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Engberg, Anna E.
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Publications (10 of 15) Show all publications
Huang, S., Engberg, A. E., Jonsson, N., Sandholm, K., Nicholls, I. A., Mollnes, T. E., . . . Nilsson Ekdahl, K. (2016). Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood.. Biomaterials, 77, 111-119
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, p. 111-119Article 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
Keywords
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: 2018-11-16Bibliographically approved
Engberg, A. E., Nilsson, P. H., Huang, S., Fromell, K., Hamad, O. A., Mollnes, T. E., . . . Nilsson Ekdahl, K. (2015). Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma. Biomaterials, 36, 55-65
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, p. 55-65Article 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.

Keywords
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: 2018-11-02Bibliographically approved
Engberg, A. E., Nilsson, P. H., Sandholm, K., Huang, S., Mollnes, T. E., Nicholls, I. A., . . . Nilsson Ekdahl, K. (2013). The ratio between C4 and C4BP adsorbed to artificial materials is a new predictor for biocompatibility. Paper presented at 14th European Meeting on Complement in Human Disease, AUG 17-21, 2013, Jena, GERMANY. Molecular Immunology, 56(3), 309-309
Open this publication in new window or tab >>The ratio between C4 and C4BP adsorbed to artificial materials is a new predictor for biocompatibility
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2013 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 56, no 3, p. 309-309Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-29195 (URN)10.1016/j.molimm.2013.05.194 (DOI)000323019700189 ()
Conference
14th European Meeting on Complement in Human Disease, AUG 17-21, 2013, Jena, GERMANY
Available from: 2013-10-08 Created: 2013-10-03 Last updated: 2018-11-16Bibliographically approved
Engberg, A. E., Nilsson, P. H., Mollnes, T. E., Rosengren-Holmberg, J. P., Nicholls, I. A., Nilsson, B. & Nilsson Ekdahl, K. (2012). The ratio between C4 and C4BP adsorbed from plasma predicts cytokine generation induced by artificial polymers in contact with whole blood. Immunobiology, 217(11), 1211-1211
Open this publication in new window or tab >>The ratio between C4 and C4BP adsorbed from plasma predicts cytokine generation induced by artificial polymers in contact with whole blood
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2012 (English)In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1211-1211Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-23358 (URN)10.1016/j.imbio.2012.08.235 (DOI)000311187800247 ()
Available from: 2013-01-09 Created: 2013-01-09 Last updated: 2017-12-06Bibliographically approved
Nilsson Ekdahl, K., Engberg, A. E., Rosengren-Holmberg, J. P., Chen, H., Lambris, J. & Nicholls, I. A. (2011). Blood protein-polymer adsorption fingerprinting: Implications for understanding hemoocompatibility and for biomaterial design.. Journal of Biomedical Materials Research. Part A, 97A(1), 74-84
Open this publication in new window or tab >>Blood protein-polymer adsorption fingerprinting: Implications for understanding hemoocompatibility and for biomaterial design.
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2011 (English)In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 97A, no 1, p. 74-84Article in journal (Refereed) Published
National Category
Biochemistry and Molecular Biology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-10057 (URN)10.1002/jbm.a.33030 (DOI)2-s2.0-79951972598 (Scopus ID)
Available from: 2011-01-17 Created: 2011-01-17 Last updated: 2017-12-11Bibliographically approved
Engberg, A. E. (2010). Biomaterials and Hemocompatibility. (Doctoral dissertation). Kalmar, Växjö: Linnaeus University Press
Open this publication in new window or tab >>Biomaterials and Hemocompatibility
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Biomaterials are commonly used in the medical clinic today; however, artificial materials can activate the cascade systems in the blood (complement-, coagulation-, contact- and fibrinolytic systems) as well as the platelets to various degrees. When an artificial surface comes in contact with blood, plasma proteins will be adsorbed to the surface within seconds. The composition of the layer of proteins differs between materials and is crucial for the hemocompatibility of the material.

This thesis includes five projects.

In Paper I the anticoagulants heparin and the thrombin inhibitor hirudin were evaluated in a whole blood model. Hirudin was found to be superior to low dose heparin since it did not affect the activation of the complement system nor the leukocytes. The most interesting observation was that expression of TF was seen on surface-attached monocytes in hirudin- treated blood but not heparin blood.

In Paper II peptides from the streptococcal M-protein, which has affinity for the human complement inhibitor C4BP, were attached to a polymeric surface. When being exposed to blood the endogenous complement regulator was enriched at the surface of the material, via the M-peptides. With this new approach we created a self-regulatory surface, showing significant lowered material-induced complement activation.

In Paper III apyrase, an enzyme which hydrolyzes nucleoside ATP and ADP, was immobilized on a polymer surface. Lower platelet activation and platelet-induced coagulation activation was seen for the apyrase-coated surface compared to control surfaces after exposure to whole human blood, due to the enzymes capability to degrade ADP released from activated platelets.

In Paper IV and V we synthesized an array of polymeric materials which were characterized regarding physical-chemical properties, adsorption of plasma proteins, and hemocompatibility. The polymers showed widely heterogeneous protein adsorption. Furthermore, when the polymers were exposed to whole blood, two of the materials showed superior hemocompatibility (monitored as complement- and coagulation activation), compared to the reference poly(vinyl chloride).

Place, publisher, year, edition, pages
Kalmar, Växjö: Linnaeus University Press, 2010. p. 167
Series
Linnaeus University Dissertations ; 2/2010
Keywords
Complement, Coagulation, Whole blood, Biomaterials, Polymers and Hemocompatibility
National Category
Immunology in the medical area
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-5437 (URN)978-91-86491-01-7 (ISBN)
Public defence
2010-01-29, N2007, Smålandsgatan 26, Kalmar, 09:30 (English)
Opponent
Supervisors
Available from: 2010-04-30 Created: 2010-04-29 Last updated: 2018-04-19Bibliographically approved
Nilsson, P. H., Engberg, A. E., Bäck, J., Faxälv, L., Lindahl, T., Nilsson, B. & Nilsson Ekdahl, K. (2010). The creation of an antithrombotic surface by apyrase immobilization. Biomaterials, 31(16), 4484-4491
Open this publication in new window or tab >>The creation of an antithrombotic surface by apyrase immobilization
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2010 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 31, no 16, p. 4484-4491Article in journal (Refereed) Published
Abstract [en]

Blood incompatibility reactions caused by surfaces often involve platelet activation and subsequent platelet-initiated activation of the coagulation and complement cascades. The goal of this study was to immobilize apyrase on a biomaterial surface in order to develop an enzymatically active surface that would have the capacity to inhibit platelet activation by degrading ADP. We were able to immobilize apyrase on a polystyrene surface with preservation of the enzymatic activity. We then analyzed the hemocompatibility of the apyrase surface and of control surfaces by incubation with platelet-rich plasma (PRP) or whole blood. Monitoring of markers of platelet, coagulation, and complement activation and staining of the surfaces revealed decreased levels of platelet and coagulation activation parameters on the apyrase surface. The formation of antithrombin-thrombin and antithrombin-factor XIa complexes and the extent of platelet consumption were significantly lower on the apyrase surface than on any of the control surfaces. No significant differences were seen in complement activation (C3a levels). Staining of the apyrase surface revealed low platelet adherence and no formation of granulocyte platelet complexes. These results demonstrate that it is possible to create an antithrombotic surface targeting the ADP amplification of platelet activation by immobilizing apyrase.

Keywords
Blood compatibiliy; Apyrase; Platelet; Platelet regulation; Adenosine diphosphate
National Category
Immunology in the medical area
Research subject
Biomedical Sciences, Immunology; Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-2176 (URN)10.1016/j.biomaterials.2010.02.036 (DOI)2-s2.0-77950061949 (Scopus ID)
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2018-01-12Bibliographically approved
Bexborn, F., Engberg, A. E., Sandholm, K., Mollnes, T. E., Hong, J. & Nilsson Ekdahl, K. (2009). Hirudin versus heparin for use in whole blood in vitro biocompatibility models. Journal of Biomedical Materials Research. Part A, 89A(4), 951-959
Open this publication in new window or tab >>Hirudin versus heparin for use in whole blood in vitro biocompatibility models
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2009 (English)In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 89A, no 4, p. 951-959Article in journal (Refereed) Published
Abstract [en]

Background: Heparin has traditionally been a widely used anticoagulant in blood research, but has been shown to be inappropriate for work with the complement system because of its complement-interacting properties. In this work, we have compared the effects of heparin with those of the specific thrombin inhibitor hirudin on complement and blood cells in vitro.

Methods: Whole blood collected in the presence of hirudin (50 µg/mL) or heparin (1 IU/mL) was incubated in the slide chamber model. The plasma was analyzed for complement activation markers C3a and sC5b-9, and the polyvinylchloride test slides were stained for adhering cells. The integrity of the complement system was tested by incubating serum and hirudin-treated plasma in the presence of various activating agents.

Results: In contrast to heparin, the addition of hirudin generally preserved the complement reactivity, and complement activation in hirudin plasma closely resembled that in normal serum. Importantly, immunochemical staining of surface-bound cells demonstrated the inducible expression of tissue factor on bound monocytes from hirudin-treated blood, an effect that was completely abolished in heparin-treated blood.

Conclusion: Our results indicate that hirudin as an anticoagulant produces more physiological conditions than heparin, making hirudin well-suited for in vitro studies, especially those addressing the regulation of cellular processes.

Place, publisher, year, edition, pages
Hoboken, NJ, US: John Wiley & Sons Inc, 2009
Keywords
biocompatibility, complement, heparin, hirudin, whole blood models
National Category
Immunology in the medical area
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:hik:diva-2786 (URN)10.1002/jbm.a.32034 (DOI)
Available from: 2010-04-07 Created: 2010-02-22 Last updated: 2018-01-12Bibliographically approved
Engberg, A. E., Sandholm, K., Bexborn, F., Persson, J., Nilsson, B., Lindahl, G. & Nilsson Ekdahl, K. (2009). Inhibition of complement activation on a model biomaterial surface by streptococcal M protein-derived peptides. Biomaterials, 30(13), 2653-2659
Open this publication in new window or tab >>Inhibition of complement activation on a model biomaterial surface by streptococcal M protein-derived peptides
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2009 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 30, no 13, p. 2653-2659Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to evaluate a new approach to inhibit complement activation triggered by biomaterial surfaces in contact with blood. In order to inhibit complement activation initiated by the classical pathway (CP), we used streptococcal M protein-derived peptides that specifically bind human C4BP, an inhibitor of the CP. The peptides were used to coat polystyrene microtiter wells which served as a model biomaterial. The ability of coated peptides to bind C4BP and to attenuate complement activation via the CP (monitored as generation of fluid-phase C3a and binding of fragments of C3 and C4 to the surface) was investigated using diluted normal human serum, where complement activation by the AP is minimal, as well as serum from a patient lacking alternative pathway activation. Complement activation (all parameters) was significantly decreased in serum incubated in well surfaces coated with peptides. Total inhibition of complement activation was obtained at peptide coating concentrations as low as 1-5 mu g/mL. Successful use of Streptococcus-derived peptides shows that it is feasible to control complement activation at a model biomaterial surface by capturing autologous complement regulatory molecules from plasma. (C) 2009 Elsevier Ltd. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2009
Keywords
Blood compatibility, Complement, C4b-binding protein (C4BP), In vitro test, Regulator of complement activation (RCA), Streptococcal M proteins
National Category
Immunology
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-73088 (URN)10.1016/j.biomaterials.2009.01.001 (DOI)000264691200026 ()19171378 (PubMedID)
Available from: 2018-04-19 Created: 2018-04-19 Last updated: 2018-04-19Bibliographically approved
Engberg, A. E., Rosengren-Holmberg, J. P., Nilsson Ekdahl, K. & Nicholls, I. A. (2009). Synthesis of new polymers and evaluation of their hemocompatibility. In: : . Paper presented at Scanbalt Forum Biomaterials Days, Kalmar.
Open this publication in new window or tab >>Synthesis of new polymers and evaluation of their hemocompatibility
2009 (English)Conference paper, Published paper (Refereed)
Identifiers
urn:nbn:se:lnu:diva-6754 (URN)
Conference
Scanbalt Forum Biomaterials Days, Kalmar
Available from: 2010-07-08 Created: 2010-07-08 Last updated: 2016-11-10Bibliographically approved
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