Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma

Anna E Engberg; Per H Nilsson; Shan Huang; Karin Fromell; Osama A Hamad; Tom Eirik Mollnes; Jenny P Rosengren-Holmberg; Kerstin Sandholm; Yuji Teramura; Ian A Nicholls; Bo Nilsson; Kristina N Ekdahl

doi:10.1016/j.biomaterials.2014.09.011

Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma

Biomaterials. 2015 Jan:36:55-65. doi: 10.1016/j.biomaterials.2014.09.011. Epub 2014 Oct 5.

Authors

Affiliations

¹ Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden; Department of Clinical Chemistry, University and Regional Laboratories, Region Skåne, Sweden.
² Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden; Department of Immunology, Oslo University Hospital Rikshopsitalet, Norway; K.G. Jebsen ICR, University of Oslo, Norway.
³ Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden.
⁴ Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, SE-751 85 Uppsala, Sweden.
⁵ Department of Immunology, Oslo University Hospital Rikshopsitalet, Norway; K.G. Jebsen ICR, University of Oslo, Norway; Research Laboratory, Nordland Hospital, Bodø, Norway; Faculty of Health Sciences, University of Tromsø, Norway.
⁶ Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden; Drugs Unit, Swedish National Laboratory of Forensic Science, SE-58194 Linköping, Sweden.
⁷ Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, SE-751 85 Uppsala, Sweden; Department of Bioengineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-8656, Japan.
⁸ Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden; Department of Chemistry, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden.
⁹ Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden; Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, SE-751 85 Uppsala, Sweden. Electronic address: kristina.nilsson-ekdahl@igp.se.

PMID: 25292422
DOI: 10.1016/j.biomaterials.2014.09.011

Abstract

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-γ, 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.

Keywords: Biomaterials; C4 binding protein (C4BP); Complement; Cytokines; Inflammation; In vitro screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biocompatible Materials / adverse effects*
Complement Activation / drug effects*
Complement C4b-Binding Protein / immunology
Complement Membrane Attack Complex / immunology
Complement System Proteins / immunology
Humans
Inflammation / blood*
Inflammation / chemically induced*
Inflammation / immunology
Interferon-gamma / immunology
Interleukin-17 / blood
Interleukin-17 / immunology
Interleukin-6 / blood
Interleukin-6 / immunology
Polymers / adverse effects*

Substances

Biocompatible Materials
Complement C4b-Binding Protein
Complement Membrane Attack Complex
Interleukin-17
Interleukin-6
Polymers
SC5b-9 protein complex
Interferon-gamma
Complement System Proteins