® ® ® th th 1990: • Idea of MARS (Molecular Adsorbents Recirculating System) 1991: •MARS therapy: First patent filed 1992: • Jan Stange receives Grant for Artifical Liver 1993: •Continuation in part patent filed 1997: • Foundation of Society for Extracorporeal Detoxication (VED) e.V. 1999: • Biopure Medizinprodukte GmbH & TERAKLIN GmbH merge to TERAKLIN AG 2000: • 40 centers used a MARS therapy 2007: • Establishment of ARTCLINE GmbH 12 March 2008: • Foundation of competence network „CEOS“ 2011: •Foundation of Fraunhofer Group „EXIM“ - Extracorporeal Immunomodulation 2013: • 13 ISAD as part of European Society for Artificial Organs (ESAO) formed at the Meeting “Artificial Liver Support” in Celle, by J. Stange and W. Ramlow (2 Mio DM by BMBF) and founds group by J. Stange, Steffen Mitzner and W. Ramlow • Establishment of Biopure Medizinprodukte GmbH & TERAKLIN GmbH •1st MARS® monitor with standardized sets for the MARS© therapy • Dr. Jan Stange moved to the United States; - Center for Extracorporeal Organ Support, - Congress in Rostock attended to multicenter study with 70 patients 2012: • Conception growth core „Support Center for Organ & Recovery“ in Rostock by Students and Mentors of Rostock with Steffen Mitzner in Rostock •1st MARS®- treatment at the Department of •National Champion „Biopure GmbH“ - •1st International Symposium on Albumin Dialysis (ISAD) in Rostock Internal Medicine, Entrepreneurs Competition „Start Up 1997“ ® 2001: • Nomination of MARS therapy for German Future Prize RTC Stemcells, Montag, 14.03.2011 Experimentelle Chirurgie

PROGRAMM Verbund 3: Organ Regeneration Gründung der Fraunhofer-Gruppe ELIMINATION OF TOXINS 2002: • TERAKLIN AG: approvals in India, Australia, South Korea and Taiwan „Extrakorporale Immunmodulation“ EXIM Support Seracell AG ® Zentrum • TERAKLIN AG: application for approval of MARS in the USA at the Food and Drug CEOS BMBF-Innovationsforum „Bioaktive Zellfilter“ Klinische Forschung, 3 Forschungsdialyse Center for Extracorporeal Organ Support Regeneration Zellbiologie Institut Elektrotechnik Administration (FDA) at the end of the year Verbund 1: Verbund 5: Organ Support-Human- Organ Support Hardware Interface Center for Bluepoint Medical Montag, 14.03.2011 Dialysis against a recycled albumin solution Organ Support Artcline GmbH GmbH & CoKG ® . In: J Artif Organs 1993; 17: 809–813. Cases of patients treated with MARS© therapy AwardsGründung der Fraunhofer-Gruppe 15:00 - 16:30 WS2 Zellaufbereitung und Zelllagerung and Regeneration Impulsvortrag: PD Dr. Hans-Gert Heuft Stange J, Ramlow W, Mitzner S, Schmidt R, Klinkmann H.: 1 5 „Extrakorporale Immunmodulation“ EXIM Medizinische Hochschule Hannover, Institut für Transfusionsmedizin enables the removal of albumin-bound toxins (FLD e.V.) th ® A carrier-mediated transport of toxins in a hybridMolecular membrane. adsorbent Safety barrierrecycling bet- sys- Diskussion 15 October 2003 : • MARS in ordinance on case payments for 2004 - catalog, D The MARS08:30 – 09:30 Pressekonferenz® therapy has been honored with 17 na- Stange J, Mitzner S.: 09:30 – 11:00 Eröffnung und feierliche Vertragsunterzeichnung 16:30 - 17:00 Kaffee ween a patients blood and a bioartificial liver. In: J Artif Organs 1996; 19: 677–691. ACUTE DECOMPENSATION OF CHRONIC LIVER DISEASE Minister Henry Tesch tional and international awards17:00 - 18:30 (list:WS3 Bioaktive extract Filter in der Bio-, on Stange J, Mitzner SR, Risler T, Erley CM, Lauchart W, Goehl H, et al.: Ministerium für Bildung, Wissenschaft und Kultur MV Transfusionsmedizin Universitätsklinik tem (MARS): clinical results of a new membrane-based blood purification system for bioartificial liver Lebensmittel- und Umwelttechnologie : J Artif Organs 1999; 23: 319–330. Improvement of hepatorenal syn- Prof. Dr. Frank Emmrich support.In Universitätsklinik Öffentlich-private Partnerschaft Dagmar Heinicke, 40 years, first MARS® patient, jaundice awards). Direktor des Fraunhofer-Institutes für Zelltherapie und Immunologie Leipzig Impulsvortrag: Prof. Dr. Thomas Groth im Biomedizinischen Forschungszentrum Rostock y Martin-Luther-Universität Halle-Wittenberg, AG Biomedizinische Materialien The Histor of MARS Verbund 4: Verbund 2: ® Prof. Dr. Wolfgang Schareck Steffen R. Mitzner, Jan Stange, Sebastian Klammt, Teut Risler, Christiane M. Erley, Brigitte D. Bader, Elke 2004: • MARS in catalogs of the defined benefit hospital financing system, Austria - admission to the Department of Internal Medicine Rostock; falls into a coma Rektor der Universität Rostock Diskussion D. Berger, Werner Lauchart, Piotr Peszynski, Jens Freytag, Heiko Hickstein, Jan Loock, Johannes-Mathias Immune Modulation Organ Support Disposables Center for Organ Support Prof. Dr. Emil C. Reisinger Löhr, Stefan Liebe, Jörg Emmrich, Gero Korten and Reinhard Schmidt: - As part of MARSDekan der Med. Fakultät der Universität® external Rostock funding18:30 - 19:00 Abschlussdiskussion investments of drome with extracorporealIn: Liver Transplantation,Volume albumin dialysis mars: 6, Issue Results 3, May of 2000,a prospective, Pages: 277–286. randomized, - Studie: controlled Tübingen/ Fraunhofer AG EXIM and Regeneration MARS clinical trial. MEMBRANE Prof. Dr. Steffen Mitzner Moderation Prof. Dr. Udo Kragl Artcline GmbH Albutec GmbH - cause: chronic hepatitis C with acute decompensation of liver function HRO CEOS – “from Science to Clinic” • Establishment of Albutec GmbH Leiter der AG EXIM Universität Rostock, Interdisziplinäre Fakultät 10 million11:00-11:30 Rundgangeuros as well as industrial investments of Jan Stange, Steffen R. Mitzner, Sebastian Klammt, Jens Freytag, Piotr Peszynski, Jan Loock, Heiko Hick- 4 2 20:00 Abendveranstaltung (separate Einladung) - after the second day of the MARS® treatment: patient wakes up from coma 11:30-12:30 Buffet 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 30 million euros were acquired. vation. In: Liver Transplantation,Volume 6, Issue 5, September 2000, Pages: 603–613. - discharge from hospital after several MARS® treatments (preparation LTx) BMBF-Innovationsforum „Bioaktive Zellfilter“ Dienstag, 15.03.2011 Molecular Adsorbents Recirculating System • 09/2004 Acquisition of TERAKLIN AG by Gambro Steffen R. Mitzner,Improvement Sebastian Klammt,of Multiple Piotr Organ Peszynski, Functions Heiko in Hickstein, Hepatorenal Gero Syndrome Korten, Jan During Stange Albumin and Rein- Verbunde 1- 5 12:30 - 13:00 Eröffnung Innovationsforum Workshop der Studiengruppe EISS-2 hard Schmidt: • 1991: PromotionManfred Hempe of MARS® in the programme Dialysis with the Molecular Adsorbent Recirculating System. In: Therapeutic Apheresis,Volume 5, Issue Für das Bundesministerium für Bildung und Forschung Studienprotokolle für extrakorporale Zelltherapien 5, October 2001, Pages: 417–422. Dr. Jens Altrichter 09:00 - 10:30 I. Medizinische Grundlagen ‚PromotingGeschäftsführer derJunior Artcline GmbH Biotechnology Groups in East Schmidt LE, Sorensen VR, Svendsen LB, Hansen BA, Larsen FS.: Hemodynamic changes during a single Impulsvortrag: Dr. Martin Sauer treatment with the molecular adsorbents recirculating system in patients with acute-on-chronic liver MARS® FLUX DIALYZER diaMARS® ADSORPTION dia FLUX DIALYZER ® 13:00 - 18:30 Themen - Workshops MULTIORGAN FAILURE Universität Rostock, Klinik für Anästhesiologie und Intensivtherapie failure. Liver Transpl 2001; 7: 1034–1039. COLUMNS 2005: • MARS approval in the USA 13:00 - 14:30 WS1 Zellen in extrakorporalen Diskussion MARS®-Therapie Germany‘, DM 2 million, 5 years Albumin dialysis in cirrhosis with superimposed acute liver injury: A prospective, therapeutischen Anwendungen 10:30 - 11:00 Kaffeepause Heemann U, Treichel U, Loock J, Philipp T, GerkenG, Malago M, Klammt S, Loehr M, Liebe S, Mitrzner S, The procedure of the MARS®-therapy - 8-year-old girl with no anamnesis - admission to the Department of Cardiology Schmidt R, Stange J: Impulsvortrag: Prof. Dr. Jörg Vienken 11:00 - 12:30 II. Praktische Umsetzung controlled study. In: Hepatology (2002), 36, S.949-958. - Studie: Essen/HRO Fresenius Medical Care AG MARS The MARS® system removes protein-bound and water-soluble toxins with albumin dialysis. Trans- • January 1994: Dr. Jan Stange Impulsvortrag: Prof. Dr. Michael Bauer The ® therapy has caused a revolution in the field of liver therapy. The blood detoxification process helps to clean the liver - diagnosis: myocarditis, consequence: cardiac arrhythmia + cardiac arrest with the conse Diskussion Universität Jena, Klinik für Anästhesiologie und Intensivtherapie Steiner C, Mitzner S.: Experiences with MARS liver support therapy in liver failure: analysis of 176 pa- Diskussion tients of the International MARS Registry. In: Liver,Volume 22, Issue Supplement s2, April 2002, Pages: 14:30 - 15:00 Kaffee 20–25. outside the body. With this method water-soluble and water-insoluble protein-bound liver toxins are removed from the patient’s port proteins with free binding sites lure behind the MARS®-membrane and remove the toxins quence of cardiogenic shock and multi-organ failure - research grant by the Sandoz Foundation in 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: blood. from the blood. Toxin-removing material as the human serum albumin (HSA) is used. It is obtained the amount of DM 10,000 Liver, Volume 22, Issue Supplement s2, April 2002, pages 43–47. - failure of kidney, liver and respiratory system Biomedizinisches Forschungszentrum (BMFZ) · Schillingallee 68 · 18057 Rostock MARS® and expenses The Molecular Adsorbents Recycling System as a Liver Support System Jan Stange, Tarek I. Hassanein, Ravindra Mehta, Steffen R. Mitzn The procedure of the MARS® system is similar to the kidney dialysis and uses a toxin removing substance called albumin. Albumin is industrially from the donor’s blood. Molecules that bind to the albumin membrane are then remo- - revival succeeds, but the status of organ function is critical er and Robert H. Bartlett: • National Prize Winner ‚Biopure GmbH‘ at the Based on Albumin Dialysis: A Summary of Preclinical Investigations, Prospective, Randomized, Cont- 2004 Inclusion of MARS® in the OPS 301-catalog (code 8-858.0) rolled Clinical Trial, and Clinical Experience from 19 Centers. In: Artificial Organs, Volume 26, Issue 2, Chronicle Kidney dialysis a human plasma protein and acts as a natural detergent drawing toxins away from the blood. ved by passing through a charcoal column and an anion exchange, before being reintroduced into - use of 3 MARS® treatments: improvement of organ functions within 3 days + February 2002, Pages: 103–110. Founders Competition ‚Start Up 1997‘ on behalf Steiner C, Mitzner S., Christian Steiner and Steffen Mitzner: Experiences with MARS liver support the- The liver dialysis MARS® has the potential to save the life of patients with threatening liver diseases by the detoxification of the circuit. Both water-soluble toxins and strongly albumin-bound toxins are removed by this pro- 2004 Inclusion of MARS® in the DRG accounting system with additional fees ZE32 rapy in liver failure: analysis of 176 patients of the International MARS Registry. In: Liver, Volume 22, prevention from endogenous toxicopathy Issue s2, April 2002, Pages: 20–25. 1748 • Discovery of renal replacement therapy by Jean Antoine Nollet of the business consultancy McKinsey, the savings the liver. ® PATIENT BLOOD CIRCUIT MARS ALBUMIN CIRCUIT DIALYSATE CIRCUIT cess. from 2005 DRG-accounting system with additional fees 2005-10 to 2012 DRG- - discharge from hospital in a healthy condition after 6 weeks banks and the magazine ‚Stern‘ (under the patro- 1802 • Discovery of hydro diffusion by Georg Friedrich Parrot MARS By the ® therapy water-soluble and albumin-bound substances such as bile acids, bilirubin, accounting system with additional fees PA 20012-10 nage of Federal President Roman Herzog) prize 1812 • Discovery of membrane diffusion by Nicolaus Wolfgang Fischer fatty acids, ammonia, urea, and copper are removed. The use of the MARS® therapy ACUTE LIVER FAILURE money: DM 100,000 to Aldinger, Gericke, 1854 • Epochal discovery of colloids and dialysis by Thomas Graham - 30-year-old man with chronic schizophrenia: after taking 40 gram of paracetamol Stange & Mitzner st Acute liver failure 1924 • 1 dialysis with semipermeable membrane by Georg Haas in Germany -> admission to hospital • 28 August 1998: Honor of the winners of the - caused by acute viral infection, poisoning 1943 • Breakthrough of artificial kidney (drum kidney) by Dutchman Willem Kolff - early signs of kidney failure + slight confusion, delivery in kidney station Entrepreneurs Competition ‚Start Up 1997‘ in (caused by alcohol, drugs or mushrooms), - signs of serious liver damage, patient is unconscious 1946 • Development of Alwall dialyzer by Nils Alwall the Baroque Hall Rostock MARS® - number of cases - identification: life-threatening complications - full screen: liver failure • 2000: TERAKLIN AG: German Business Award in By 2012 the number of treated patients increased to more than 1948 • Skeggs and Leonards developed the first slabs dialyzer ( hepatic encephalopathy, jaundice, renal failure, multi-organ failure) - use of 5 MARS® treatments: improvement of clinical biochemical parameters st the amount of DM 50,000 1950 • 1 clinically effective dialysis in Germany by Curd Moeller After liver transplant surgery: transplant liver failure or severe graft - discharge from hospital in a healthy condition after 26 days 12,000 with more than 67,000 individual treatments in nearly 1960 • 1st long-term patient with chronic renal failure receives hemodialysis dysfunction • 2001 Nomination of the MARS® therapy for 450 centers in 30 countries. This includes more than 450 children the German Future Prize (under the patronage of who were treated with MARS®. 1963 • Horst Klinkmann developed artificial kidney in the GDR () Forum Leberdialyse (FLD) e.V. - was founded in 1997 as an association for extracorporeal detoxification (VED) e.V. Federal President Johannes Rau) st 1968 • 1 home dialysis in Germany 1999 Organization and execution – 1st International Symposium 2004 Nomination project „Olympia at the Schwanenteich“ for the 2010 Kick Off Project „Health Net-MV“ MARS© therapy has a positive effect on: on Albumin Dialysis (ISAD) 1st German Prevention Award by the Federal Ministry of 2011 Foundation of the Fraunhofer Group „Extracorporeal 2001 Execution of the first seminar on albumin dialysis in Health and Social Security Immunomodulation“ (EXIM) • survival rate/ - time • renal function • intracranial pressure Northern Germany • hemodynamics • hepatic encephalopathy • jaundice / cholestasis 2006 Execution of the course „Hepatitis B + C“ as part of the 7th 2012 Development of the concept “Wachstumskern „ - Center for Pathologies: • hepatic function 2002 Participation: 10th Day of Action against addictive dangers in Rostock German Liver Congress in Warnemünde Organ & Recovery Support“ • Autoimmune hepatitis • Alpha-1- antitrypsin deficiency 2008 Foundation of the Center for Extracorporeal Organ Support 2012 13th ISAD as part of the European Society for Artificial • Primary biliary cirrhosis (PBC) • Budd-Chiari Syndrome 2003 Renaming to FORUM LIVER DIALYSIS (FLD) e.V. • Primary sclerosing cholangitis (PSC) • Hepatocellular carcinoma (HCC) (CEOS); 12 March 2008 in Rostock Organs (E.S.A.O) – Congress in Rostock • Hemochromatosis sponsored by the Ministry of Education and Research, the state of -Western Pomerania and the University of Rostock Executive Board: Prof. Dr. Steffen Mitzner (Chairman)