Materials, surfaces, and systems for extracorporeal therapies and beyond
Int J Artif Organs 2017; 40(1): 1 - 3
Article Type: EDITORIAL
AuthorsViktoria Weber, Thomas Groth
- • Accepted on 24/02/2017
- • Published in print on 06/03/2017
- • Available online on 07/03/2017
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This issue is dedicated to Dr. Dieter Falkenhagen, physicist and nephrologist, one of the pioneers in the field of artificial organs and blood purification, whose work and activities profoundly influenced and stimulated the development of extracorporeal therapies (1, 2). Extracorporeal therapies were his central topic of interest, and the development of blood compatible materials and therapies for extracorporeal blood purification to provide better care for patients with acute and chronic kidney and liver failure was always in the focus of his scientific work. He never ceased to thrive for new technological developments and the translation of these findings into medical products and eventually into clinical application – from the development of hemocompatible materials and the introduction of the Prometheus extracorporeal liver support system to regional citrate anticoagulation.
According to Louis Pasteur, there are no such things as applied sciences, but only applications of science. It was Dieter Falkenhagen’s scientific background and his education in physics and medicine that provided him with an understanding of both: medical challenges and physical phenomena such as interfacial properties or mass transfer to approach the development of biomedical devices and new therapies.
As a highly active member of the scientific community in the field of artificial organs, Dieter Falkenhagen contributed greatly to the collaboration and to the education of scientists, engineers, and clinicians across disciplines. He was elected board member of the European Society for Artificial Organs (ESAO) for many years, served as ESAO president from 2000-2002, organized the ESAO Congress 2007 in Krems and established the ESAO Winter and Summer schools to provide a platform for the exchange of knowledge between students, postdoctoral fellows, clinicians, and engineers.
The current issue reflects a number of topics brought forward by Dieter Falkenhagen in the field of extracorporeal therapies and biomedical technology, which has grown into a highly interdisciplinary area of artificial organ research and an important pillar of Regenerative Medicine.
Summary of contents
Sepsis remains one of the leading causes of morbidity and mortality worldwide, and its incidence continues to increase (3). Due to the heterogeneity of septic patients, the development of targeted sepsis treatments remains a major challenge (4). Numerous clinical trials using antagonists such as antibodies or soluble receptor constructs to target individual inflammatory mediators have failed to improve survival rates (5). Extracorporeal therapies aiming at the restoration of immune homeostasis have delivered promising preclinical and early clinical results, but have not yet been translated into clinical routine. A potential advantage of extracorporeal approaches is that they affect only excess circulating pools of inflammatory mediators, whereas the systemic administration of antagonists can lead to a complete blockade of their targets at tissue level as well (6, 7). Adsorbent and filter-based blood purification systems aim to lower levels of pathogen-associated molecular patterns, such as lipopolysaccharide (endotoxin), and of cytokines, chemokines, as well as complement or coagulation factors (8). Techniques for the nonselective removal of a variety of inflammatory mediators include high-volume hemofiltration, high cut-off hemofiltration, coupled plasma filtration adsorption, and hemoadsorption. Adsorption of endotoxin, the main component of the outer membrane of Gram-negative bacteria and the primary trigger of Gram-negative sepsis, from human blood has been clinically applied since its introduction in Japan in the early 1990s (9). It is based on cartridges containing polystyrene fibers functionalized with polymyxin B (PMX-DHP, Toraymyxin), a cationic antibiotic with high affinity for endotoxin. Its primary mechanism of action is through neutralization of circulating endotoxin, while secondary effects may include the entrapment of inflammatory cells in the fiber cartridge (10), the binding of circulating apoptotic fragments (11), as well as the release of low doses of polymyxin B from the polystyrene carrier (12), as discussed in the contribution by Hartmann et al in this issue (13).
The endothelium, located at the interface of the vasculature and the surrounding tissues, is among the first host tissues to interact with invading pathogens, microbial components, as well as with endogenous metabolite-related danger signals in the circulation during systemic infection (14-15-16). Pathogen recognition by the innate immune system induces a shift of the endothelium from a nonadhesive, anticoagulant surface into an adhesive, procoagulant state. Immune cells recruited to the activated endothelium enhance coagulation, for example, via the release of neutrophil extracellular traps, resulting in a propagation of the inflammatory response and an exacerbation of endothelial activation (17, 18), organ damage, and multiple organ failure. A deeper understanding of the response to inflammatory stimuli may add to the progress in specific interventions to protect the host against its own overwhelming defense mechanisms. In this context, experimental models using endothelial cells have become valuable tools supporting the exploration of therapeutic approaches targeting endothelial dysfunction (16, 19), as reviewed in the contribution of Eichhorn et al (20) in this issue.
As a general feature of all extracorporeal treatment approaches, the blood compatibility of biomaterials used in these devices is crucial in order to minimize an activation of coagulation factors, platelets, and the innate immune system triggered by contact of blood with large foreign surfaces. Blood compatibility is not only influenced by the nature of the biomaterials used in extracorporeal devices, but may also be impacted by anticoagulation, as shown in the contribution by Strobl et al in this issue (21), which addresses the impact of regional citrate anticoagulation on inflammatory parameters. On the biomaterial level, coatings of surfaces with bioinspired patterns have been employed to improve the blood compatibility of biomaterial surfaces, such as adsorbent polymers, as shown in the contribution by Semak et al (22). Different strategies have been described in this publication to improve blood compatibility in reducing adsorption of proteins by decrease of interfacial energy and steric repulsion using synthetic, hydrophilic polymers (23, 24), but also through application of glycans in a biomimetic manner (25).
Glycosaminoglycans (GAG) represent a specific class of these glycans found on the surface of mammalian cells, but also in the extracellular matrix. They have a large range of activities including cytokine stabilization and activation, anticoagulant activity (e.g., by heparin) and direct interactions with cell receptors involved in activation of cell migration and growth (e.g., hyaluronan and CD 44 cell receptor) (26). Immobilization of GAG on biomaterials can be made in a variety of manners either covalently (e.g., 27), but also by physical adsorption, which is particularly stable when done by means of layer-by-layer technique (28). It has been found that GAGs play an important role in the development and progression of cancer affecting adhesion, growth, and migration as well as the invasiveness and metastatic potential of cancer cells (29). Hence, immobilization of GAGs on the surfaces of materials can be used to develop models systems for studying tumor cell biology or to establish cocultures of cancer cells with stroma cells and leukocytes (30). The contribution from Köwitsch et al published in this issue (31) demonstrates that thiolated GAGs maintain their bioactivity towards adsorption of proteins with heparin-binding domains, like fibronectin, when they are covalently immobilized on surfaces by photochemical reactions. More importantly, it was shown that thiolated GAGs affect adhesion of 2 different breast cancer cell lines, showing an increase in attachment with the increase in the degree of GAG sulfation and enhanced migration on hyaluronan-coated surfaces. This certified that thiolation of GAGs did not impair their bioactivity, which makes them suitable for development of tumor models.
The last contribution of this special issue devoted to our colleague and friend Dieter Falkenhagen is focused on accidental hypothermia, which is a rare but life-threatening situation and was the topic of an ESAO Winterschool organized jointly by Dieter Falkenhagen and Beat Walpoth. The article written by Beat Walpoth et al (32) describes encouraging long-term, sequelae-free survival rates of 47% after rewarming of deep accidental hypothermic patients in cardiac arrest using cardiopulmonary bypass in a Swiss multicenter study. The article calls for more participation in a registry to find new outcome predictors and propose better guidelines for the treatment of deep accidental hypothermia victims (https://www.hypothermia-registry.org), which will permit more cases to be collected in order to achieve statistical significance and provide better evidence-based recommendations.
Weber V Groth T In memoriam Dieter Falkenhagen (1942-2015): Pioneer, enthusiast, visionary. 2015 38 11 615 616
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Strobl K Harm S Weber V Hartmann J The role of ionized calcium and magnesium in regional citrate anticoagulation and its impact on inflammatory parameters. 2017 40 1 15 21
Semak V Fischer MB Weber V Biomimetic Principles to Develop Blood Compatible Surfaces. 2017 40 1 22 30
Groll J Fiedler J Bruellhoff K Moeller M Brenner RE Novel surface coatings modulating eukaryotic cell adhesion and preventing implant infection. 2009 32 9 655 662
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Dickinson LE Ho CC Wang GM Stebe KJ Gerecht S Functional surfaces for high-resolution analysis of cancer cell interactions on exogenous hyaluronic acid. 2010 20 31 5472 5478
Köwitsch A Chhalotre A Groth T Effect of thiolated glycosaminoglycans on the behavior of breast cancer cells - Towards development of in vitro models of cancer, 2017 40 1 31 39
Walpoth BH Meyer M Gaudet-Blavignac C Baumann P Gilquin P Lovis C The International Hypothermia Registry (IHR) - Dieter’s ESAO Winter Schools & Beat’s International Hypothermia Registry. 2017 40 1 40 42
- Weber, Viktoria [PubMed] [Google Scholar] 1, * Corresponding Author (firstname.lastname@example.org)
- Groth, Thomas [PubMed] [Google Scholar] 2, 3, * Corresponding Author (email@example.com)
Center for Biomedical Technology, Christian Doppler Laboratory for Innovative Therapy Approaches in Sepsis, Danube University Krems, Krems - Austria
Biomedical Materials Group, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale) - Germany
Interdisciplinary Center of Materials Science, Martin Luther University Halle-Wittenberg, Halle (Saale) - Germany