells (n = 3) or pure particles (n = 4) were transplanted to minipigs via intraportal infusion into the liver, direct injection into the splenic parenchyma, or intra-arterial infusion to the spleen. Recipients were investigated by repeated 3.0 Tesla MRI and computed tomography angiography up to 8 weeks after transplantation. Labeling with MPIO, which are known to have a strong effect on the magnetic field, enabled non-invasive detection of cell aggregates by MRI. Following intraportal application, which is commonly applied for clinical LCT, MRI was able to visualize the microembolization of transplanted cells in the liver that were not detected by conventional imaging modalities. Cells directly injected into the spleen were retained, whereas cell infusions intraarterially into the spleen led to translocation and engraftment of transplanted cells in the liver, with significantly fewer microembolisms compared to intraportal application. These findings demonstrate that MRI can be a valuable tool for non-invasive elucidation of cellular processes of LCT and - if clinically applicable MPIO are available - for monitoring of LCT under clinical conditions.  Moreover, the results clarify mechanisms relevant for clinical practice of LCT, suggesting that the intra-arterial route to the spleen deserves further evaluation.

Hypothermia-induced cell protection & microglial cells

The XXIV International Congress of The Transplantation Society 2012 will take place in Berlin, Germany from 15-20 July, 2012. Chaired by Prof. Dr. Peter Neuhaus the specific objectives of the XXIV International Congress of The Transplantation Society (TTS) will be to promote dialogue and the exchange of experts from around the world. An attractive scientific program will be developed together with the Deutsche Transplantationsgesellschaft (DTG). The Local Organizing Committee (LOC) consists of Prof. Dr. Bernhard Banas, PD Dr. Olaf Guckelberger, PD Dr. Marcus Bahra, PD Dr. Igor M. Sauer and Sylvia Albrecht.

More information, soon via www.transplantation2012.org !

Modified nanoparticles & multimodal imaging

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The XXXVII ESAO Congress will take place in Skopje at the Macedonian Academy of Sciences and Arts on September 8-11, 2010.
Skopje is the capital of Macedonia and the centre of the political, cultural and social life. It is a modern, urban city with a history dating more than 2000 years back. Skopje, once called Skupi, over the history was conquered and ruined several times, but always rebuilt again. It has suffered several natural catastrophes, the last being the earthquake in 1963. Some of the monuments from long ago have still remained: the remainings from the old city, the roman architecture, the fortress, the stone bridge, many churches and monasteries, frescoes and carvings from the middle ages, mosques and amams built by the ottomans in the old bazaar. Old Skopje with its very rich treasures is a very attractive tourist destination. It is very well connected by air and land with the rest of the world.
The Macedonian Academy of Sciences and Arts, as the venue of the ESAO Congress in 2010, will provide the atmosphere for a perfect scientific event. You will enjoy “state of the art” presentations and lectures in some of the most attractive fields of medicine. The ESAO Congress 2010 will bring together distinguished clinicians and scientists of biotechnologies and bioengineering from all over the world. They will discuss results from scientific research in all areas of artificial organs. Our aim is to bring together and to foster exchange and collaboration among scientists, clinicians and industrial partners.
Aleksandar Sikole, the Congress President 2010, cordially welcomes you to Skopje to the ESAO 2010 Annual Congress.
More information via
http://www.esao2010.org.mk/ .

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Haluk Morgül successfully defended his medical doctoral thesis "magna cum laude".
After years of extremely fruitful research in the field of liver support, hepatocyte isolation and cell imaging via MRI he is (co-)author of 5 papers in peer reviewed journals (with more to come)!

Two articles among top 25

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During the HAI 2009 a workshop will be dedicated to "New aspects in extracorporeal liver support". It will take place September 17th, 2009 in Saal A 05 / 30 (17.00 - 19.00)

Chair: A. Jörres, Berlin and L. Renders, Kiel
Welcome and introduction  - A. Krause (Bad Homburg)
Liver support systems: functioning and Biochemical efficiency - I.M. Sauer (Berlin)
Liver support systems: Clinical spectrum of indications and results - A. Jörres (Berlin)
Prometheus: Practical aspects and Anticoagulation - L. Renders (Kiel)
Prometheus: Hands-on 
With the friendly support of Fresenius Medical Care Deutschland GmbH

Hypothermia induced endothelial dysfunction

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Nathanael Raschzok successfully defended his medical doctoral thesis "summa cum laude". After three years of extremely fruitful research and development in the field of hepatocyte transplantation, cell labeling, and MR imaging of transplanted cells he is first author of three papers in peer reviewed journals (with more to come...). He currently is finishing his in vivo MRI studies of MPIO labeled transplanted hepatocytes. 
Transplantation of primary human hepatocytes is a promising approach in certain liver diseases. For visualisation of hepatocytes during and following cell application and the ability of a timely response to potential complications, a non-invasive modality for imaging of the transplanted cells has to be established. The aim of his studies was to label primary human hepatocytes with micron-sized iron oxide particles (MPIOs), enabling the detection of cells by clinical magnetic resonance imaging (MRI). The feasibility of preparing MPIO-labelled primary human hepatocytes detectable by clinical MR equipment was shown in vitro. MPIO-labelled cells could serve for basic research and quality control in the clinical setting of human hepatocyte transplantation.
He also investigated techniques for evaluation of the particle uptake via continuum source atomic absorption spectrometry (CSAAS). Porcine liver cells were labelled with MPIOs and the iron concentration of the cell samples was investigated by a CSAAS spectrometer equipped with a Perkin-Elmer THGA graphite furnace. CSAAS enabled rapid quantification of particle load from small quantities of cells without extensive preparation steps. CSAAS could be used for quality control in a clinical setting of cell transplantation.

CSAAS and MPIO-labelled cells

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Antje Diestel's manuscript entitled "Tacrolimus and methylprednisolone prevent hypothermia induced endothelial dysfunction" has been accepted for publication in the Journal of Heart and Lung Transplantation. Co-authors are Nils Billecke, Joerg Roessler, Boris Schmitt, Silke Troeller, Ruth Schwartlander, Felix Berger, Igor Maximilian Sauer and Katharina Rose Luise Schmitt.
Hypothermia is used to preserve organs for transplant and it is the oldest method to protect organs during complex pediatric cardiac surgery. Loss of tissue function and tissue edema are common complications in children undergoing cardiac surgery and heart transplantation. The present study was designed to examine the effects of methylprednisolone (MP) and Tacrolimus (TAC) on endothelial cell function and morphology after deep hypothermia and rewarming. Human umbilical vein endothelial cells (HUVECs) were pretreated with MP and/orTAC and incubated either within a specially designed bioreactor or in monolayers. They were then exposed to a dynamic cooling and rewarming protocol. Immunocytochemistry, time lapse video microscopy within the SlideReactor bioreactor system, cell permeability and adherence assays and western blot analysis were performed. Confluent endothelial cells exposed to hypothermia displayed elongated cell shapes with intercellular gap formation, increased endothelial cell-layer permeability and loss in adherence. Upon rewarming, however, endothelial cell integrity was restored. Opening and closing of intercellular gaps was dependent on ERK 1/2 activation and connexin 43 (Cx43) expression. The combined treatment with MP and TAC inhibited these hypothermia-induced changes. These results suggest that MP and TAC inhibit hypothermia induced endothelial gap formation via pERK 1/2 inhibition and connexin 43 stabilization. Application of combined drugs that affect multiple targets may therefore be considered as a possible new therapeutic strategy to prevent endothelial dysfunction after hypothermia and rewarming.

Management of Acute Kidney Problems

Imaging of human hepatocytes via MPIO and MRI

Florian Vondran successfully defended his thesis "summa cum laude".
After years of extremely fruitful research in the field of liver support, hepatocyte isolation and cryopreservation he is (co-)author of 7 papers in peer reviewed journals.

Tat-peptide modified MPIO

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Nathanel Raschzok's and Haluk Morgül's manuscript entitled "Imaging of Primary Human Hepatocytes Using Micron-Sized Iron Oxide Particles and Clinical Magnetic Resonance Tomography" has been accepted for publication in the Journal of Cellular and Molecular Medicine (impact factor: 6,55). Authors are Nathanael Raschzok, Mehmet H. Morgul, Jens Pinkernelle, Florian W.R. Vondran, Nils Billecke, Nora N. Kammer, Gesine Pless, Michaela K. Adonopoulou, Christian Leist, Lars Stelter, Ulf Teichgraber, Ruth Schwartlander and Igor M. Sauer. Nathanael Raschzok and Mehmet Haluk Morgul contributed equally to this work. The contribution of Ruth Schwartländer has to be emphasised as well. Transplantation of primary human hepatocytes is a promising approach in certain liver diseases. For visualisation of hepatocytes during and following cell application and the ability of a timely response to potential complications, a non-invasive modality for imaging of the transplanted cells has to be established. The aim of this study was to label primary human hepatocytes with micron-sized iron oxide particles (MPIOs), enabling the detection of cells by clinical magnetic resonance imaging (MRI). Primary human hepatocytes isolated from 13 different donors were used for labelling experiments. Following dose finding studies, hepatocytes were incubated with 30 particles/cell for 4 hours in adhesion culture. Particle incorporation was investigated via light, fluorescence and electron microscopy and labelled cells were fixed and analysed in an agarose suspension by a 3.0 Tesla MR scanner. Hepatocytes were enzymatically resuspended and analysed during a five-day reculture period for viability, total protein, enzyme leakage (AST, LDH) and metabolic activity (urea, albumin). A mean uptake of 18 particles/cell could be observed, and primary human hepatocytes were clearly detectable by MR instrumentation. The particle load was not affected by resuspension and showed no alternations during the culture period. Compared to control groups, labelling and resuspension had no adverse effects on viability, enzyme leakage and metabolic activity of human hepatocytes. Conclusion: The feasibility of preparing MPIO-labelled primary human hepatocytes detectable by clinical MR equipment was shown in vitro. MPIO-labelled cells could serve for basic research and quality control in the clinical setting of human hepatocyte transplantation.

Isolation of primary human hepatocytes

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Haluk Morgül and Nathanael Raschzok published their first results on "Tracking of primary human hepatocytes with clinical MRI: Initial results with Tat-peptide modified superparamagnetic iron oxide particles." in the March issue of IJAO (Int J Artif Organs 2008, 31:252-257): The transplantation of primary human hepatocytes is a promising approach in the treatment of specific liver diseases. However, little is known about the fate of the cells following application. Magnetic resonance imaging (MRI) could enable real-time tracking and long-term detection of transplanted hepatocytes. The use of superparamagnetic iron oxide particles as cellular contrast agents should allow for the non-invasive detection of labelled cells on high-resolution magnetic resonance images. Experiments were performed on primary human hepatocytes to transfer the method of detecting labelled cells via clinical MRI into human hepatocyte transplantation. For labelling, Tat-peptide modified nano-sized superparamagnetic MagForce particles were used. Cells were investigated via a clinical MR scanner at 3.0 Tesla and the particle uptake within single hepatocytes was estimated using microscopic examinations. The labelled primary human hepatocytes were clearly detectable by MRI, proving the feasibility of this new concept. Therefore, this method is a useful tool to investigate the effects of human hepatocyte transplantation and to improve safety aspects of this method.

MELS CellModule vs. AMC-BAL

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The Retreat 2007 of the group took place in Binz, a small seaside village on the German island Ruegen. Venue was the coast guard station designed an built by the architect Ulrich Müther. It was built in 1968 and serves as a great example of the hyperbal concrete structures that he used in most of his works (for more information [in German] see article in brand eins 9/2003: "Nach der Utopie" .

SlideReactor: Proof of concept

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The paper Cryopreservation of primary human hepatocytes – the benefit of trehalose as an additional cryoprotective agent by Ekaterina Katenz, Florian W.R. Vondran, Ruth Schwartlander, Gesine Pless, Xiaobing Gong, Xiandong Cheng, Peter Neuhaus and Igor M. Sauer is published in the January 2007 issue of Liver Transplantation. Problems with the limited availability of human hepatocytes for cell transplantation may be overcome by efficient cryopreservation techniques and formation of appropriate cell banking. In the present study we investigated the effect of the disaccharide trehalose on the cryopreservation of human hepatocytes. For analysis, liver cells were frozen in culture medium containing 10% DMSO that was supplemented with varying concentrations of trehalose. During the post-thawing culture period, viability, plating efficiency, total protein, cell proliferation, enzyme leakage, albumin and urea formation as well as phase I and II metabolism were analyzed. In the pilot study, among the concentrations investigated, 0.2 M trehalose showed the best overall outcome. Compared to the use of DMSO alone, we found significant improvement in post-thaw cell viability (62.9 ± 13 vs. 46.9 ± 11 %, p < 0.01) and plating efficiency (41.5 ± 18 vs. 17.6 ± 13 %, p < 0.01) in the trehalose group. The use of trehalose as an additive for cryopreserving human hepatocytes resulted in a significantly increased total protein level in the attached cells, higher secretion of albumin and a lower AST level after thawing. The use of trehalose as cryoprotective agent significantly improves the outcome of human hepatocyte cryopreservation.

Trehalose cryoprotective

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The Charité Welcome Center at Charité International Cooperation would like to extend you a warm welcome and wish you all the best as you begin your stay in Berlin. The Charité Welcome Center offers a variety of services to foreign scientists to cope with obstacles they face when moving to Berlin and working at the Charité. When you reach Berlin, the Welcome Center should be you first source of information. The staff members can help answer questions about visa applications, registration procedures, financial concerns, health matters, housing and other issues relating to your stay in Berlin.
Contact: Pamela Glowacki phone: +49 30 4505-70076
Monika Schnitger phone: +49 30 4505-70077
Email: info.international@charite.de

Special issue of Therapeutic Apheresis and Dialysis: Cell-Free Artificial Liver Support

Paul S. Malchesky, Editor-in chief of Artificial Organs, informed us that the articles "In vitro evaluation of the transportability of viable primary human liver cells originating from discarded donor organs in bioreactors" (Artificial Organs 2005, 29: 141-151) and "'Blogs' and 'Wikis' are valuable software tools for communication within research groups" (Artificial Organs 2005, 29: 82-83) were in the top 25 and top 10, respectively, concerning articles viewed online in 2005 at Blackwell Synergy. The latter was N°. 2 of Artifcial Organs in 2005...

Articles in the top 25 / top 10 articles viewed online

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Das Buch Chirurgische Forschung von Manfred G. Krukemeyer von Hans-Ullrich Spiegel (2006, 576 S., 188 Abb., geb., ISBN-10: 3131336617, ISBN-13: 9783131336613) fasst die Grundlagen der chirurgischen Forschung zusammen. Es richtet sich insbesondere an die in der chirurgischen Forschung tätigen Ärzte und Naturwissenschaftler wie auch an Doktoranden der Medizin und der verwandten Disziplinen. Dem jungen medizinisch-naturwissenschaftlich interessierten Forscher wird in diesem Werk ein umfassender Einblick in die unterschiedlichen chirurgischen Forschungsprojekte geboten. Dadurch kann er seine Zielvorstellungen näher definieren. Mithilfe von Adressen und ausführlichen Literaturverzeichnissen findet er einen optimalen Einstieg in sein wissenschaftliches Curriculum vor. Das Werk dient aber auch dem bereits tätigen Forscher zur Planung, Weiterentwicklung und Neudefinition seiner Projekte. Die insgesamt rund 190 Abbildungen, der Großteil davon in Farbe, sowie zahlreiche Tabellen liefern anschauliches Material für das Verständnis des Textes. Mehr Informationen, Musterseiten sowie das Inhaltsverzeichnis finden Sie hier.

Gene transfer into primary human hepatocytes

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Today, the BMBF prize (Innovation Competition for Medical Technology) for medical technology was awarded to our joint project with Prof. A. Joerres and Dr. U. Baurmeister concerning the development of a new detoxification system based on our experience with the Single Pass Albumin Dialysis. Research on the technique of diasorption utilising nanoparticles will be funded with approx. 300.000 Euro. More information (in German) here...

Artificial Liver Support

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The 2nd Swiss Experimental Surgery Symposium will be held Thursday 12 and Friday 13 January, 2006 in Geneva, Switzerland. Medical research, especially surgical research, is becoming more and more important in our current world of innovations, fast application of new devices and implementation of new techniques in humans. All these projects necessarily require pre-clinical testing which is normally carried out in large animal trials. Thus, it is of utmost importance to train young researchers, whether medical or veterinary doctors, biologists or engineers in order that they may acquire the necessary competencies.
A wide panel of Swiss and international experts are invited to make it a state-of-the-art symposium. Such meetings are not only important for the teaching of technical aspects, but they also give the opportunity to consider ethical and regulatory aspects of animal use for experimentation. Finally, the human networking aspect of such a meeting and exchanging ideas and knowledge is equally important. More information here.

Article in the top 25 most viewed

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This article by R. Vanholder, J.F. Del Canizo, I.M. Sauer, and B. Stegmayr summarizes the current evolutions regarding artificial organs in Europe. The review emanates from the activities by four of the work groups of the European Society for Artificial Organs (ESAO) and is essentially based on the reports by these work groups at the latest ESAO meeting in Warsaw, Poland (2004). The topics are: apheresis, heart support, liver support, uremic toxins. Artif Organs. 2005 Jun;29(6):498-506.

The European artificial organ scene: present status

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The XXXII Congress of the European Society for Artificial Organs (ESAO) will be held in Bologna from 5 to 8 October, 2005. The Congress will be combined with the first Congress of the International Federation for Artificial Organs (IFAO), which is a newly formed ISAO-derived umbrella structure, embracing ESAO, the American Society for Artificial Internal Organs (ASAIO), the Japanese Society for Artificial Organs (JSAO) and the International Faculty for Artificial Organs (INFA). The annual "One day on the liver" held by the Liver Support Working Group (LSWG) will have a focus on research concerning liver support in China and will be a kick-off meeting for closer collaboration of the ESAO-LSWG with Chinese groups.

The SlideReactor

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The Third International Symposium on Hepatic failure and Artificial Liver will be held from Mar 24-27, 2005 in Suzhou, China. The sponsors include Chinese Medical Association Zhejiang Branch and First Affiliated Hospital, Medical College, Zhejiang University. This symposium is aimed to promote the international communication, further the study on artificial liver, popularize the usage of artificial liver system. The conference is focussing on “Developing Artificial Liver, Curing Hepatic Diseases”.

Transportability of bioreactors

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"Blogs" and "Wikis" Are Valuable Software Tools for Communication Within Research Groups (Igor M. Sauer, Dominik Bialek, Ekaterina Efimova, Ruth Schwartlander, Gesine Pless, Peter Neuhaus) was published in the Januar 2005 issue of Artificial Organs, Volume 29 Issue 1 Pages 82-83  - January 2005. Appropriate software tools may improve communication and ease access to knowledge for research groups. A weblog is a website which contains periodic, chronologically ordered posts on a common webpage, whereas a wiki is hypertext-based collaborative software that enables documents to be authored collectively using a web browser. Although not primarily intended for use as an intranet-based collaborative knowledge warehouse, both blogs and wikis have the potential to offer all the features of complex and expensive IT solutions. These tools enable the team members to share knowledge simply and quicklythe collective knowledge base of the group can be efficiently managed and navigated.

Kichchadi sums up some further ideas on using RSS, blogs and wikis in research and education: here and here.
At CiteULike and "Weblogs in Higher Education" further information is available.

"Blogs" and "Wikis"

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Drawn mainly from the collections of the U.S. National Library of Medicine, Dream Anatomy shows off the anatomical imagination in some of its most astonishing incarnations, from 1500 to the present:

In antiquity, the body's internal structure was the subject of speculation, fantasy, and some study, but there were few efforts to represent it in pictures. The invention of the printing press in the 15th century-and the cascade of print technologies that followed-helped to inspire a new spectacular science of anatomy, and new spectacular visions of the body. Anatomical imagery proliferated, detailed and informative but also whimsical, surreal, beautiful, and grotesque — a dream anatomy that reveals as much about the outer world as it does the inner self.
Fritz Kahn (1888-1968): Der Mensch als Industriepalast (Man as Industrial Palace), Stuttgart, 1926. Chromolithograph, U.S. National Library of Medicine.
Kahn’s modernist visualization of the digestive and respiratory system as "industrial palace," really a chemical plant, was conceived in a period when the German chemical industry was the world’s most advanced.

M.I.T. Technology Review: Regenerative Medizin

The Editor-in-Chief of Artificial Organs informed us that the article "Modular Extracorporeal Liver Support" - published in volume 26, issue 8 of Artificial Organs - was among the top 10 most cited for the year 2003!

Article on "MELS" in top 10 most cited AO articles

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Prior to the GASL meeting 2005 the FALK Symposium No 145: "Artificial Liver Support" will take place in Ulm, January 27-28, 2005.
The Falk Symposium No145 on Artificial Liver Support is held to provide an overview on the possibilities and limitations of the up-to-now existing procedures and devices available for artificial liver support. Future perspectives like stem cell differentiation and their therapeutical implications will also be discussed. Leading experts in the field of artificial devices, bioartificial devices, hepatocyte transplantation and stem cells will present the latest data on the various topics, thus promising a very exciting meeting which will be of high interest for all clinicians involved in the treatment of hepatic failure.
More information via
http://www.medkongresse.de/gasl2005/. The program is available here. Registration may be performed via this document.

Hepatology: SPAD vs. MARS

Dear Colleagues,
The deadline for abstract submission is approaching (26th of April).
Unfortunately, up to now, very few contributions have been submitted. We ask
all of you to prepare abstracts as well as to stimulate other researchers to
submit appropriate contribution.
Think about supporting ESAO and Warsaw ESAO Congress !