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The History of MARS ® Molecular Adsorbents Recirculating System Stange J, Ramlow W, Mitzner S, Schmidt R, Klinkmann H.: Dialysis against a recycled albumin solution enables the removal of albumin-bound toxins. In: J Artif Organs 1993; 17: 809–813. Stange J, Mitzner S.: A carrier-mediated transport of toxins in a hybrid membrane. Safety barrier bet- ween a patients blood and a bioartificial liver. In: J Artif Organs 1996; 19: 677–691. Stange J, Mitzner SR, Risler T, Erley CM, Lauchart W, Goehl H, et al.: Molecular adsorbent recycling sys- tem (MARS): clinical results of a new membrane-based blood purification system for bioartificial liver support.In : J Artif Organs 1999; 23: 319–330. Steffen R. Mitzner, Jan Stange, Sebastian Klammt, Teut Risler, Christiane M. Erley, Brigitte D. Bader, Elke D. Berger, Werner Lauchart, Piotr Peszynski, Jens Freytag, Heiko Hickstein, Jan Loock, Johannes-Mathias Löhr, Stefan Liebe, Jörg Emmrich, Gero Korten and Reinhard Schmidt: Improvement of hepatorenal syn- drome with extracorporeal albumin dialysis mars: Results of a prospective, randomized, controlled clinical trial. In: Liver Transplantation,Volume 6, Issue 3, May 2000, Pages: 277–286. - Studie: Tübingen/ HRO Jan Stange, Steffen R. Mitzner, Sebastian Klammt, Jens Freytag, Piotr Peszynski, Jan Loock, Heiko Hick- stein, Gero Korten, Reinhardt Schmidt, Jörg Hentschel, Martin Schulz, Matthias Löhr, Stefan Liebe, Wolf- gang Schareck and Ullrich T. Hopt: Liver support by extracorporeal blood purification: A clinical obser- vation. In: Liver Transplantation,Volume 6, Issue 5, September 2000, Pages: 603–613. Steffen R. Mitzner, Sebastian Klammt, Piotr Peszynski, Heiko Hickstein, Gero Korten, Jan Stange and Rein- hard Schmidt: Improvement of Multiple Organ Functions in Hepatorenal Syndrome During Albumin Dialysis with the Molecular Adsorbent Recirculating System. In: Therapeutic Apheresis,Volume 5, Issue 5, October 2001, Pages: 417–422. Schmidt LE, Sorensen VR, Svendsen LB, Hansen BA, Larsen FS.: Hemodynamic changes during a single treatment with the molecular adsorbents recirculating system in patients with acute-on-chronic liver failure. Liver Transpl 2001; 7: 1034–1039. Heemann U, Treichel U, Loock J, Philipp T, GerkenG, Malago M, Klammt S, Loehr M, Liebe S, Mitrzner S, Schmidt R, Stange J: Albumin dialysis in cirrhosis with superimposed acute liver injury: A prospective, controlled study. In: Hepatology (2002), 36, S.949-958. - Studie: Essen/HRO Steiner C, Mitzner S.: Experiences with MARS liver support therapy in liver failure: analysis of 176 pa- tients of the International MARS Registry. In: Liver,Volume 22, Issue Supplement s2, April 2002, Pages: 20–25. Novelli G, Rossi M, Pretagostini R, Poli L, Novelli L, Berloco, P, Ferretti G, Lappelli M, Cortesini R: MARS (Molecular Adsorbent Recirculating System): experience in 34 cases of acute liver failure. In: Liver, Volume 22, Issue Supplement s2, April 2002, pages 43–47. Jan Stange, Tarek I. Hassanein, Ravindra Mehta, Steffen R. Mitzn er and Robert H. Bartlett: The Molecular Adsorbents Recycling System as a Liver Support System Based on Albumin Dialysis: A Summary of Preclinical Investigations, Prospective, Randomized, Cont- rolled Clinical Trial, and Clinical Experience from 19 Centers. In: Artificial Organs, Volume 26, Issue 2, February 2002, Pages: 103–110. Steiner C, Mitzner S., Christian Steiner and Steffen Mitzner: Experiences with MARS liver support the- rapy in liver failure: analysis of 176 patients of the International MARS Registry. In: Liver, Volume 22, Issue s2, April 2002, Pages: 20–25. Verbunde 1- 5 Center for Organ Support and Regeneration (FLD e.V.) Fraunhofer AG EXIM Artcline GmbH Transfusionsmedizin Universitätsklinik Zentrum Klinische Forschung, Zellbiologie Seracell AG RTC Stemcells, Experimentelle Chirurgie Bluepoint Medical GmbH & CoKG Forschungsdialyse Institut Elektrotechnik Albutec GmbH Universitätsklinik Artcline GmbH Verbund 1: Organ Support-Human- Interface Verbund 2: Organ Support Disposables Verbund 3: Organ Regeneration Verbund 4: Immune Modulation Verbund 5: Organ Support Hardware 1 2 3 4 5 MARS ® FLUX DIALYZER PATIENT BLOOD CIRCUIT DIALYSATE CIRCUIT MARS ® ALBUMIN CIRCUIT diaMARS ® ADSORPTION COLUMNS dia FLUX DIALYZER MARS MEMBRANE ELIMINATION OF TOXINS CEOS Center for Extracorporeal Organ Support Support Regeneration Gründung der Fraunhofer-Gruppe „Extrakorporale Immunmodulation“ EXIM BMBF-Innovationsforum „Bioaktive Zellfilter“ Montag, 14.03.2011 PROGRAMM Öffentlich-private Partnerschaft im Biomedizinischen Forschungszentrum Rostock Center for Organ Support and Regeneration CEOS – “from Science to Clinic” MARS®-Therapie The MARS ® therapy has caused a revolution in the field of liver therapy. The blood detoxification process helps to clean the liver outside the body. With this method water-soluble and water-insoluble protein-bound liver toxins are removed from the patient’s blood. The procedure of the MARS ® system is similar to the kidney dialysis and uses a toxin removing substance called albumin. Albumin is a human plasma protein and acts as a natural detergent drawing toxins away from the blood. The liver dialysis MARS ® has the potential to save the life of patients with threatening liver diseases by the detoxification of the liver. The procedure of the MARS®-therapy The MARS® system removes protein-bound and water-soluble toxins with albumin dialysis. Trans- port proteins with free binding sites lure behind the MARS®-membrane and remove the toxins from the blood. Toxin-removing material as the human serum albumin (HSA) is used. It is obtained industrially from the donor’s blood. Molecules that bind to the albumin membrane are then remo- ved by passing through a charcoal column and an anion exchange, before being reintroduced into the circuit. Both water-soluble toxins and strongly albumin-bound toxins are removed by this pro- cess. By the MARS® therapy water-soluble and albumin-bound substances such as bile acids, bilirubin, fatty acids, ammonia, urea, and copper are removed. 1999 Organization and execution – 1st International Symposium on Albumin Dialysis (ISAD) 2001 Execution of the first seminar on albumin dialysis in Northern Germany 2002 Participation: 10th Day of Action against addictive dangers in Rostock 2003 Renaming to FORUM LIVER DIALYSIS (FLD) e.V. 2004 Nomination project „Olympia at the Schwanenteich“ for the 1st German Prevention Award by the Federal Ministry of Health and Social Security 2006 Execution of the course „Hepatitis B + C“ as part of the 7th German Liver Congress in Warnemünde 2008 Foundation of the Center for Extracorporeal Organ Support (CEOS); 12 March 2008 in Rostock 2010 Kick Off Project „Health Net-MV“ 2011 Foundation of the Fraunhofer Group „Extracorporeal Immunomodulation“ (EXIM) 2012 Development of the concept “Wachstumskern „ - Center for Organ & Recovery Support“ 2012 13th ISAD as part of the European Society for Artificial Organs (E.S.A.O) – Congress in Rostock Cases of patients treated with MARS© therapy ACUTE DECOMPENSATION OF CHRONIC LIVER DISEASE Dagmar Heinicke, 40 years, first MARS® patient, jaundice - admission to the Department of Internal Medicine Rostock; falls into a coma - cause: chronic hepatitis C with acute decompensation of liver function - after the second day of the MARS® treatment: patient wakes up from coma - discharge from hospital after several MARS® treatments (preparation LTx) MULTIORGAN FAILURE - 8-year-old girl with no anamnesis - admission to the Department of Cardiology - diagnosis: myocarditis, consequence: cardiac arrhythmia + cardiac arrest with the conse quence of cardiogenic shock and multi-organ failure - failure of kidney, liver and respiratory system - revival succeeds, but the status of organ function is critical - use of 3 MARS® treatments: improvement of organ functions within 3 days + prevention from endogenous toxicopathy - discharge from hospital in a healthy condition after 6 weeks ACUTE LIVER FAILURE - 30-year-old man with chronic schizophrenia: after taking 40 gram of paracetamol -> admission to hospital - early signs of kidney failure + slight confusion, delivery in kidney station - signs of serious liver damage, patient is unconscious - full screen: liver failure - use of 5 MARS® treatments: improvement of clinical biochemical parameters - discharge from hospital in a healthy condition after 26 days Pathologies: • Autoimmune hepatitis • Primary biliary cirrhosis (PBC) • Primary sclerosing cholangitis (PSC) • Hemochromatosis • Alpha-1- antitrypsin deficiency • Budd-Chiari Syndrome • Hepatocellular carcinoma (HCC) The use of the MARS® therapy Acute liver failure - caused by acute viral infection, poisoning (caused by alcohol, drugs or mushrooms), - identification: life-threatening complications ( hepatic encephalopathy, jaundice, renal failure, multi-organ failure) After liver transplant surgery: transplant liver failure or severe graft dysfunction MARS© therapy has a positive effect on: • survival rate/ - time • hemodynamics • hepatic function • renal function • hepatic encephalopathy • intracranial pressure • jaundice / cholestasis MARS® and expenses 2004 Inclusion of MARS® in the OPS 301-catalog (code 8-858.0) 2004 Inclusion of MARS® in the DRG accounting system with additional fees ZE32 from 2005 DRG-accounting system with additional fees 2005-10 to 2012 DRG- accounting system with additional fees PA 20012-10 MARS® - number of cases By 2012 the number of treated patients increased to more than 12,000 with more than 67,000 individual treatments in nearly 450 centers in 30 countries. This includes more than 450 children who were treated with MARS®. Awards The MARS® therapy has been honored with 17 na- tional and international awards (list: extract on awards). As part of MARS® external funding investments of 10 million euros as well as industrial investments of 30 million euros were acquired. • 1991: Promotion of MARS® in the programme ‚Promoting Junior Biotechnology Groups in East Germany‘, DM 2 million, 5 years • January 1994: Dr. Jan Stange - research grant by the Sandoz Foundation in the amount of DM 10,000 • National Prize Winner ‚Biopure GmbH‘ at the Founders Competition ‚Start Up 1997‘ on behalf of the business consultancy McKinsey, the savings banks and the magazine ‚Stern‘ (under the patro- nage of Federal President Roman Herzog) prize money: DM 100,000 to Aldinger, Gericke, Stange & Mitzner • 28 August 1998: Honor of the winners of the Entrepreneurs Competition ‚Start Up 1997‘ in the Baroque Hall Rostock • 2000: TERAKLIN AG: German Business Award in the amount of DM 50,000 • 2001 Nomination of the MARS® therapy for the German Future Prize (under the patronage of Federal President Johannes Rau) Forum Leberdialyse (FLD) e.V. - was founded in 1997 as an association for extracorporeal detoxification (VED) e.V. sponsored by the Ministry of Education and Research, the state of Mecklenburg-Western Pomerania and the University of Rostock Executive Board: Prof. Dr. Steffen Mitzner (Chairman) 1990: • Idea of MARS ® (Molecular Adsorbents Recirculating System) formed at the Meeting “Artificial Liver Support” in Celle, Germany by Students and Mentors of Rostock 1991: •MARS ® therapy: First patent filed by J. Stange and W. Ramlow 1993: •Continuation in part patent filed by J. Stange, Steffen Mitzner and W. Ramlow •1 st MARS ® - treatment at the Department of Internal Medicine, University of Rostock 1992: • Jan Stange receives Grant for Artifical Liver (2 Mio DM by BMBF) and founds group with Steffen Mitzner in Rostock 1997: • Foundation of Society for Extracorporeal Detoxication (VED) e.V. • Establishment of Biopure Medizinprodukte GmbH & TERAKLIN GmbH • National Champion „Biopure GmbH“ - Entrepreneurs Competition „Start Up 1997“ 1999: • Biopure Medizinprodukte GmbH & TERAKLIN GmbH merge to TERAKLIN AG •1 st MARS ® monitor with standardized sets for the MARS© therapy •1 st International Symposium on Albumin Dialysis (ISAD) in Rostock 2000: • 40 centers used a MARS ® therapy • Dr. Jan Stange moved to the United States; attended to multicenter study with 70 patients 2001: • Nomination of MARS ® therapy for German Future Prize 2002: • TERAKLIN AG: approvals in India, Australia, South Korea and Taiwan • TERAKLIN AG: application for approval of MARS ® in the USA at the Food and Drug Administration (FDA) at the end of the year 15 th October 2003 : • MARS ® in ordinance on case payments for 2004 - catalog, D 2004: • MARS ® in catalogs of the defined benefit hospital financing system, Austria • Establishment of Albutec GmbH • 09/2004 Acquisition of TERAKLIN AG by Gambro 2005: • MARS ® approval in the USA 2007: • Establishment of ARTCLINE GmbH 12 th March 2008: • Foundation of competence network „CEOS“ - Center for Extracorporeal Organ Support, Rostock 2011: •Foundation of Fraunhofer Group „EXIM“ - Extracorporeal Immunomodulation 2013: • 13 th ISAD as part of European Society for Artificial Organs (ESAO) - Congress in Rostock 2012: • Conception growth core „Support Center for Organ & Recovery“ in Rostock Chronicle Kidney dialysis 1748 • Discovery of renal replacement therapy by Jean Antoine Nollet 1802 • Discovery of hydro diffusion by Georg Friedrich Parrot 1812 • Discovery of membrane diffusion by Nicolaus Wolfgang Fischer 1854 • Epochal discovery of colloids and dialysis by Thomas Graham 1924 • 1 st dialysis with semipermeable membrane by Georg Haas in Germany 1943 • Breakthrough of artificial kidney (drum kidney) by Dutchman Willem Kolff 1946 • Development of Alwall dialyzer by Nils Alwall 1948 • Skeggs and Leonards developed the first slabs dialyzer 1950 • 1 st clinically effective dialysis in Germany by Curd Moeller 1960 • 1 st long-term patient with chronic renal failure receives hemodialysis 1963 • Horst Klinkmann developed artificial kidney in the GDR (East Germany) 1968 • 1 st home dialysis in Germany
