IJAO ISSN 0391-3988
Int J Artif Organs 2017; 40(1): 1-3 DOI: 10.5301/ijao.5000576
EDITORIAL
Materials, surfaces, and systems for extracorporeal therapies and beyond Viktoria Weber1, Thomas Groth2,3 Center for Biomedical Technology, Christian Doppler Laboratory for Innovative Therapy Approaches in Sepsis, Danube University Krems, Krems - Austria 2 Biomedical Materials Group, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale) - Germany 3 Interdisciplinary Center of Materials Science, Martin Luther University Halle-Wittenberg, Halle (Saale) - Germany
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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 20002002, 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.
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Accepted: February 24, 2017 Published online: March 7, 2017 Corresponding authors: Viktoria Weber Christian Doppler Laboratory for Innovative Therapy Approaches in Sepsis and Center for Biomedical Technology Danube University Krems Dr.-Karl-Dorrek-Strass 30 3500 Krems, Austria
[email protected] Thomas Groth Biomedical Materials Group Martin Luther University Halle-Wittenberg Heinrich-Damerow-Strasse 4 06120 Halle (Saale), Germany
[email protected]
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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 Gramnegative sepsis, from human blood has been clinically applied since its introduction in Japan in the early 1990s (9). It is based
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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.
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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 (14-16). 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
Disclosures Financial support: No grants or funding have been received for this study. Conflict of interest: None of the authors has financial interest related to this study to disclose.
References 1. 2. 3. 4. 5. 6. 7. 8. 9.
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