Abstract
Medicine today uses a wide range of biomaterials, most of which make contact with blood permanently or transiently upon implantation. Contact between blood and nonbiological materials or cells or tissue of nonhematologic origin initiates activation of the cascade systems (complement, contact activation/coagulation) of the blood, which induces platelet and leukocyte activation.
Although substantial progress regarding biocompatibility has been made, many materials and medical treatment procedures are still associated with severe side effects. Therefore, there is a great need for adequate models and guidelines for evaluating the blood compatibility of biomaterials. Due to the substantial amount of cross talk between the different cascade systems and cell populations in the blood, it is advisable to use an intact system for evaluation.
Here, we describe three such in vitro models for the evaluation of the biocompatibility of materials and therapeutic cells and tissues. The use of different anticoagulants and specific inhibitors in order to be able to dissect interactions between the different cascade systems and cells of the blood is discussed. In addition, we describe two clinically relevant medical treatment modalities, the integration of titanium implants and transplantation of islets of Langerhans to patients with type 1 diabetes, whose mechanisms of action we have addressed using these in vitro models.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B et al (2010) Molecular intercommunication between the complement and coagulation systems. J Immunol 185(9):5628–5636
Andersson J, Ekdahl KN, Larsson R, Nilsson UR, Nilsson B (2002) C3 adsorbed to a polymer surface can form an initiating alternative pathway convertase. J Immunol 168(11):5786–5791
Andersson J, Sanchez J, Ekdahl KN, Elgue G, Nilsson B, Larsson R (2003) Optimal heparin surface concentration and antithrombin binding capacity as evaluated with human non-anticoagulated blood in vitro. J Biomed Mater Res A 67(2):458–466
Andersson J, Ekdahl KN, Lambris JD, Nilsson B (2005a) Binding of C3 fragments on top of adsorbed plasma proteins during complement activation on a model biomaterial surface. Biomaterials 26(13):1477–1485
Andersson M, Andersson J, Sellborn A, Berglin M, Nilsson B, Elwing H (2005b) Quartz crystal microbalance-with dissipation monitoring (QCM-D) for real time measurements of blood coagulation density and immune complement activation on artificial surfaces. Biosens Bioelectron 21(1):79–86
Arima Y, Toda M, Iwata H (2011) Surface plasmon resonance in monitoring of complement activation on biomaterials. Adv Drug Deliv Rev 63:988–999
Attanasio M, Gori AM, Giusti B, Pepe G, Comeglio P, Brunelli T et al (1998) Cytokine gene expression in human LPS- and IFN gamma-stimulated mononuclear cells is inhibited by heparin. Thromb Haemost 79(5):959–962
Bäck J, Huber-Lang M, Elgue G, Kalbitz M, Sanchez J, Ekdahl KN et al (2009) Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces. Biomaterials 30(34):6573–6580
Bäck J, Sanchez J, Elgue G, Ekdahl KN, Nilsson B (2010) Activated human platelets induce factor XIIa-mediated contact activation. Biochem Biophys Res Commun 391(1):11–17
Bennet W, Sundberg B, Groth CG, Brendel MD, Brandhorst D, Brandhorst H et al (1999) Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes 48(10):1907–1914
Bennet W, Sundberg B, Elgue G, Larsson R, Korsgren O, Nilsson B (2001) A new in vitro model for the study of pig-to-human vascular hyperacute rejection. Xenotransplantation 8(3):176–184
Berglin M, Pinori E, Sellborn A, Andersson M, Hulander M, Elwing H (2009) Fibrinogen adsorption and conformational change on model polymers: novel aspects of mutual molecular rearrangement. Langmuir 25(10):5602–5608
Bexborn F, Engberg AE, Sandholm K, Mollnes TE, Hong J, Nilsson Ekdahl K (2009) Hirudin versus heparin for use in whole blood in vitro biocompatibility models. J Biomed Mater Res A 89(4):951–959
Bogdanov V, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y (2003) Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 9(4):458–462
Cabric S, Sanchez J, Lundgren T, Foss A, Felldin M, Kallen R et al (2007) Islet surface heparinization prevents the instant blood-mediated inflammatory reaction in islet transplantation. Diabetes 56(8):2008–2015
Cabric S, Eich T, Sanchez J, Nilsson B, Korsgren O, Larsson R (2008) A new method for incorporating functional heparin onto the surface of islets of Langerhans. Tissue Eng C Methods 14(2):141–147
Chang JY (1983) The functional domain of hirudin, a thrombin-specific inhibitor. FEBS Lett 164(2):307–313
Christensen K, Larsson R, Emanuelsson H, Elgue G, Larsson A (2001) Heparin coating of the stent graft—effects on platelets, coagulation and complement activation. Biomaterials 22(4):349–355
Christensen K, Larsson R, Emanuelsson H, Elgue G, Larsson A (2006) Effects on blood compatibility in vitro by combining a direct P2Y12 receptor inhibitor and heparin coating of stents. Platelets 17(5):318–327
Distelmaier K, Adlbrecht C, Jakowitsch J, Winkler S, Dunkler D, Gerner C et al (2009) Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction. Thromb Haemost 102(3):564–572
Ekdahl KN, Nilsson B, Pekna M, Nilsson UR (1992) Generation of iC3 at the interface between blood and gas. Scand J Immunol 35(1):85–91
Ekdahl KN, Lambris JD, Elwing H, Ricklin D, Nilsson PH, Teramura Y et al (2011) Innate immunity activation on biomaterial surfaces: a mechanistic model and coping strategies. Adv Drug Deliv Rev 63(12):1042–1050
Engberg AE, Rosengren-Holmberg JP, Chen H, Nilsson B, Lambris JD, Nicholls IA et al (2011) Blood protein-polymer adsorption: implications for understanding complement-mediated hemoincompatibility. J Biomed Mater Res A 94A:74–84
Engstad CS, Gutteberg TJ, Osterud B (1997) Modulation of blood cell activation by four commonly used anticoagulants. Thromb Haemost 77(4):690–696
Ettelaie C, Fountain D, Collier M, Elkeeb A, Xiao Y, Maraveyas A (2011) Low molecular weight heparin downregulates tissue factor expression and activity by modulating growth factor receptor-mediated induction of nuclear factor-κB. Biochim Biophys Acta 1812(12):1591–1600
Fink H, Hong J, Drotz K, Risberg B, Sanchez J, Sellborn A (2011) An in vitro study of blood compatibility of vascular grafts made of bacterial cellulose in comparison with conventionally-used graft materials. J Biomed Mater Res A [Epub ahead of print]
Ghebrehiwet B, Randazzo BP, Dunn JT, Silverberg M, Kaplan AP (1983) Mechanisms of activation of the classical pathway of complement by Hageman factor fragment. J Clin Invest 71(5):1450–1456
Gong J, Larsson R, Ekdahl KN, Mollnes TE, Nilsson U, Nilsson B (1996) Tubing loops as a model for cardiopulmonary bypass circuits: both the biomaterial and the blood-gas phase interfaces induce complement activation in an in vitro model. J Clin Immunol 16(4):222–229
Gorbet MB, Sefton MV (2004) Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes. Biomaterials 25(26):5681–5703
Gori AM, Pepe G, Attanasio M, Falciani M, Abbate R, Prisco D et al (1999) Tissue factor reduction and tissue factor pathway inhibitor release after heparin administration. Thromb Haemost 81(4):589–593
Grabowski E (1990) Platelet aggregation in flowing blood at a site of injury to an endothelial cell monolayer: quantitation and real-time imaging with the TAB monoclonal antibody. Blood 75(2):390–398
Grabowski E, Curran M, Van Cott E (2012) Assessment of a cohort of primarily pediatric patients with a presumptive diagnosis of type 1 von Willebrand disease with a novel high shear rate, non-citrated blood flow device. Thromb Res [Epub ahead of print]
Gulla K, Gupta K, Krarup A, Gal P, Schwaeble W, Sim R et al (2010) Activation of mannan-binding lectin-associated serine proteases leads to generation of a fibrin clot. Immunology 129(4):482–495
Gustafson EK, Elgue G, Hughes RD, Mitry RR, Sanchez J, Haglund U et al (2011) The instant blood-mediated inflammatory reaction characterized in hepatocyte transplantation. Transplantation 91(6):632–638
Hamad OA, Ekdahl KN, Nilsson PH, Andersson J, Magotti P, Lambris JD et al (2008) Complement activation triggered by chondroitin sulfate released by thrombin receptor-activated platelets. J Thromb Haemost 6(8):1413–1421
Hamad OA, Nilsson PH, Wouters D, Lambris JD, Ekdahl KN, Nilsson B (2010a) Complement component C3 binds to activated normal platelets without preceding proteolytic activation and promotes binding to complement receptor 1. J Immunol 185(5):2686–2692
Hamad O, Nilsson P, Lasaosa M, Ricklin D, Lambris J, Nilsson B et al (2010b) Contribution of chondroitin sulfate A to the binding of complement proteins to activated platelets. PLoS One 5(6):e12889
Harboe M, Ulvund G, Vien L, Fung M, Mollnes TE (2004) The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation. Clin Exp Immunol 138(3):439–446
Hess K, Alzahran SH, Mathai M, Schroeder V, Carter A, Howell G et al (2011) A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3. Diabetologia [Epub ahead of print]
Hojima Y, Pierce J, Pisano J (1980) Hageman factor fragment inhibitor in corn seeds: purification and characterization. Thromb Res 20:149–162
Hong J, Nilsson Ekdahl K, Reynolds H, Larsson R, Nilsson B (1999a) A new in vitro model to study interaction between whole blood and biomaterials. Studies of platelet and coagulation activation and the effect of aspirin. Biomaterials 20(7):603–611
Hong J, Andersson J, Ekdahl KN, Elgue G, Axen N, Larsson R et al (1999b) Titanium is a highly thrombogenic biomaterial: possible implications for osteogenesis. Thromb Haemost 82(1):58–64
Hong J, Larsson A, Ekdahl KN, Elgue G, Larsson R, Nilsson B (2001) Contact between a polymer and whole blood: sequence of events leading to thrombin generation. J Lab Clin Med 138(2):139–145
Hong J, Azens A, Ekdahl K, Granqvist CG, Nilsson B (2005) Material-specific thrombin generation following contact between metal surfaces and whole blood. Biomaterials 26:1397–1403
Hong J, Kurt S, Thor A (2011) A hydrophilic dental implant surface exhibit thrombogenic properties in vitro. Clin Implant Dent Relat Res [Epub ahead of print]
Howes J, Richardson V, Smith K, Schroeder V, Somani R, Shore A et al (2012) Complement C3 is a novel plasma clot component with anti-fibrinolytic properties. Diab Vasc Dis Res [Epub ahead of print]
Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR et al (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12(6):682–687
Hussaini B, Treanor P, Healey N, Tilahun D, Srey R, Lu X et al (2009) Evaluation of blood components exposed to coated arterial filters in extracorporeal circuits. Perfusion 24(5):317–323
Ikeda K, Nagasawa K, Horiuchi T, Tsuru T, Nishizaka H, Niho Y (1997) C5a induces tissue factor activity on endothelial cells. Thromb Haemost 77(2):394–398
Johansson U, Olsson A, Gabrielsson S, Nilsson B, Korsgren O (2003) Inflammatory mediators expressed in human islets of Langerhans: implications for islet transplantation. Biochem Biophys Res Commun 308(3):474–479
Johansson H, Lukinius A, Moberg L, Lundgren T, Berne C, Foss A et al (2005) Tissue factor produced by endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation. Diabetes 54(6):1755–1762
Johnell M, Larsson R, Siegbahn A (2005) The influence of different heparin surface concentrations and antithrombin-binding capacity on inflammation and coagulation. Biomaterials 26(14):1731–1739
Jokiranta TS, Westin J, Nilsson B, Ekdahl KN, Hellwage J, Gordon DL et al (2001) Complement C3b interactions with its ligands measured by Biacore equipment: a new powerful and informative method. Int Immunopharmacol 1:495–506
Katragadda M, Lambris JD (2006) Expression of compstatin in Escherichia coli: incorporation of unnatural amino acids enhances its activity. Protein Expr Purif 47(1):289–295
Keil L, Jimenez E, Guma M, Reyes M, Liguori C, DeBari V (1995) Biphasic response of complement to heparin: fluid-phase generation of neoantigens in human serum and in a reconstituted alternative pathway amplification cycle. Am J Hematol 50(4):254–262
Kourtzelis I, Markiewski MM, Doumas M, Rafail S, Kambas K, Mitroulis I et al (2010) Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood 116(4):631–639
Krarup A, Gulla C, Gál P, Hajela K, Sim R (2008) The action of MBL-associated serine protease 1 (MASP1) on factor XIII and fibrinogen. Biochim Biophys Acta 1784:1294–1300
Lachmann PJ, Pangburn MK, Oldroyd RG (1982) Breakdown of C3 after complement activation. Identification of a new fragment C3g, using monoclonal antibodies. J Exp Med 156(1):205–216
Lappegård K, Fung M, Bergseth G, Riesenfeld J, Lambris J, Videm V et al (2004) Effect of complement inhibition and heparin coating on artificial surface-induced leukocyte and platelet activation. Ann Thorac Surg 77(3):932–941
Lappegård K, Riesenfeld J, Brekke O, Bergseth G, Lambris J, Mollnes T (2005) Differential effect of heparin coating and complement inhibition on artificial surface-induced eicosanoid production. Ann Thorac Surg 79(3):917–923
Lappegård KT, Bergseth G, Riesenfeld J, Pharo A, Magotti P, Lambris JD et al (2008) The artificial surface-induced whole blood inflammatory reaction revealed by increases in a series of chemokines and growth factors is largely complement dependent. J Biomed Mater Res A 87(1):129–135
Larsson R, Elgue G, Larsson A, Ekdahl KN, Nilsson UR, Nilsson B (1997) Inhibition of complement activation by soluble recombinant CR1 under conditions resembling those in a cardiopulmonary circuit: reduced up-regulation of CD11b and complete abrogation of binding of PMNs to the biomaterial surface. Immunopharmacology 38(1–2):119–127
Lindorfer M, Pawluczkowycz A, Peek E, Hickman K, Taylor R, Parker CJ (2010) A novel approach to preventing the hemolysis of paroxysmal nocturnal hemoglobinuria: both complement-mediated cytolysis and C3 deposition are blocked by a monoclonal antibody specific for the alternative pathway of complement. Blood 115(11):2283–2291
Logue GL (1977) Effect of heparin on complement activation and lysis of paroxysmal nocturnal hemoglobinuria (PNH) red cells. Blood 50(2):239–247
Mahoney W, Hermodson M, Jones B, Powers D, Corfman R, Reeck G (1984) Amino acid sequence and secondary structural analysis of the corn inhibitor of trypsin and activated Hageman Factor. J Biol Chem 259(13):8412–8416
Mangsbo SM, Sanchez J, Anger K, Lambris JD, Ekdahl KN, Loskog AS et al (2009) Complement activation by CpG in a human whole blood loop system: mechanisms and immunomodulatory effects. J Immunol 183(10):6724–6732
Matsushita M, Thiel S, Jensenius J, Terai I, Fujita T (2000) Proteolytic activities of two types of mannose-binding lectin-associated serine protease. J Immunol 165:2637–2642
Moberg L, Johansson H, Luknius A, Berne C, Foss A, Källen R et al (2002) Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet 360:2039–2045
Moberg L, Olsson A, Berne C, Felldin M, Foss A, Kallen R et al (2003) Nicotinamide inhibits tissue factor expression in isolated human pancreatic islets: implications for clinical islet transplantation. Transplantation 76(9):1285–1288
Moberg L, Korsgren O, Nilsson B (2005) Neutrophilic granulocytes are the predominant cell type infiltrating pancreatic islets in contact with ABO-compatible blood. Clin Exp Immunol 142(1):125–131
Mollnes TE, Riesenfeld J, Garred P, Nordstrom E, Hogasen K, Fosse E et al (1995) A new model for evaluation of biocompatibility: combined determination of neoepitopes in blood and on artificial surfaces demonstrates reduced complement activation by immobilization of heparin. Artif Organs 19(9):909–917
Mollnes TE, Brekke OL, Fung M, Fure H, Christiansen D, Bergseth G et al (2002) Essential role of the C5a receptor in E. coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation. Blood 100(5):1869–1877
Nilsson B, Larsson R, Hong J, Elgue G, Ekdahl KN, Sahu A et al (1998) Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation. Blood 92(5):1661–1667
Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD (2007) The role of complement in biomaterial-induced inflammation. Mol Immunol 44(1–3):82–94
Nilsson P, Engberg A, Bäck J, Faxälv L, Lindahl T, Nilsson B et al (2010) The creation of an antithrombotic surface by apyrase immobilization. Biomaterials 31(16):4484–4491
Nilsson B, Nilsson Ekdahl K, Korsgren O (2011) Control of IBMIR (Instant Blood-Mediated Inflammatory Reaction) to improve islets of Langerhans engraftment. Curr Opin Organ Transplant 16(6):620–626
Ozmen L, Ekdahl KN, Elgue G, Larsson R, Korsgren O, Nilsson B (2002) Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation. Diabetes 51(6):1779–1784
Patston P, Gettins P, Beechem J, Schapira M (1991) Mechanism of serpin action: evidence that C1 inhibitor functions as a suicide substrate. Biochemistry 30(36):8876–8882
Ratner BD (2007) The catastrophe revisited: blood compatibility in the 21st century. Biomaterials 28(34):5144–5147
Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P et al (2006) A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol 177(7):4794–4802
Schousboe I, Nystrøm BT, Hansen GH (2008) Differential binding of factor XII and activated factor XII to soluble and immobilized fibronectin–localization of the Hep-1/Fib-1 binding site for activated factor XII. FEBS J 275(20):5161–5172
Selborn A, Andersson M, Fant C, Gretzer C, Elwing H (2003) Methods for research on immune complement activation on modified sensor surfaces. Colloids Surf B: Biointerfaces 27:295–301
Seyfert UT, Biehl V, Schenk J (2002) In vitro hemocompatibility testing of biomaterials according to the ISO 10993–4. Biomol Eng 19(2–6):91–96
Shankar R, de la Motte CA, Poptic EJ, DiCorleto PE (1994) Thrombin receptor-activating peptides differentially stimulate platelet-derived growth factor production, monocytic cell adhesion, and E-selectin expression in human umbilical vein endothelial cells. J Biol Chem 269(19):13936–13941
Sinn S, Scheuermann T, Deichelbohrer S, Ziemer G, Wendel HP (2011) A novel in vitro model for preclinical testing of the hemocompatibility of intravascular stents according to ISO 10993–4. J Mater Sci Mater Med 22(6):1521–1528
Strey CW, Markiewski M, Mastellos D, Tudoran R, Spruce LA, Greenbaum LE et al (2003) The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med 198(6):913–923
Taylor F, Müller-Eberhard H (1970) Qualitative description of factors involved in the retraction and lysis of dilute whole blood clots and in the aggregation and retraction of platelets. J Clin Invest 49(1):2068–2085
Tengvall P, Askendal A, Lundstrom I (2001) Ellipsometric in vitro studies on the activation of complement by human immunoglobulins M and G after adsorption to methylated silicon. Colloids Surf B: Biointerfaces 20(1):51–62
Thoman ML, Meuth JL, Morgan EL, Weigle WO, Hugli TE (1984) C3d-K, a kallikrein cleavage fragment of iC3b is a potent inhibitor of cellular proliferation. J Immunol 133(5):2629–2633
Thor A, Rasmusson L, Wennerberg A, Thomsen P, Hirsch JM, Nilsson B et al (2007) The role of whole blood in thrombin generation in contact with various titanium surfaces. Biomaterials 28(6):966–974
Wettero J, Bengtsson T, Tengvall P (2001) C1q-independent activation of neutrophils by immunoglobulin M-coated surfaces. J Biomed Mater Res 57(4):550–558
Wouters D, Wiessenberg H, Hart M, Bruins P, Voskuyl A, Daha M et al (2005) Complexes between C1q and C3 or C4: novel and specific markers for classical complement pathway activation. J Immunol Methods 298:35–45
Wu Y, Simonovsky FI, Ratner BD, Horbett TA (2005) The role of adsorbed fibrinogen in platelet adhesion to polyurethane surfaces: a comparison of surface hydrophobicity, protein adsorption, monoclonal antibody binding, and platelet adhesion. J Biomed Mater Res A 74(4):722–738
Acknowledgments
This work was supported by grants from the Swedish Research Council (VR) 2009–4675, 2009–4462, the Swedish Research Council, and the Swedish Research Council/SSF/Vinnova contract grant number 60761701 and by faculty grants from the Linnæus University. Reagents for preparing heparin-coated surfaces were obtained from Corline Systems AB. We thank Dr. Deborah McClellan for excellent editorial assistance and Mr. Hans Nilsson for preparing the illustrations in Fig. 18.1.
Conflict of Interest StatementThe author Professor R. Larsson is an employee of Corline Systems AB, Uppsala, Sweden. None of the other authors has conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Ekdahl, K.N., Hong, J., Hamad, O.A., Larsson, R., Nilsson, B. (2013). Evaluation of the Blood Compatibility of Materials, Cells, and Tissues: Basic Concepts, Test Models, and Practical Guidelines. In: Lambris, J., Holers, V., Ricklin, D. (eds) Complement Therapeutics. Advances in Experimental Medicine and Biology, vol 735. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4118-2_18
Download citation
DOI: https://doi.org/10.1007/978-1-4614-4118-2_18
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-4117-5
Online ISBN: 978-1-4614-4118-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)