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Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood.
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University and Regional Laboratories Region Skåne. (BMC)
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University. (BMC)
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (BMC)
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2016 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 77, 111-119 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Inappropriate and uncontrolled activation of the cascade systems in the blood is a driving force in adverse inflammatory and thrombotic reactions elicited by biomaterials, but limited data are available on the activation of the contact system by polymers and the present study was undertaken to investigate these mechanisms in established models.

METHODS: Polymer particles were incubated in (1) EDTA-plasma (10 mM) to monitor the adsorption of 20 selected proteins; (2) lepirudin-anticoagulated plasma to evaluate contact system activation, monitored by the formation of complexes between the generated proteases factor[F]XIIa, FXIa and kallikrein and the serpins C1-inhibitor [C1INH] and antithrombin [AT]; (3) lepirudin-anticoagulated whole blood to determine cytokine release.

RESULTS: Strong negative correlations were found between 10 cytokines and the ratio of deposited FXII/C1INH, generated FXIIa-C1INH complexes, and kallikrein-C1INH complexes. Formation of FXIIa-C1INH complexes correlated negatively with the amount of C3a and positively with deposited IgG.

CONCLUSIONS: A reciprocal relationship was found between activation of the contact system and the complement system induced by the polymers studied here. The ratios of FXII/C1INH or C4/C4BP, adsorbed from EDTA-plasma are useful surrogate markers for cytokine release and inflammatory response to materials intended for blood contact.

Place, publisher, year, edition, pages
Elsevier, 2016. Vol. 77, 111-119 p.
Keyword [en]
Biomaterials, Complement system, Contact system, FXII, In vitro screening
National Category
Biomaterials Science
Research subject
Chemistry, Biochemistry
Identifiers
URN: urn:nbn:se:lnu:diva-47390DOI: 10.1016/j.biomaterials.2015.10.067ISI: 000367118200010PubMedID: 26584351OAI: oai:DiVA.org:lnu-47390DiVA: diva2:873616
Available from: 2015-11-24 Created: 2015-11-24 Last updated: 2017-02-16Bibliographically approved
In thesis
1. Interaction between biomaterials and innate immunity with clinical implications
Open this publication in new window or tab >>Interaction between biomaterials and innate immunity with clinical implications
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Today there is an increasing clinical demand and expectation of patients for biomaterials, which underscores the importance of discovering the correlations between biomaterials and biological systems, especially blood. When an artificial material makes contact with blood, the first event is a rapid adsorption of plasma protein on the material surface, on top of which the innate immune system is triggered, with potentially detrimental consequences. The work presented in this thesis, reported in four papers, was designed to investigate complications associated with (a) biomaterial-induced immune systems, including activation mechanisms and crosstalk between cascades on the biomaterial surface, and with (b) clinical investigations.

In Paper I and Paper II, a series of studies led to the development of a direct prediction of the subsequent biological events based on the pattern of initially bound proteins. A reciprocal relationship was demonstrated between activation of the contact system and the complement system when they were induced on artificial material surfaces. Based on these studies, a robust and simple method for biocompatibility testing was proposed and validated, yielding high specificity and sensitivity when compared to today’s gold standard. Paper III investigated biomaterial-induced activation of complement and leukocytes in dialysis treatment-related conditions. The results suggested that citrate is more biocompatible than the conventionally used acetate. This reduction in activation could be further enhanced with higher citrate concentrations, suggesting that dialysis fluid containing citrate is a promising alternative to acetate dialysis fluid. Paper IV investigated complement initiation mechanisms with clinical implications. An experimental system was set up to revisit the initiation of the complement alternative pathway, and correlations were found between chaotropic or nucleophilic agents and iC3 generation under physiologically relevant conditions. A clinical study of hepatic encephalopathy patients indicated a direct correlation between elevated plasma ammonia and iC3 formation, as well as with complement activation in vivo

Taken together, these studies have provided a model for a robust biomaterial test and have investigated biomaterial-induced complications in the fluid phase in clinically related conditions; furthermore, the basic mechanisms of complement activation have been dissected in relation to disease symptoms.

Keywords: Complement system, contact system, blood, biomaterials, biocompatibility, in vitro screening, iC3, dialysis

Place, publisher, year, edition, pages
Växjö: Linnaeus University Press, 2015
Series
Linnaeus University Dissertations, 236/2015
Keyword
Complement system, contact system, blood, biomaterials, biocompatibility, in vitro screening, iC3, dialysis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:lnu:diva-47391 (URN)978-91-87925-87-0 (ISBN)
Public defence
2015-12-18, N2007, Smålandsgatan 24, Kalmar, 09:30 (English)
Opponent
Supervisors
Available from: 2015-11-26 Created: 2015-11-24 Last updated: 2015-11-26Bibliographically approved

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