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Interaction between biomaterials and innate immunity with clinical implications
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
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 [en]
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: urn:nbn:se:lnu:diva-47391ISBN: 978-91-87925-87-0 (print)OAI: oai:DiVA.org:lnu-47391DiVA: diva2:873627
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
List of papers
1. Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma
Open this publication in new window or tab >>Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma
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2015 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 36, 55-65 p.Article in journal (Refereed) Published
Abstract [en]

Inappropriate complement activation is often responsible for incompatibility reactions that occur when biomaterials are used. Complement activation is therefore a criterion included in legislation regarding biomaterials testing. However, no consensus is yet available regarding appropriate complement-activation-related test parameters. We examined protein adsorption in plasma and complement activation/cytokine release in whole blood incubated with well-characterized polymers. Strong correlations were found between the ratio of C4 to its inhibitor C4BP and generation of 10 (mainly pro-inflammatory) cytokines, including IL-17, IFN-gamma, and IL-6. The levels of complement activation products correlated weakly (C3a) or not at all (C5a, sC5b-9), confirming their poor predictive values. We have demonstrated a direct correlation between downstream biological effects and the proteins initially adhering to an artificial surface after contact with blood. Consequently, we propose the C4/C4BP ratio as a robust, predictor of biocompatibility with superior specificity and sensitivity over the current gold standard. (C) 2014 Elsevier Ltd. All rights reserved.

Keyword
Biomaterials, C4 binding protein (C4BP), Complement, Cytokines, Inflammation, In vitro screening
National Category
Immunology Biomaterials Science
Research subject
Chemistry, Organic Chemistry; Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-39124 (URN)10.1016/j.biomaterials.2014.09.011 (DOI)000345728200006 ()2-s2.0-84921965003 (Scopus ID)
Available from: 2015-01-15 Created: 2015-01-15 Last updated: 2017-12-05Bibliographically approved
2. Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood.
Open this publication in new window or tab >>Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood.
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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
Keyword
Biomaterials, Complement system, Contact system, FXII, In vitro screening
National Category
Biomaterials Science
Research subject
Chemistry, Biochemistry
Identifiers
urn:nbn:se:lnu:diva-47390 (URN)10.1016/j.biomaterials.2015.10.067 (DOI)000367118200010 ()26584351 (PubMedID)2-s2.0-84949221849 (Scopus ID)
Available from: 2015-11-24 Created: 2015-11-24 Last updated: 2017-12-01Bibliographically approved
3. Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood
Open this publication in new window or tab >>Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood
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2015 (English)In: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 8, no 1, 31-37 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:The use of acetate in haemodialysis fluids may induce negative effects in patients including nausea and increased inflammation. Therefore, haemodialysis fluids where acetate is substituted with citrate have recently been developed. In this study, we investigated the biocompatibility of citrate employing concentrations used in haemodialysis.

METHODS:The effects of citrate and acetate were investigated in human whole blood in vitro under conditions promoting biomaterial-induced activation. Complement activation was measured as generation of C3a, C5a and the sC5b-9 complex, and granulocyte activation as up-regulation of CD11b expression. For the experimental set-up, a mathematical model was created to calculate the concentrations of acetate and citrate attained during haemodialysis.

RESULTS:Citrate reduced granulocyte activation and did not induce higher complement activation compared with acetate at concentrations attained during haemodialysis. Investigating different citrate concentrations clearly showed that citrate is a potent complement inhibitor already at low concentrations, i.e. 0.25 mM, which is comparable with concentrations detected in the blood of patients during dialysis with citrate-containing fluids. Increased citrate concentration up to 6 mM further reduced the activation of C3a, C5a and sC5b-9, as well as the expression of CD11b.

CONCLUSIONS:Our results suggest that citrate is a promising substitute for acetate for a more biocompatible dialysis, most likely resulting in less adverse effects for the patients.

National Category
Immunology in the medical area Urology and Nephrology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-40430 (URN)10.1093/ckj/sfu127 (DOI)25713707 (PubMedID)2-s2.0-84928381906 (Scopus ID)
Available from: 2015-02-25 Created: 2015-02-25 Last updated: 2017-12-04Bibliographically approved
4. An assay to monitor in vitro generation of non-proteolytically activated C3 in human plasma
Open this publication in new window or tab >>An assay to monitor in vitro generation of non-proteolytically activated C3 in human plasma
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(English)Manuscript (preprint) (Other academic)
Keyword
C3, chaotropic agents, hepatic encephalopathy, iC3, nucleophilic agents, surface interaction
National Category
Immunology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-47388 (URN)
Funder
Carl Tryggers foundation Swedish Research CouncilEU, FP7, Seventh Framework Programme
Available from: 2015-11-24 Created: 2015-11-24 Last updated: 2016-11-10Bibliographically approved

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