Before medical devices can be developed, produced and distributed on the market, special requirements first have to be met. Strict regulatory demands are placed on medical devices in order to transfer new therapeutic approaches or innovative products into clinical application and exploit them commercially. These requirements help ensure optimal product and patient safety. European conformity (CE) often implies high costs for companies, which is why experienced external experts, though not usually research institutes, are regularly called upon to verify that these requirements have been met (in the form of CE marking).
Thanks to the close collaboration between engineers, scientists and medical practitioners at Rostock's EXIM Unit, stretching back decades in some cases, the unit has the respective expertise, as seen in particular in the development and testing of new blood purification procedures and products right over to their successful market launch.
The basic idea behind the submitted project is to create a central facility for all companies and institutes that develop and produce medical devices, particularly in the field of blood purification, both on a regional and national level. Cost-intensive resources such as a certified test laboratory with qualified staff can be used by companies as an external service as and when required. Having a suitably accredited test laboratory on hand makes things a lot easier for the manufacturer as they work towards placing their product on the market. The project aims to establish a specialized, independent facility for assessing medical devices for blood purification and create the bases for its economic operation following start-up funding. The goal here is to become accredited as a test laboratory for medical devices by the German accreditation body (DAkkS). There is also a strong possibility that a spin-off can be founded once the funding period has expired.
The project is being funded using means provided by the European Union made available through the European Regional Development Fund (ERDF) and the Ministry for Economic Affairs, Labor and Health of Mecklenburg-West Pomerania
Funding reference number: GW-19-0001
Patients whose bodies have a weakened detoxification function due to a late-stage chronic kidney disease regularly need to have dialysis. The principle behind this procedure has been established for decades and is based on extracting water-soluble toxins (uremia toxins) in an extracorporeal filter, i.e. the dialyzer. The toxins pass from the blood into the purifying dialysis water (dialysate) via a membrane in the dialyzer. Around 120 liters of dialysate are required for every dialysis treatment, which usually takes four hours and is repeated three times a week. This water is taken from reverse osmosis (RO) plants in hospitals and specialized dialysis practices. Not only do these plants take up a lot of space and energy, but the water can only be used once as it disappears as waste water following dialysis. Based on a one-year time frame and 90 000 patients in Germany, over 1.7 million cubic meters of highly purified water are needed, without even taking the lost RO water into account.
Based on an approach which has never been applied to dialysis in the past, a procedure is being developed in the Department of Extracorporeal Immunomodulation that facilitates the regeneration of used dialysis water and could therefore completely change the huge problem of water dependability affecting the use of dialysis today. This procedure draws on the concept of freeze concentration used in the beverage industry and is based on the principle that the crystal lattice structure of frozen water excludes any previously dissolved foreign substances. As part of an automatable cycle, the procedure enables contaminated dialysate to be separated into pure water and a small residual volume containing impurities. This residual volume may arise from the patient’s regular liquid intake, removing the dialysis’ dependency on a pure water supply and making entirely mobile solutions conceivable. The fact that this separation occurs regardless of substance properties such as solubility, polarity, size, density, etc. is hugely beneficial compared with all conventional filter-based procedures, which do not demonstrate a sufficient filter capacity, especially for urea.
The procedure is currently being patented and an automated solution is undergoing development. This technical solution will then be used to carry out extensive investigations to specify process parameters that can later be used when working towards the initial clinical application. Notable industrial companies have already shown an interest in the procedure despite it’s early stage of development.
This sub-project forms part of the HOGEMA joint project: "Researching novel approaches to provide improved tissue replacement materials based on hydrostatic high-pressure treatment".
The project sees partners from the University of Rostock, Greifswald University Hospital, Wismar University of Applied Sciences, Fraunhofer IZI and the University of Rostock's Department of Medicine working together to explore new ways of providing more effective tissue replacement materials based on hydrostatic high-pressure treatment.
Fraunhofer IZI’s Extracorporeal Immunomodulation Unit (EXIM) will investigate the applicability of hydrostatic high-pressure technology in rodents, looking at soft tissue such as the kidneys or intestines. The aim here is to produce tissue scaffolds with a much higher matrix integrity than when using wet chemical methods. By subsequently repopulating the scaffolds with human cells, these models can be used for a number of medical, pharmacological and biotechnical investigations.
More information on the "HOGEMA" research alliance can be found at: hogema.med.uni-rostock.de
The project is supported using funds provided by the European Social Fund (ESF) within the scope of the qualification program "Promotion of junior scientists in outstanding research alliances – excellence in research program of the state of Mecklenburg-Western Pomerania".
Funding reference number: ESF/14-BM-A55-0012/18
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.
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.
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.
Sepsis, also commonly referred to as blood poisoning, is a complex systemic inflammatory response produced by the body. It is usually triggered by bacteria and their toxins when they manage to enter the bloodstream and results in a powerful immune response which is also directed in part against the patient’s own body. In severe cases, the patient becomes highly susceptible to secondary infections and multiple organ failure. Sepsis and its serious forms of progression is becoming more and more prevalent around the world. This explains why severe cases of sepsis still prove fatal in over 50 per cent of cases today, in spite of the various state-of-the-art intensive care options available. It is essential that the disease is diagnosed and effective antibiotic treatment initiated as quickly as possible: this can mean the difference between life and death. In order to improve a patient’s prognosis, various therapeutic approaches such as renal replacement therapy or adsorptive procedures can be introduced in addition to standard treatment. Hemoperfusion is an important adsorptive procedure, whereby the patient’s blood passes extracorporeally through a cartridge containing an adsorbent. The various commercially available adsorbers target either the removal of toxins (lipopolysaccharides) or of inflammatory mediators (cytokines / chemokines), which are increasingly released during the overreaction of the immune system. This type of cytokine adsorber (CytoSorb) was examined in collaboration with the company CytoSorbents Europe GmbH. CytoSorb adsorption columns are approved in Europe as an auxiliary extracorporeal treatment for sepsis. The columns aim to remove pro- and anti-inflammatory messenger substances from the blood during the immediate defense response where possible. As, however, this adsorption is a non-specific process, investigations were carried out into whether and to what extent different medications used in intensive care such as antibiotics and also other substances such as painkillers, sedatives, cardiovascular drugs and anticoagulants are similarly retained by the adsorber. In in-vitro studies it could be shown that the investigated adsorber removes a significant amount of an anticoagulant-inhibitor (rivaroxaban) from the blood. This finding is of direct clinical relevance: patients who take this anticoagulant-inhibitor and require emergency surgery cannot be subjected to surgery before the active agent has been completely excreted from the body – a process that can take up to eight hours. The adsorber could notably reduce this waiting time, thereby gaining valuable therapy time. Further investigations into the removal of various other interesting substance classes are scheduled for 2018.
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.
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.
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).
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.