Extracorporeal Immunomodulation

The Fraunhofer project group Extracorporeal Immunomodulation (EXIM) in Rostock is dedicated to the development of new diagnostic and treatment procedures in the field of extracorporeal organ replacement systems. Here, work is focused around innovative systems which support the immune system, as well as on functional analyses, improvements to existing medical engineering systems, cell culture based in vitro diagnostics and clinical trials.

The group offers the entire spectrum of preclinical and clinical analyses of extracorporeal technologies based on a broad spectrum of in vitro simulations and animal models as well as on a strong clinical study network for in- and out-patients. Furthermore, the group offers a range of analytical and diagnostic methods, including a cell sensor it developed itself and various molecular assays. By drawing on its close-knit network of cooperation partners, the group also has access to additional state-of-the-art technologies.

The project group is funded by:

Logo EFRE
Logo Ministry of Education, Science and Culture Mecklenburg-Vorpommern

EXTHER – Extracorporeal therapy systems

The EXTHER project area focuses on the development and testing of innovative therapies, in particular those which aim to support the immune system. Novel treatment strategies are developed on the basis of classic extracorporeal technology platforms, such as dialysis and plasma separation. Special emphasis is placed on the development of extracorporeal blood treatment methods for sepsis therapy. Another approach is the development of extension systems for dialysis.

Development of the extracorporeal immune support system (EISS)

Over 18 million people around the world suffer from severe sepsis every year. In Germany alone, up to 60,000 people die from the disease every year. This is why, together with the company Artcline GmbH, the EXIM group has developed and evaluated a cell bioreactor system which can be used to treat sepsis using immune cells (granulocytes) taken from healthy donors. In doing so, the patient's plasma is circulated extracorporeally in a bioreactor with a granulocyte concentrate taken from a donor of a compatible blood group. During this process, bacterial toxins and other inflammatory substances are removed from the blood plasma by means of phagocytosis, allowing the purified patient plasma to be fed back into the patient's bloodstream. Initial clinical results show a clear improvement in patients' cellular immunocompetence, alongside the decrease in bacterial components. Further clinical trials with adjusted parameters are planned for the near future.

Granulocyte purification

This project looks at optimizing the purification of granulocytes, which are required for the extracorporeal immune support system. A key goal here is to extend storage time under currently applicable transfusion medicine conditions. At present, granulocyte concentrates can only be stored for up to 24 hours at 20–24 °C. An increase in the durability of granulocyte concentrates would significantly increase the flexibility of the therapies to be conducted in an everyday clinical setting and also the logistics associated with donations. Furthermore, pure granulocyte concentrations cannot be manufactured at present as the preparation becomes contaminated by a certain amount of erythrocytes and thrombocytes during apheresis. This project therefore also aims to process human blood preparations in such a way that allows the purest granulocyte fraction possible to be obtained and, in turn, optimally used in a clinical and therapeutic context.

EXSIM – Extracorporeal simulation & models

The EXSIM project area primarily evaluates the therapeutic and toxic effects (hepatotoxicity) of innovative active ingredient components with the aid of in vitro and in vivo models.

Biosensor technology for the prevention or early detection of liver failure

Liver failure is associated with a high mortality rate and can be caused by acute liver diseases or by the deterioration of an existing liver disease. However, medication such as paracetamol may also cause acute liver failure. Liver damage caused by medication is the most common reason for withdrawing drugs that have already been approved for the market. However, there is no reliable test system available at present to detect liver failure at an early stage. This gave rise to the development of a microtiter plate assay based on human liver cells that can be used to detect liver failure at an early stage in a clinical setting and to evaluate the toxicity of drugs and medical devices. By optimizing and standardizing the procedure, reliable statements can be made with regard to exogenous, and also endogenous, toxicity.

Clay minerals in the treatment of CKD and CIBD

The use of clay minerals represents an innovative therapeutic approach in the treatment of chronic inflammatory bowel disease (CIBD). The therapeutic and prophylactic potential of the envisaged clay minerals is currently being characterized in detail with the aid of cell-based models and animal trials. Besides the positive therapeutic and prophylactic effects in the case of CIBD, clay minerals have already been proven to have no toxic potential. The applied clay minerals are assumed to have effects which strengthen the intestinal barrier, such as an antioxidant potential, as well as the ability to bind endotoxins and thus support the treatment of CIBD.

An additional field of application uses clay minerals as phosphate binders in patients suffering from chronic kidney disease (CKD). Patients with renal insufficiency often suffer from much higher phosphate concentrations in the blood serum, which can lead to cardiovascular diseases. To counter this, the phosphate-binding capacity of clay minerals is currently being investigated in a new therapeutic approach with regard to the prevention of cardiovascular diseases. The therapeutic potential is currently being analyzed using an in vitro calcification model for human coronary artery smooth muscle cells (HCASMC) and also in animal trials involving rats with chronic renal failure (5/6 nephrectomy, 5/6 NX).

ECOS – Study center for extracorporeal methods and biosimulation

In order to translate the scientific concepts of the project group into clinical applications in a timely manner, the ECOS study center has now been integrated into the group. On the one hand, the study center will be dedicated to implementing its own scientific concepts and developments in practice; on the other, it shall conduct clinical and preclinical trials in the field of medical extracorporeal therapies and systems on behalf of industry partners and in close cooperation with the University of Rostock's Department of Medicine (UMR) and local hospitals. The research concerns both interventional and non-interventional trials with drugs and medical devices. Our chain of competence here covers all aspects of clinical trials, from planning over to conduct and monitoring through to biometric evaluation and publication. Another key research area lies in analyzing the spread, causes and processes as well as the influencing factors and interactions of diseases in the field of indication, based on clinical and representative population data.

At present, ECOS is involved in a multicenter clinical trial investigating the efficacy and safety of the extracorporeal liver assist device ELAD® in patients with severe alcoholic hepatitis. Two additional observational studies will investigate the effectiveness of using different adsorbers in albumin dialysis and / or for the treatment of patients with severe sepsis.

The Fraunhofer unit in Rostock mainly works in the areas of blood purification and detoxification therapies.

Medical device development

  • In vitro models for extracorporeal methods (organ support outside the patient's body)
  • Process development (e.g. new methods for liver replacement therapy)
  • Creating prototypes
  • Constructing bioreactors
  • Analyzing functional models (e.g. testing dialysis membranes or adsorber cartridges)

Diagnostic and therapeutic cell cultures

  • In-vitro toxicity according to ISO 10933-5 for medical products
  • Analysis of hepatotoxicity (drugs and medical products)
  • Biosensor technology: Early detection of liver failure
  • Producing immune cell concentrates (accumulating granulocytes from whole blood)

Chemical analysis (GCMS, LCMS)

  • Endotoxins
  • Lipophilic protein ligands (especially albumin-bound toxins)

Clinical trials

  • Preclinical and clinical trials with large patient populations
  • Study design, conduct and evaluation
  • Regulatory aspects

Clinical expertise

  • Nephrology
  • Dialysis
  • Intensive medicine
  • Sepsis

  • Albutec GmbH
  • ALLMED Medical GmbH
  • Analytic Jena AG
  • Artcline GmbH
  • BioArtProducts GmbH
  • CytoSorbents Europe GmbH
  • Fibron GmbH
  • FIM Biotech GmbH
  • Furtwangen University, Faculty Medical and Life Sciences (MLS)
  • Gambro Dialysatoren GmbH
  • infomed – Blood purification devices
  • Leib­niz In­sti­tu­te for Plas­ma Sci­ence and Tech­no­lo­gy
  • PRIMACYT Cell Culture Technology GmbH
  • Serumwerk Bernburg AG
  • University Hospital Rostock, Center for Internal Medicine, Clinic II, Department of Gastroenterology
  • University of Greifswald, University Medicine, Institute for Immunology and Transfusion Medicine
  • University of Rostock, Center for Internal Medicine, Clinic II, Department for Nephrology
  • University of Rostock, Faculty of Medicine, Institute for Transfusion Medicine
  • Vital Therapies, Inc.

Publications

  • Ehler J, Koball S, Sauer M, Mitzner S, Hickstein H, Benecke R, Zettl UK. Response to Therapeutic Plasma Exchange as a Rescue Treatment in Clinically Isolated Syndromes and Acute Worsening of Multiple Sclerosis: A Retrospective Analysis of 90 Patients. Plos One 2015 Aug 5;10(8):e0134583. DOI dx.doi.org/10.1371/journal.pone.0134583. eCollection 2015
  • Maruschke M, Riebold D, Holtfreter MC, Sombetzki M, Mitzner S, Loebermann M, Reisinger EC, Hakenberg OW. Pneumocystis pneumonia (PCP) and Pneumocystis jirovecii carriage in renal transplantation patients: a single-centre experience. Wien Klin Wochenschr. 2014 Dec;126(23-24):762-6.
  • Frimmel S, Schipper J, Henschel J, Yu TT, Mitzner SR, Koball S. First description of single-pass albumin dialysis combined with cytokine adsorption in fulminant liver failure and hemophagocytic syndrome resulting from generalized herpes simplex virus 1 infection. Liver Transpl. 2014 Dec;20(12):1523-4.
  • Klammt S, Mitzner SR, Reisinger EC, Stange J. No sustained impact of intermittent extracorporeal liver support on thrombocyte time course in a randomized controlled albumin dialysis trial. Ther Apher Dial. 2014 Oct;18(5):502-8.
  • Mencke T, Jacobs RM, Machmueller S, Sauer M, Heidecke C, Kallert A, Pau HW, Noeldge-Schomburg G, Ovari A. Intubating conditions and side effects of propofol, remifentanil and sevoflurane compared with propofol, remifentanil and rocuronium: a randomised, prospective, clinical trial. BMC Anesthesiology 2014; DOI dx.doi.org/10.1186/1471-2253-14-39.
  • Ehler J, Koball S, Sauer M, Hickstein H, Mitzner S, Benecke R, Zettl UK. Therapeutic plasma exchange in glucocorticosteroid-unresponsive patients with Clinically Isolated Syndrome. Therapeutic Apheresis and Dialysis. 2014 Oct;18(5):489-96.DOI dx.doi.org/10.1111/1744-9987.12176
  • Frimmel S, Schipper J, Henschel J, Yu TT, Mitzner SR, Koball S. First description of single-pass albumin dialysis combined with cytokine adsorption in fulminant liver failure and hemophagocytic syndrome resulting from generalized herpes simplex virus 1 infection. Liver Transplantation. 2014 Dec;20(12):1523-4. DOI dx.doi.org/10.1002/lt.24005
  • Klammt S, Mitzner SR, Reisinger EC, Stange J. No sustained impact of intermittent extracorporeal liver support on thrombocyte time course in a randomized controlled albumin dialysis trial. Therapeutic Apheresis and Dialysis. 2014 Oct;18(5):502-8. DOI dx.doi.org/10.1111/1744-9987.12124
  • Breitrück A, Sparmann G, Mitzner S, Kerkhoff C. Establishment of a novel extracorporeal bowel model to study luminal approaches to treat inflammatory bowel disease. Dis Model Mech. 2013; 6:1487-1493. DOI dx.doi.org/10.1242/dmm.011734
  • Bañares R, Nevens F, Stolze Larsen F, Jalan R, Albillos A, Dollinger M, Saliba F, Sauerbruch T, Klammt S, Ockenga J, Pares A, Wendon J, Brünnler T, Kramer L, Mathurin P, Mata MD, Gasbarrini A, Müllhaupt B, Wilmer A, Laleman W, Eefsen M, Sen S, Zipprich A, Tenorio T, Pavesi M, Schmidt HH, Mitzner S, Williams R, Arroyo V. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: The RELIEF trial. Hepatology 57 (2013)3: 1153-1162. DOI dx.doi.org/10.1002/hep.26185
  • Mitzner S, Gloger M, Henschel J, Koball S. Improvement of hemodynamic and inflammatory parameters by combined hemoadsorption and hemodiafiltration in septic shock: A case report. Blood purification 35 (2013) 4: 314-315. DOI dx.doi.org/10.1159/000351206
  • Sauer M, Altrichter J, Mencke T, Klöhr S, Thomsen M, Kreutzer HJ, Nöldge-Schomburg G, Mitzner S. Role of different replacement fluids during extracorporeal treatment in a pig model of sepsis. Ther Apher Dial. 17 (2013) 1:84-92. DOI dx.doi.org/10.1111/j.1744-9987.2012.01103.x
  • Mitzner S. Stellenwert der MARS®-Dialyse beim Acute-on-chronic-Leberversagen: Role of MARS® dialysis in acute-on-chronic liver failure. Z Gastroenterol. 51 (2013) 10: 1193-1194. DOI dx.doi.org/10.1055/s-0033-1350351
  • Averill MM, Kerkhoff C, Bornfeldt KE. S100A8 and S100A9 in cardiovascular biology and disease. Arterioscler Thromb Vasc Biol. 32 (2012), 2, S. 223-9. DOI dx.doi.org/10.1161/ATVBAHA.111.236927.
  • Kerkhoff C, Voss A, Scholzen TE, Averill MM, Zänker KS, Bornfeldt KE. Novel insights into the role of S100A8/A9 in skin biology. Exp Dermatol. 21 (2012), 11, S. 822 - 6. DOI dx.doi.org/10.1111/j.1600-0625.2012.01571.x.
  • Kielstein JT, Beutel G, Fleig S, Steinhoff J, Meyer TN, Hafer C, Kuhlmann U, Bramstedt J, Panzer U, Vischedyk M, Busch V, Ries W, Mitzner S, Mees S, Stracke S, Nürnberger J, Gerke P, Wiesner M, Sucke B, Abu-Tair M, Kribben A, Klause N, Schindler R, Merkel F, Schnatter S, Dorresteijn EM, Samuelsson O, Brunkhorst R; Collaborators of the DGfN STEC-HUS registry. Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry. Nephrol Dial Transplant. 27 (2012), 10, S. 3807-15. DOI dx.doi.org/10.1093/ndt/gfs394.
  • Klammt S, Wojak HJ, Mitzner A, Koball S, Rychly J, Reisinger EC, Mitzner S. Albumin-binding capacity (ABiC) is reduced in patients with chronic kidney disease along with an accumulation of protein-bound uraemic toxins. Nephrol Dial Transplant. 27 (2012), 6, S. 2377-83. DOI dx.doi.org/10.1093/ndt/gfr616.
  • Klionsky DJ and 1269 others. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 8 (2012), 4, S. 445 - 544. DOI dx.doi.org/10.4161/auto.19496.
  • Maletzki C, Bodammer P, Breitrück A, Kerkhoff C. S100 proteins as diagnostic and prognostic markers in colorectal and hepatocellular carcinoma. Hepat Mon. 2012, 12 (10 HCC):e7240. DOI dx.doi.org/10.5812/hepatmon.7240.
  • Sauer M, Altrichter J, Mencke T, Klöhr S, Thomsen M, Kreutzer HJ, Nöldge-Schomburg G, Mitzner SR. Plasma separation by centrifugation and subsequent plasma filtration: impact on survival in a pig model of sepsis. Ther Apher Dial. 16 (2012), 3, S. 205-12. DOI dx.doi.org/10.1111/j.1744-9987.2011.01055.x.
  • Sauer M, Haubner C, Mencke T, Nöldge-Schomburg G, Mitzner S, Altrichter J, Stange J. Impaired cell functions of hepatocytes incubated with plasma of septic patients. Inflamm Res. 61 (2012), 6, S. 609-16. DOI dx.doi.org/10.1007/s00011-012-0451-9.
  • Voss A, Bode G, Kerkhoff C. Double-stranded RNA induces IL-8 and MCP-1 gene expression via TLR3 in HaCaT-keratinocytes. Inflamm Allergy Drug Targets. 11 (2012), 5, S. 397-405.
  • Voss A, Gescher K, Hensel A, Nacken W, Zänker KS, Kerkhoff C. Double-stranded RNA induces S100 gene expression by a cycloheximide-sensitive factor. FEBS Lett. 586 (2012), 2, S. 196-203. DOI dx.doi.org/10.1016/j.febslet.2011.12.022
  • Kohl M, Koch S, Keller M, Deigner HP. Biochips: Bright Future in Clinical Dx? J Biochip Tissue chip 2011, S1. DOI dx.doi.org/10.4172/2153-0777.S1-e003

Patents

  • Altrichter, J, Mitzner, S, Lübcke A, Selleng K, Doss F, Koch S. Verfahren zum Herstellen einer Leukozytenpräparation und Leukozytenpräparation. METHOD FOR PRODUCING A LEUKOCYTE PREPARATION, AND LEUKOCYTE PREPARATION. DE 102012209673 A1: 20120608
  • Mitzner S, Kerkhoff C, Bodammer P, Breitrück A, Krüger G. Mineralische Verbindung zur Reduzierung von anorganischen Phosphaten, insbesondere im Rahmen einer Nierenersatztherapie. CLAY MINERAL FOR REDUCING INORGANIC PHOSPHATES, IN PARTICULAR IN RENAL REPLACEMENT THERAPY. DE 102012209411 A1: 20120604
  • Mitzner S, Kerkhoff C, Emmrich F, Breitrueck A, Bodammer P, Krueger G, Dallwig R. Mineralische Verbindung und deren Modifikationen zur Anwendung bei chronisch-entzündlichen Darmerkrankungen. CLAY MINERAL AND ITS MODIFICATIONS FOR USE IN THE TREATMENT OF CHRONIC INFLAMMATORY BOWEL DISEASES. DE 102012207471 A1: 20120504

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MEDICA 2017 - World Forum for Medicine | November 13 – 16, 2017 | Düsseldorf, Germany | hall 15, stand 15/E05