title: Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma.
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.
authors.affiliation: Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden; Department of Clinical Chemistry, University and Regional Laboratories, Region Skåne, Sweden.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Engberg
authors.affiliation: 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.
authors.forename: Per H
authors.initials: PH
authors.lastname: Nilsson
authors.affiliation: Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden.
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Fromell
authors.affiliation: Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Osama A
authors.initials: OA
authors.lastname: Hamad
authors.affiliation: 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.
authors.forename: Tom Eirik
authors.initials: TE
authors.lastname: Mollnes
authors.affiliation: Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden; Drugs Unit, Swedish National Laboratory of Forensic Science, SE-58194 Linköping, Sweden.
authors.forename: Jenny P
authors.initials: JP
authors.lastname: Rosengren-Holmberg
authors.affiliation: Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sandholm
authors.affiliation: 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.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Teramura
authors.affiliation: Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden; Department of Chemistry, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Nicholls
authors.affiliation: Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Nilsson
authors.affiliation: 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.
authors.forename: Kristina N
authors.initials: KN
authors.lastname: Ekdahl
mesh_terms: D001672:Biocompatible Materials / Q000009:adverse effects*; D003167:Complement Activation / Q000187:drug effects*; D050716:Complement C4b-Binding Protein / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000139:chemically induced* / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D011108:Polymers / Q000009:adverse effects*
chemical_list: D001672:Biocompatible Materials; D050716:Complement C4b-Binding Protein; D015938:Complement Membrane Attack Complex; D020381:Interleukin-17; D015850:Interleukin-6; D011108:Polymers; C047610:SC5b-9 protein complex; D007371:Interferon-gamma; D003165:Complement System Proteins
keywords: Biomaterials; C4 binding protein (C4BP); Complement; Cytokines; Inflammation; In vitro screening