Titanium Is a Highly Thrombogenic Biomaterial: Possible Implications for Osteogenesis

Summary

Titanium has superior osteointegrating properties compared to other biomaterials. The mechanism for this is unknown. During the initial phase of bone implantation the biomaterial comes into direct contact with whole blood. In this study we use a newly developed in vitro chamber model to compare different commonly used biomaterials in contact with whole blood. These materials were selected with respect to their different osteointegrating properties in order to correlate these properties with the response to whole blood. In the presence of 3 IU/ml of heparin only titanium induced macroscopic clotting. This was reflected by the generation of thrombin-antithrombin which was much increased in blood in contact with titanium compared with steel and PVC. The coagulation activation caused by titanium was triggered by the intrinsic pathway because the generation of FXIIa-AT/C1 esterase inhibitor paralleled that of thrombin-antithrombin, and both thrombinantithrombin complex and FXIIa-AT/C1 esterase inhibitor generation were abrogated by corn trypsin inhibitor, which is a specific inhibitor of FXIIa. The binding of platelets was increased on the titanium surface compared to the other biomaterial surfaces and the state of platelet activation was much more pronounced as reflected by the levels of β-thromboglobulin and PDGF. This study indicates that titanium is unsuitable as a biomaterial in devices which are in direct contact with blood for a prolonged period. Furthermore, PDGF and other α-granule proteins e.g. TGF-β, are known to be potent promotors of osteogenesis which suggests that the pronounced thrombogenic properties of titanium might contribute to the good osteointegrating properties.

• References

• 1 Hong J, Nilsson Ekdahl K, Reynolds H, Larsson R, Nilsson B. 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 1999; 20: 603-11.
• 2 Gong J, Larsson R, Nilsson Ekdahl K, Mollnes TE, Nilsson U, Nilsson B. Tubing loops as a model for cardiopulmonary bypass circuits: Both the bio-material and the blood-gas phase interfaces induce complement activation in an in vitro model. J Clin Immunol 1996; 16: 222-9.
• 3 Nygren H, Eriksson C, Lausmaa J. Adhesion and activation of platelets and polymorphonuclear cells at TiO2 surfaces. J Labor Clin Med 1997; 129 (01) 35-46.
• 4 Nygren H, Tengvall P, Lundström I. The inital reactions of TiO2 with blood. J Biomed Mat Res 1997; 34: 487-92.
• 5 Salzman EW, Lindon J, McManama G, Ware JA. Role of fibrinogen in activation of platelets by artificial surfaces. Ann N Y Acad Sci 1987; 516: 184-95.
• 6 Basmadjian D, Sefton MV, Baldwin SA. Coagulation on biomaterials in flowing blood: some theoretical considerations. Biomaterials 1997; 18: 1511-22.
• 7 Larsson R, Elgue G, Larsson A, Nilsson Ekdahl K, Nilsson UR, Nilsson B. 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 bio-material surface. Immunopharmacology 1997; 38: 119-27.
• 8 Nilsson B, Larsson R, Hong J, Elgue G, Nilsson Ekdahl K, Sahu A, Lam-bris JD. Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation. Blood 1998; 92: 1661-7.
• 9 McNally AK, Anderson JM. Complement C3 participation in monocyte adhesion to different surfaces. Proc Natl Acad Sci, USA 1994; 91: 10119-23.
• 10 Peerschke EIB, Reid KMB, Ghebrehiwet B. Platelet activation by C1q results in the induction of αIIb/β3 integrins (GPIIb-IIIa) and the expression of P-selectin and procoagulant activity. J Exp Med 1993; 178: 579-87.
• 11 Spycher MO, Nydegger UE. Participation of the blood platelet in immune reactions due to platelet- complement interaction. Infusionsther Transfusionsmed 1995; 22: 36-43.
• 12 Kaplan K. Proteins secreted by platelets: Significance in detecting thrombosis. Adv Exp Med Biol 1978; 102: 105-19.
• 13 Courtney JM, Lamba NM, Sundaram S, Forbes CD. Biomaterials for blood-contacting applications. Biomaterials 1994; 15: 737-44.
• 14 Ross R, Raines EW, Bowen-Pope DF. The biology of platelet-derived growth factor. Cell 1986; 46: 155-69.
• 15 Gotman I. Characteristics of metals used in implants. J Endourol 1997; 11: 383-9.
• 16 Branemark I P. Osseointegration and its experimental background. J Prosthet Dent 1983; 50: 399-410.
• 17 Larsson M, Bromark M, Hedenqvist P, Hogmark S. Deposition and mechanical evaluation of multilayered PVD Ti-TiN coatings. Surface Coat Tech-nol 1995; 76 77.: 202-5.
• 18 Dion I, Baquey C, Candelon B, Monties JR. Hemocompatibility of titanium nitride. Int J Artif Org 1992; 15: 617-21.
• 19 Dion I, Rouais F, Trut L, Baquey C, Monties JR, Havlik P. TiN coating: surface characterization and haemocompatibility. Biomaterials 1993; 14: 169-76.
• 20 Monties JR, Dion I, Havlik P, Rouais F, Trinkl J, Baquey C. Cora rotary pump for implantable left ventricular assist device: biomaterial aspects. Artif Organs 1997; 21: 730-4.
• 21 Yang Y, Franzen SF, Olin CL. In vivo comparison of hemocompatibility of materials used in mechanical heart valves. J Heart Valve Dis 1996; 5: 532-7.
• 22 Mishra AK, Davidsson JA, Kovacs P, Roggie RA. 1993. Ti-13Nb-13Zr: A new low modulus, high strength, corrosion resistant near-beta alloy for orthopaedic implants. In Beta Titanium Alloys in the 1990´s. Eylon D, Boyer RR, Koss DA. The minerals; metals and materials Society: 61-72.
• 23 Ekvall P, Johansson E, Aén N. Tribological properties of nitrided titanium alloys. Tribologia 1998; 17: 20-6.
• 24 Larsson R, Rosengren Å, Olsson P. Determination of platelet adhesion to polyethylene and heparinized surfaces with the aid of bioluminicence and 51chomium labelled platelets. Thrombosis Research 1977; 11: 51730
• 25 Nilsson Ekdahl K, Nilsson B, Pekna M, Nilsson UR. Generation of iC3 on the interphase between blood and gas. Scand J Immunol 1992; 35: 85-91.
• 26 Mollnes TE, Riesenfeldt J, Garred P, Nordström E, Høgasen K, Fosse E, Götze O, Harboe M. 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. Artificial Organs 1995; 19: 909-17.
• 27 Sanchez J, Elgue G, Riesenfeld J, Olsson P. Studies of adsorption, activation, and inhibition of factor XII on immobilized heparin. Thromb Res 1998; 89: 41-50.
• 28 Wälivaara B, Askendal A, Lundström I, Tengvall P. Blood protein interactions with titanium surfaces. J Biomater Sci Polymer Edit 1996; 8: 41-8.
• 29 Courtney JM, Forbes CD. Thrombosis on foreign surfaces. Br Med Bull 1994; 50: 966-81.
• 30 Wälivaara B, Aronsson B-O, Rodahl M, Lausmaa J, Tengvall P. Titanium with different oxides: in vitro studies of protein adsoption and contact activation. Biomaterials 1994; 15: 827-34.
• 31 Kanagaraja S, Lundström I, Nygren H, Tengvall P. Platelet binding and protein adsorption to titanium and gold after short time exposure to heparinized plasma and whole blood. Biomaterials 1996; 17: 2225-32.
• 32 Yun YH, Turitto VT, Daigle KP, Kovacs P, Davidson JA, Slack SM. Initial hemocompatibility studies of titanium and zirconium alloys: prekallikrein activation, fibrinogen adsorption, and their correlation with surface electrochemical properties. J Biomed Mater Res 1996; 32: 77-85.
• 33 Amirkhosravi A, Alexander M, May K, Francis DA, Warnes G, Biggerstaff J, Francis JL. The importance of platelets in the expression of monocyte tissue factor antigen measured by a new whole blood flow cytometric assay. Thromb Haemost 1996; 75: 87-95.
• 34 Sims PJ, Wiedmer T. The response of human platelets to activated components of the complement system. Immunol Today 1991; 12: 338-42.
• 35 Harrison P, Cramer EM. Platelet alpha-granules. Blood Rev 1993; 7: 52-62.
• 36 Sherris DA, Murakami CS, Larrabee WF, Bruce AG. Mandibular reconstruction with transforming growth factor-beta1. Laryngoscope 1998; 108: 368-72.
• 37 Sun Y, Zhang W, Lu Y, Hu Y, Ma F, Cheng W. Role of transforming growth factor beta (TGF-beta) in repairing of bone defects. Chin Med Sci J 1996; 11: 209-14.
• 38 Wroblewski J, Edwall C. PDGF BB stimulates proliferation and differentiation in cultured chondrocytes from rat rib growth plate. Cell Biol Int Rep 1992; 16: 133-44.
• 39 Antoniades HN. PDGF: a multifunctional growth factor. Baillières Clin Endocrinol Metab 1991; 5: 595-613.
• 40 Boyan BD, Hummert TW, Dean DD, Schwartz Z. Role of material surfaces in regulating bone and cartilage cell response. Biomaterials 1996; 17: 137-46.
• 41 Suzuki K, Aoki K, Ohya K. Effects of surface roughness of titanium implants on bone remodeling activity of femur in rabbits. Bone 1997; 21: 507-14.
• 42 Wennerberg A, Ektessabi A, Albrektsson T, Johansson C, Andersson B. A 1-year follow-up of implants of differing surface roughness placed in rabbit bone. Int J Oral Maxillofac Implants 1997; 12: 486-94.