D. M. Brunette - P. Tengvall M. Textor - P. Thomsen Titanium in Medicine es my Springer oa ateD.M. Brunette P. Tengvall M. Textor P. Thomsen Titanium in Medicine Material Science, Surface Science, Engineering, Biological Responses and Medical Applications Bs Bo pringerProf. Dr. Donald M. Brunette University of British Columbia Faculty of Dentistry Vancouver Canada Prof. Dr. Pentti Tengvall Linképing University Department of Physics and Measurement Technology Linképing Sweden Dr. Marcus Textor Swiss Federal Institute of ‘Technology (ETH) Department of Materials Zurich Switzerland Prof. Dr. Peter Thomsen Géteborg University Institute of Anatomy & Cell Biology Goteborg Sweden ISEN 978-3-642-63119-1 CiP-data applied for Die Deutsche Bibliothek - CiP-Einheitsaufnahme ‘Titanium in medicine : material science, surface science, engineering, iological responses and medical applications / ed.: Donald M. Brunette... - Berlin ; Heidelberg : New York ; Barcelona ; Hongkong ; London ; Mailand ; Paris ; Singapur ; Tokio : Springer,2001 ‘(Engineering meterials) ISBN a7B44nd97 BN oR2 6 hate ook Dotenoor/eres-otesbating This work is subject to copyright. All rights are reserved, whether the whole or part of the material is con- ‘cemed, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, repro-~ duction on microfilm or in other ways, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 196s. in its cur rent version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. http:l/swwspringerde © Springer-Verlag Berlin Heidelberg 2001 Originally published by Springer-Verlag Berlin Heidelberg, New York in 2001 ‘The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Coverdesign: deblik, Berlin ‘Typeseiting: Digital data supplied by author Printed on acid-free paper SPIN: 11320470 Golgi wei - 543.21Contents x! Contents Part! Introductory Survey 1. A Perspective on Titanium Biocompatibility Buddy D. Ratner 2. Titanium for Medical Applications ........ +... .-e sees eeeeeene ee 13 David F. Williams Part Il Metallurgy and Fabrication; Surface and Technological Properties 3. Metallurgy and Technological Properties of Titanium and Titanium Alloys ..... . Howard L. Freese, Michael G. Volas, J. Randolph Wood > Titanium-Nickel Shape Memory Alloys in Medical Applications ...... 53 Peter Filip w . Characterization of Titanium Surfaces . Janos Vérés, Marco Wieland, Laurence Ruiz—Taylor, Marcus Textor, Donald M. Brunette a . The Corrosion Properties of Titanium and Titanium Alloys Rolf Schenk x Properties and Biological Significance of Natural Oxide Films on Titanium and Its Alloys _. Marcus Textor, Caroline Sittig, Vinzenz Frauchiger, Samuele Tosatti, Donald M. Brunette 171 Part Ill Surface Engineering 8. Mechanical, Thermal, Chemical and Electrochemical Surface Treatment of Titanium ...........0:eseeeeeeereeeeeeeee 231 Jukka Lausmaa 9. Sol-Gel Coatings on Titanium Laurent-Dominique Piveteau 10. Physical and Chemical Vapor Depo Plasma-assisted Techniques for Coating Titanium ..........66.005 283 Roger Thull, David Grantxl Introduction 11. Production of Microfabricated Surface Their Effects on Cell Behavior .... Nicolas A.F. Jaeger, Donald M. Brunette 12. Thermal Spray Coatings on Titanium ........seseesssseesesesee 375 Heiko Gruner 13. Biochemical Modification of Titanium Surfaces ............+.0+++ 417 Shou-Jun Xiao, Gregory Kenausis, Marcus Textor Part IV Biological Performance 14. Proteins at Titanium Interfaces ......0..00.ceeeeees eee eesv eee 457 Pentti Tengvall 15. Principles of Cell Behavior on Titanium Surfaces and Their Application to Implanted Devices ..........0eseeeeeeereees 485 Donald M. Brunette (aT NGO ERIE «S13 Kajsa~Mia Holgers, Marco Esposito, Mia Kailltorp, Peter Thomsen 16. Titanium in Soft Tissues ......... 17. The Titanium-Bone Cell Interface In Vitro: The Role of the Surface in Promoting Osteointegration ............ 561 Barbara D. Boyan, David D. Dean, Christoph H. Lohmann, David L. Cochran, Victor L. Sylvia, Zvi Schwartz, 18, The Titanium-Bone Interface In Vivo Cecilia Larsson, Marco Esposito, Haihong Liao, Peter Thomsen 19. Titanium Ceramics for Cell-Carriers and for Medical Applications .. 649 Erich Wintermantel, Karl-Ludwig Eckert, Ning-Ping Huang. Marcus Textor, Donald M. Brunette Part V Medical Applications 20. Design and Engineering Criteria for Titanium Devices ....+. +. ++ 673 Beat Gasser 21. Titanium for Hip and Knee Prostheses ............+:eeeeeeereeee 703 Markus Windler, Ralf Klabunde 22. Wear of Titanium 6—4 Alloy in Laboratory Tests and in Retrieved Human Joint Replacements ..........0.-0020000-08+ 747 Harry A. McKellop, Tord Rostlund, Edward Ebramzadeh, Augusto SarmientoContents —_Xill 23. Titanium as Implant Material for Osteosynthesis Applications ...... 77 Stephan M. Perren, Ortrun E.M. Pohler, Erich Schneider 24. tanium for Dental Applications (I) .......... seseeneeeeeeeeenes 827 Marco Esposito 25. Titanium for Dental Applications (ID) Implants with Roughened Surfaces Daniel Buser 26. Titanium in Cardiac and Cardiovascular Applications ............. 889 Christian Olin 27.Titanium in Audiology ...... acerate wet Kajsa-Mia Holgers, Bo Hakansson 28. Regulatory Aspects in the Use of Titanium-based Mate for Medical Applications ...... ve Karl-Gustay Strid Part VI Appendices Appendix A Color Figures ........0cceeeeeeeeeeeeeeeeeeee eee ce eeeeeeee eee es 949 Appendix B Biographies of Editors and Authors .........eceeceeeeeeeeeneeeeees 971 Appendix C Abbreviations 6. .ccccscccessscsccccscseveccccescccccsssccscecs 995 Appendix D World-Wide-Web Sites (URL Addre: Appendi Index . Appendix F Spectacles for Stereo-View of Color Figures (App. A) ...scsseceeeesseceeeeeseueee insert at end of book1_A Perspective on Titanium Biocompatibility Buddy D. Ratner Ur ity of Wa: ton Engineered Biomater Seattle, WA, USA What is Biocompatibility? ...........+.+++ What are the Issues in Titanium Bioeompat Corrosion and Surface Reaction Interactions with Proteins and Cells ‘Surface Modification ........ Healing in Bone Titanium and Bioc A Perspective for the 21st Century ..... Titanium and Sachets and the 2ist Century Conclusic Reference: Bahan dengan hak cipta2 1 A Perspective on Titanium Biocompatibility The widespread and successful application of titanium (Ti) in medical implants is unquestionable. If, each year, Ti is used with good outcomes in hundreds of thou- sands of clinical implants, surely it must be biocompatible? This supposition will be examined in light of the definition of biocompatibility, ideas on the foreign body reaction and new developments in surface modification. 1.1 What is Biocompati The word “biocompatibility” is freely used in the biomaterials community, and by the general population, as well. Almost universally, titanium is said to be “biocom- patible”. It is worthwhile, before addressing the subject of titanium biocompatibil- ity, to examine what we mean by biocompatibility. There is an official definition for biocompatibility, a procedural definition and a practical or “world” definition. Each of these definitions can be helpful, but, unfortunately, they fail to address certain key issues. Let us examine these definitions. The most widely used definition, the “official definition” for biocompatibility, comes from a consensus conference on definitions in biomaterials: “Biocompatibility is the ability of a material to perform with an appropriate host response in a specific application.” [1] This definition, though obviously accurate, offers little insight into how to mea- sure biocompatibility or how to engincer for improved biocompatibility. The procedural definition comes from the ISO standards on biocompatibility. A series of tests is detailed, and a device that passes those tests might be rated as “bio- compatible”. Table 1.1 briefly outlines the ISO tests for biocompatibility. Many of the tests are oriented to studying extracts from the material or device and offer screens for genotoxicity, carcinogenicity, reproductive toxicity, cytotoxicity, irrita- tion, sensitivity and sterilization agent residues. Table 1.1. Biological evaluation of medical devices according to ISO 10993-1 * Animal welfare requirements + EO sterilization residuals * Tests for genotoxicity, carcinogenicity | * Degradation of materials + Reproductive toxicity + Irritation and sensitivity * Interactions with blood + Systemic toxicity + Invitro cytotoxicity + Sample preparation + Local effects after implantation + Identification and quantification of degradation products The tests for “local effects after implantation” aim to observe the normal foreign body reaction. If, after approximately one month of implantation, the implant is walled off in a tough, thin, avascular capsule, and the reaction site is relatively qui-1.2 What are the Issues In Titanium Blocompatibility? 3 escent, the implant is called “biocompatible”. Most surgeons would agree with this definition. This, in fact, is the practical, or real-world, definition. In clinical prac- tice, a surgeon can predict this relatively benign response and make the best of the foreign body reaction for achieving a therapeutic objective. Biocompatibility, as defined using this real-world definition, is observed in many (perhaps most) materials. For example, we have recently implanted subcuta- neously in the backs of mice a large series of synthetic surfaces varying widely in surface and materials properties [2]. All the materials were assayed prior to implan- tation to ensure that they had low cytotoxic leachables and freedom from endo- toxin! Also, all materials were thoroughly surface characterized so that we were confident that they were what they were supposed to be. Two of the materials in this set were chemically pure Ti and Ti treated by the Kokubo process [3]. Based on literature reports suggesting that the amount of fibrinogen adsorbed dictates the magnitude of the foreign body reaction [4], fibrinogen adsorption levels to each of the materials was measured. Ti and Kobubo Ti had almost an order of magnitude difference in the level of fibrinogen that will adsorb from plasma to their surfaces. Yet, the Ti, the Kokubo-treated Ti and all the other materials exhibited almost indis- tinguishable healing in soft tissue — a response best described as the classical for- eign body reaction and typified by a thin, acellular, collagenous capsule. Are there exceptions to this monotonous encapsulated healing? In fact, a few interesting cases are noted. Certain porous structures can heal in soft tissue with enhanced vascularity and little or no encapsulation [5]. By inhibiting the protein thrombospondin, a more vascularized and less collagenous healing can be noted [6]. Bioglass heals into both soft tissue and bone with essentially no encapsulation [7]. Titanium treated by the Kokubo method heals into bone with no encay and bonding to bone [8]. And, finally, pure titanium, in its own way exhibits good healing in bone. Specifically. there is no obvious foreign body capsule or signs of chronic inflammation. Bone is in close apposition to the Ti, but does not adhere to it. At the ultrastructural level, there is a biological layer, often just 5-10 nm thick, separating Ti and bone [9] ulation 1.2 What are the Issues in Titanium Biocompatibility? The literature on the biological reaction to titanium, in vitro and in vivo, is exten- sive. This literature centers about a few themes: corrosion and bioinertness; Ti interaction with cells and proteins; surface modification; healing in bone. Let us examine these themes, especially as they offer insights into biocompatibility. | Endotoxin contamination, often from water supplies, is remarkably common. Implant studies in which the absence of endotonin at surfaces and in solution is not explicitly measured are almost uninterpretable.4 1 A Perspective on Titanium Biocompatibility 1.2.1 Corrosion and Surface Reaction Titanium is a relatively inert, corrosion resistant metal because of its thin (approxi- mately 4 nm), surface oxide layer. Although the corrosion resistance of Ti is similar to high grade 316 stainless steel in non-proteinaceous solutions [10], stainless steel always exhibits higher reactivity in cell culture and after implantation in animals. This may be because protein solutions speed the corrosion of stainless steel, com- pared to equivalent saline solutions [11]. Ti, on the other hand, does not show an enhanced corrosion rate in biological media. Stress and wear, however, can acceler- ate the corrosion rate of Ti. Steinemann effectively makes the case that Ti alloys (e.g. TiAIV) are not as well integrated in bone as pure Ti, perhaps because of their enhanced corrosion rates [10]. The possibility of the formation of Ti-organic complexes (for example, Ti-pro- tein) has been raised [10]. Thus, even though Ti ion is present at exceedingly low levels, the complexation process removes the ion from solution in the vicinity of the implant permitting more metal to solubilize. Speculation about the bioactivity of Ti-organic complexes and their importance for Ti biocompatibility is appropri- ate. Yet, such complexes have yet to be properly isolated, characterized or (most importantly) shown to have a potentiating effect on cells and tissues. 1.2.2 Interactions with Proteins and Cells Titanium readily adsorbs proteins from biological fluids. Many papers have been published on this subject and specific proteins addressed include albumin [12,13], laminin V [14], glycosaminoglycans [15], collagenase [16], fibronectin [10,17], complement proteins [18] and fibrinogen [19], just to name a few of the many pro- teins studied. There are no generally accepted conclusions as to the importance of the protein film, or specific proteins, on biological reaction to Ti. Ti surfaces also can support cell growth and differentiation. As with all other implant biomaterials, neutrophils and macrophages are first noted on the biomate- rial. Foreign body giant cells next form from the activated macrophages. It is well accepted that osteoprogenitor cells migrate to the implant site and differentiate into the osteoblasts that make bone. This process may be potentiated by bone morpho- genic protein. Hundreds of papers have been published on cell interactions with Ti surfaces. Since correlations have never been established between in vitro cell adhesion and in vivo healing, the value of these studies for predicting the performance of bone implants is questionable. However, studies dealing with the differentiation of cells on Ti surfaces are of much interest. A key question is whether Ti surfaces have an active role in inducing such differentiation.1.2 What are the Issues in Titanium Biocompatibility? 5 1.2.3 Surface Modification ‘The surface of titanium has been the subject of exhaustive study. Ti? surfaces are, of course, never seen in the real world because of their extraordinarily high reactiv- ity. The ubiquitous surface oxide of titanium presents a surprising richness of pos- ties. The insulating oxide layer can be glass or crystalline and can entrain or adsorb halogens (Cl, F), calcium ion, lanthanum ion and phosphates. The effect of fluoride ion on Ti in enhancing bone pull-out strength is intriguing [20], but might be explained by mechanical effects (hardening) as much as by alterations in bio- compatibility. Two classes of surface modification are scen in the Ti literature: textures (includ- ing patterns and pores), and chemical modifications. Both will be briefly discussed. Textures, pores and patterns have been fertile themes to explore and improve the biological performance of titanium devices. On the length scale of millimeters, many studies have looked at the nature of screw threads in Ti devices and their influence on performance. It is clear that such structures are important. However, almost certainly, the effect is completely mechanical and will not be further addressed here. On the micron scale, roughness is clearly important. A casual liter- ature search turned up 29 papers on titanium roughness and its biological effect. This is far from a complete literature survey, but it is consistent with the fact that large effects are seen, so researchers explore these avenues. A good overview of this literature is given by Ellingsen [21]. There is a substantial range of roughnesses and textures that have been purported to be important for bone bonding. However, probably textures/pores in the range of 100 ym to 500 ym are important. The unique control of the foreign body reaction seen in very small pores has been largely ignored in the study of bone implants [5]. In any event, this body of litera- ture continues to emphasize the importance of mechanical interlocking to titanium device performance. Textures can also be important on the nanoscale. Although there are investiga- tions at this size scale, firm conclusions are not in at this time [22,23]. Patterning of Ti surfaces is another related area of interest, but rules for the significance of sur- face patterns have yet to be established [24]. Chemical modifications of Ti surfaces are so prevalent in the literature that hun- dreds of papers on this subject could be casually cited. A substantial portion of these papers center on coating titanium devices with bioactive ceramics and glasses in order to achieve true bone bonding at the interface. However, silane treatments, protein coatings, peptide immobilizations, reactions with antibiotics and other sur- face modifications are seen. Bioactive ceramics on Ti generally produce the expected bone biointegration with primary considerations centering around the bonding of the ceramic to the Ti and the strength of the ceramic itself. Most other chemical surface treatments show significant effects in in vitro studies but less effect in vivo.6 1 A Perspective on Titanium Biocompatibility The reaction of Ti surfaces with strong base and high temperature produces a surface titanate gel that exhibits what appears to be true bone bonding [3]. This may be related to the healing seen with other bioactive ceramic 1.2.4 Healing in Bone Bone is a tissue comprised of mineral, a considerable fraction of proteinaceous material and an extensive and complex vascular system. The starting point for understanding healing in bone is the inflammatory process, defined as the response of vascularized tissue to injury. Device healing in bone always starts with injury (the surgical procedure — the implant site). Early events include protein adsorption, neutrophil interrogation, macrophage attack, giant cell formation, cytokine release, fibroblast recruitment and collagenous encapsulation. These events occur with all implant biomaterials, titanium included. At some later stage during this initial period, osteoblast precur- sor cells differentiate to osteoblast-phenotypical cells, and coordinate the proc of bone mineralization. The etiology of bone formation from this point on has been nicely reviewed by Schenk and Buser [25]. A progression from an unoriented woven bone to a highly organized bone is consistently seen. 1.3 Titanium and Biocompati A Perspective for the 21st Century At the interface of the 20th and 21st centuries, biocompatibility is largely defined in terms of low toxicity (low leachables) and a reaction in soft tissue where the implant, after a few weeks of implantation, is found within a relatively acellular foreign body capsule (Table 1.1). Ti solidly fits this description. In bone, under appropriate conditions, Ti heals in close apposition to the miner- alized tissue. However, a thin (approximately 10 nm but occasionally as thick as 400 nm) non-mineral layer separates the Ti from the bone [26]. True adhesion of Ti to bone is not observed. Rather, the “bond” associated with osteointegration has been attributed to a mechanical interlocking of biomaterial surface asperities and pores with the bone. Bone formation upon implantation in bone is seen with Teflon, zirconium and gold (26,27). Teflon and zirconium are quite similar in their healing to Ti, although zirconium was reported to produce a thicker amorphous layer sepa- rating bone and metal (100-4000 nm) [26]. The authors commented that there was considerable variation in the thickness of this amorphous layer for both Ti and zir- conium and no error bars were offered. Gold produced soft tissue at the interface upon implantation in bone, and giant cells were observed [26]. Some mineraliza tion was seen even with gold. Teflon seems to heal with close apposition to bone, much like titanium [27]. Titanium and zirconium have exceedingly low ion release1.3 Titanium and Biocompatibility: A Perspective for the 21st Century 7 in biological fluid, while gold does show some dissolution [10]. Teflon also gener- ates essentially no leachables. Thus these observations are consistent with a toxi- cology model: the lower the leachables, the closer the apposition of bone to biomaterial. This healing behavior in bone for materials like Ti is unique compared to other anatomical sites in the body, and the etiology of this good healing is largely unex- plained. The important point here is that the healing of Ti is similar to other non- leaching materials, making it difficult to ascribe a unique biocompatibility to it For materials implanted in the body, the first stage of reaction (after interaction with water and ions) is a non-specific protein adsorption. Following protein adsorp- tion, neutrophils and macrophages interrogate the implant (of course, seeing only the adsorbed protein film). The macrophage interaction, in particular, and the cytokines released by those macrophages, is believed to attract fibroblasts and drive the foreign body encapsulation [28]. Ti heals similarly to most all other materials in soft tissue. At this point, I offer two hypotheses: Hypothesis one: on the ubiquity of the healing reaction I hypothesize that non-specifically adsorbed protein films are the similarity between most non-toxic materials that leads to similar healing in soft tissue. There are a few key characteristics of this protein film relevant to this discussion (Fig. 1.1). It is comprised of many different proteins. These proteins are oriented ran- domly and are also in various states of denaturation ranging from native to highly denatured. Finally, we, the biomaterials design engineers, have little say as to which proteins adsorb. Importantly, there is no parallel to this type of non-specific protein surface in living systems. It is characteristic only of our synthetic biomate- rials. Thus, the body may examine such protein films, conclude they are foreign, and respond to them as foreign objects to be attacked and digested, or, if this impossible, walled off. I sometimes refer to this process as “biocombatibility”. Hypothesis two: on the origins of the unique bone healing noted for titanium Thypothesize that non-leaching, mechanically immobile and non-reactive materials in bone (including Ti) trigger the foreign body reaction. The collagen sac that begins to form in a few days serves as a nucleation template for mineralization in the ionically rich environment in the bone (collagen is the natural template for the formation of real bone). Thus, the good healing we see in bone is really a fortuitous reaction to the low toxicological potential of Ti, but also its biological incompati- bility, i.e., the capsular walling-off response of the body to the foreign object (Ti). Where ionic release is not stimulating cells, this generates a good template for min- eralization. More specifically, where long-term, inflammatory cytokine release from macrophages stimulated by leachants does not occur, the collagen forms quickly, and in a form appropriate to provide the template for bone formation. Fur-8 1 A Perspective on Titanium Biocompatibility thermore, certain inflammatory cytokines may interfere with the ability of the osteoblast progenitor cells to differentiate to osteoblasts. It is interesting to observe that Ti ions can stimulate biological reactions [29]. However, the ion release is effectively so low that it allows good bone healing around Ti to occur. In other tis- sues, such mineralization is a problem [30]. In bone, luck is on the side of the bio- materials scientist ~ nature helps us to reorganize the injury site in an appropriate manner by providing a natural scaffold for bone formation. 8, The biomaterial i encapulated and G isolated 2. protein adsorption Mant proteins in any states ve ed . fibronectin laminin SPARC ouritar ECM: coliagen | GAG TSP In conjunction with ECM molecules, 7 a cell interrogation fibroblast ‘monocyte / reutaphni Communication to macrophage + fibroblasts release “= ¥ Growth and attachment inhibitors and stimulators (ka AO" ea PDGF TGFa or B FGF EGF 5, Sian cel formation at the interleukins TNF * Implant surface ~ Frustrated phagocytosis, Fig. 1.1. Key characteristics of protein adsorption during the healing process. Color version of this figure: see Appendix A in Part VI of the book. A recent paper reports that Ti surfaces are highly thrombogenic [31]. The release and production of many active molecules associated with thrombosis (FXIIa, thrombin, C3a, PDGF, for example) may stimulate a vigorous, short term foreign body reaction leading to more rapid collagenous encapsulation and faster reminer- alization. Let us further examine if titanium is special in its biological reaction. First, how might the body “see” that it has a piece of Ti in it, and not, for example, gold? Evo- lution has not had the necessary eons to develop mechanisms to respond to the TiO, surface of Ti. Also, recognition mechanisms always involve complex, multi- functional group interactions. It is not easy to see where the required structures for molecular recognition would come from on a titanium surface. One might hypothe- size an epitaxial orientation of adsorbed proteins due to the oxide crystal surface.1.4 Titanium and Biocompatibility and the 21st Century 9 However, the polycrystalline TiO, surface with many terminating structures seems far from the defined crystal faces that epitaxially orient adsorbates. This leads us back to the important characteristics of Ti. It resists corrosion and leaching, and it has reasonable mechanical properties. 1.4 Titanium and Biocompatibility and the 21st Century Titanium is successful as a clinically used biomaterial. This article and the analysis herein can in no way diminish that success. However, we biomaterials scientist have Ti now, and we usc it routinely in clinical application. We are acutely aware of its good points and limitations. If Ti functions because of its low corrosion rate, we are exploiting a phenomenon that was well explored and clarified in the earliest era of biomaterials research [32]. We are researchers and we need new horizons. So, we've done our good work — let's move on. The next evolution in Ti devices will come through biologically specific surface modifications. We will place recognition groups on the surface of Ti devices to trig- get specific aspects of healing and regeneration. The groups will be oriented and organized, in analogy to the way nature arrays its signal groups (receptors) at cell surfaces. This will put the biomaterial designer in charge of the biological reaction that will occur, rather than leaving it to stochastic protein adsorption events [33,34]. Another component of this next generation titanium biomaterial will be to discover the biological signals that we want to deliver to the body. Osteopontin probably has an important effect on bone healing [35-37] and inflammation [38] as do the bone morphogenic proteins [39,40]. Immobilization of such proteins and recognition peptides to Ti surfaces is already underway [41,42]. However, unless non-specific interactions (¢.g., biological “noise” associated with non-specific pro- tein adsorption) are addressed simultaneously with the efforts to drive specific bio- logical reactions, these approaches may have diminished success. Engineering of biospecific control of the macrophage on the implant may allow us to control the production of proteins of interest at the healing site [43]. Most likely, the macroph- age can synthesize all the needed proteins, delivering them temporally. The mac- rophage makes the correct proteins and signaling agents inexpensively, uncontaminated, immunologically correct and in a sterile, stable and FDA- approved form. 1.5 Conclusions A surface modification approach based upon well-defined biological mechanisms allows us to exploit the excellent properties of titanium such as mechanical strength and bioinertness, yet aim for 21st century biocompatibility — the surface is specifi- cally recognized by the body and the correct reaction is triggered. In this way, the10 1 A Perspective on Titanium Biocompatibility manufacturing expertise, regulatory approval, surgeon acceptance and experience base with existing orthopedic and dental devices can be built upon, rather than re- engineering such devices from ground zero. This surface strategy is a reasonable path to future medical devices and has been adopted by the University of Washing- ton Engineered Biomaterials (UWEB) program, a National Science Foundation Engineering Research Center. 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J Biomed Mater Res 47:220-227 Schoen FJ, Harasaki H, Kim KM, Anderson HC, Levy RI (1988) Biomaterial-associated cal- cification: pathology, mechanisms, and strategies for prevention. J Biomed Mater Res: Appl Biomat 22:1 1-36 . Hong J, Andersson J, Ekdahl KN, Elgue G, Axén N, Larsson R, Nilsson B (1999) Titanium is a highly thrombogenic biomaterial: Possible implications for osteogenesis. Thromb Haemost 82(1):58-64 Homsey CA (1970) Bio-compatibility in selection of materials for implantation, J Biomed Mater Res 4:341-356 Ratner BD (1993) New ideas in biomaterials science — a path to engineered biomaterials. J Biomed Mater Res 27:837-850 Ratner BD (1997) The engineering of biometerials exhibiting recognition and specificity. J Mol Rec 9:617-62512 1 A Perspective on Titanium Biocompatibility 36. 37. 39, 40. al. 42. McKee MD, Nanci A (1995) Osteopontin and the bone remodeling sequence. Colloidal-gold immunocytochemistry of an interfacial extracellular matrix protein. Ann NY Acad Sci 760:177-189 Butler WT, Ridall AL, McKee MD (1996) Chap. 13 Osteopontin. In: Bilezikian JP, Raisz LG, Rodan GA (eds) Principles of Bone Biology. Academic Press, San Diego, pp 167-181 Giachelli CM, Bae N, Almeida M, Denhardt DT, Alpers CE, Schwartz SM (1993) Osteopon- tin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques. J Clin Invest 92:1686-1696 . Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF and Giachelli CM (1998) NF- kB mediates @,B; integrin-induced endothelial cell survival. J Cell Biol 141:1083-1093 Wang X, Jin Y, Liu B, Zhou S, Yang L, Xi Y, White FH (1994) Tissue reactions to titanium implants containing bovine bone morphogenetic protein: a scanning electron microscopic investigation. Int J Oral Maxillofac Surg 23:1 15-119 Dee KC, Bizios R (1996) Mini-review: Proactive biomaterials and bone tissue engineering, Biotechnol Biceng 50(4):438-442 Nanci A, Wuest JD, Peru L, Brunet P, Sharma V, Zalzal S, McKee MD (1998) Chemical mod- ification of titanium surfaces for covalent attachment of biological molecules. J Biomed Mater Res: 40(2):324-335 Xiao SI, Textor M, Spencer ND, Sigrist H (1998) Covalent attachment of cell-adhesive, (Arg- Gly-Asp)-containing peptides to titanium surfaces. Langmuir 14:5507-5516 Riches DWH (1996) Chap. 3. Macrophage involvement in wound repair, remodeling, and fibrosis. In: Clark RAF (ed) The Molecular and Cellular Biology of Wound Repair, second edn, Plenum Press, New York, pp 95-1412 Titanium for Medical Applications avid E. Williams - University of Liverpool, Liverpool, UK Introduction _. 2 The Validity of the Concept of Biostability and Biological Safety Titanium and Tissue Engineering . Bioactivity and Titanium Conclusions a i 2 ic i 223 References ........ is ees Bahan dengan hak cipta14 2 Titanium for Medical Applications 24 Introduction Ina review of the biocompatibility of clinical implant materials some twenty years ago [1] I referred to a statement given in the preface of the Proceedings of an Inter- national Conference on the Science, Technology and Applications of Titanium in 1968 which stated that: Never has there been, as in the case of titanium, the concentration of scientific and technical devotion to a single metal, with so much money, over such diversi- fied areas, both technical and geographical. Never has a metal invited and received such attention, not only from the technical viewpoint, but also from the political arena and the world of finance. Never has metal, normally considered so mundane, been so extravagantly described as the wonder metal, the glamour metal and the metal of promise. Afier considering the properties and characteristics of titanium and its alloys with respect to biocompatibility and applications in implanted devices, I then concluded that this excitement about this metal in general engineering was reflected in the specific situation in the medical field, with the following comment: The extensive list of clinical uses of titanium and the titanium—aluminium—vana- dium alloy is a clear indication of the suitability of these materials for implant applications. There is no doubt, of course, that both stainless steel and cobalt- chromium alloys are widely used and generally accepted as good biomaterials However, the fact that titanium is being used preferentially in many of the more recent applications in maxillofacial and oral surgery, neurosurgery and cardio- vascular surgery, indicates a slight superiority. There is a clear advantage in corrosion resistance, and probably the titanium—aluminium-vanadium alloy has the best combination of mechanical and physical properties, corrosion resis- tance and general biocompatibility of all metallic biomaterials. Twenty years tory of biomaterials and medical devices and it is appropriate and opportune to consider whether this superiority exists today and whether titanium and its alloys can still be regarded as exceptionally good biomate- rials. This chapter represents an attempt to update this analysis of titanium in the context of medical devices. It does so partly with an attempt to review the perfor- mance of current medical devices that employ titanium and its alloys and partly with an analysis of the requirements of medical devices today, and indeed tomor- row. The latter point shall be dealt with first. a long time in the2.2 The Role of Titanium in Current Medical Devices 15 2.2 The Role of Titanium in Current Medical Devices Whenever titanium is mentioned in the context of medical applications, it is usually assumed that it is long term implantable devices that are under consideration since, as noted above, it is the combination of corrosion resistance and biocompatibility with mechanical performance that is the principal attribute of the metal. This chap- ter, and indeed the whole of this book, assumes the same fundamental position, although this is without prejudice to the excellent properties in general, which make these alloys very attractive, if expensive, engineering alloys for non-implan- tation medical applications. The list of past and current applications of titanium (which, in this section of the chapter will be taken to mean titanium or any titanium-rich alloy, but not any shape memory alloy), as reviewed in detail in the later chapters of the book, are varied and wide ranging in their function and expectations. Nevertheless, a relatively small number of generic applications can be identified. The reader will readily see that these applications and expectations are consistent with the general principles upon which materials selection for medical devices are founded. First, there are those situations where a tissue or organ has suffered from some disease or condition that has resulted in pain, malfunction, structural degeneration, or any combination of these, and which can only be alleviated by replacement, or possibly augmentation, of the affected part. The causative agent or factor could be bacterial, viral or fungal, autoimmunity, sclerosis, neoplasia, or simply age-related degeneration. The patients are often elderly, but need not necessarily be so, and require that any pain be reduced or eliminated and the offending tissue circum- vented by an alternative structure that is able to provide a degree of function equiv- alent to that which might be expected in such a person without the condition. It may well be that this is best achieved by excision of the tissue and its replacement, but the objective may be best satisfied by introducing an additional functional com- ponent into the body that takes on the role of the affected tissue. For example, the best solution to the arthritic hip may be to remove the affected bone and cartilage and replace them in their entirety with a total joint prosthesis, but with an athero- sclerotic artery, the objective may be more easily satisfied with a by-pass rather than a replacement. The important thing is that function is restored. It is, with a few exceptions, not necessary to make the prosthetic component look like or otherwise physically resemble the tissue that it is replacing, as long as it carries out the appro- priate function. It follows from this that it is a further requirement that this pros- thetic component is able to continue to perform this function for as long as the patient is alive. This is obviously where titanium comes in, because, as noted above, it has very good mechanical properties that are more than adequate for most stress systems in the body and has excellent biostability and biocompatibility char- acteristics. Examples where titanium has been used to good effect here are replace- ments for teeth (dental implants) and bones (maxillofacial devices, components of hip and knee replacements).16 2 Titanium for Medical Applications Secondly, there are those situations in which there is a malfunction of a tissue or organ and where relief may be obtained by the implantation of an engineering device which can assist that tissue or organ in its normal function. Typically such devices will be active, or powered, and will supply mechanical or physical energy to the affected part. Implantable electronic devices such as cardiac pacemakers, cochlear implants and defibrillators form a major group in this category, but thi also includes the powered systems that assist cardiac function such as the experi- mental heart pumps. Such devices generally have three sections, the internal func- tional components such as signal generators, power sources and pumping chambers, the parts that contain such components and the active interface between the device and the relevant tissues. The materials used for the internal functional components are not generally considered to be biomaterials since, by definition, they do not contact tissues. However, the containment materials are crucial and require to be diffusion barriers as well as mechanically robust and biostable, with excellent biocompatibility. The attributes of titanium can again be seen positively here. Thirdly, there are situations in which control is required over regeneration pro- cesses in tissues and where a device is used to either enhance or repress tissue growth or proliferation. Two examples may be cited here. The first is the stent that is used within a tubular system in order to maintain patency through the control of shape and the restriction of endothelial and muscle tissue proliferation, such as with the intravascular stent. The second is the structure, such as a cage, which is used to direct the process of new bone growth in attempts to repair defects or pro- duce bony fusion, such as in the spinal cage systems used in inter-body fusion. The requirements here will not be dissimilar to those of the first type of application. The fourth type of application is transient and directed towards the temporary support of traumatized or deformed tissues. Generically this could include sutures, clips, adhesives and staple for soft tissue, haemostatic and sealant devices and materials in the vascular system, plates, screws, pins and fixators for bone fracture repair and wires, brackets and other devices for orthodontic applications. The requirements here will be varied depending upon the stress transfer systems required in the device-tissue complex, and on the desire for biostability or biodeg- radation. It is self evident from the above brief analysis of the generic nature of implanta- tion applications that involve, or could involve titanium, that there are just a few generic requirements of titanium in order to perform the desired function. The first is that the material must have the appropriate mechanical properties, taking into account the stress levels and frequencies that will be encountered, and the expecta tions for stress transfer within the relevant part of the body. The second is that the material must be sufficiently corrosion resistant, taking into account the duration of implantation and the consequences of any corrosion process should it take place in that particular situation. The third is that the material should have adequate biolog- ical safety, which will be predicated upon the lack of cytotoxicity, mutagenicity, carcinogenicity, immunogenicity and thrombogenicity.2.2 The Role of Titanium in Current Medical Devices 17 When considering these requirements, it is not surprising that titanium has been used so much, and indeed has, for most applications, become the clear metallic material of choice for implantation. Titanium has, in fact, become the archetypal biomaterial, the uses of which are based upon the classical foundations of inert- ness, biological safety and adequate mechanical performance. If the actual contri- butions that the titanium makes to an implantable medical device are analyses, it will become obvious that titanium is not a great deal different to other real and potential biomaterials except that it gives marginally better performance in a num- ber of areas and probably gives better complete performance when taking all fac- tors into account. With respect to mechanical performance in implanted devices, a number of parameters may be considered and used in the selection process and risk analysis, but these do narrow to a very small number of critical factors for most structural applications, representing the need to resist fracture or permanent deformation over a sustained period of dynamic stress and the need for an appropriate elastic modu- lus taking into account the stress transfer mentioned earlier. Making an assumption that a metallic material has to be used for a given application, an assumption that sometimes may be intuitive but may not always be valid, bearing in mind the quali- ies of many engineering polymers, ceramics and composites, this means that a high fatigue endurance limit (or more correctly corrosion fatigue endurance limit), a high elastic limit, proof strength or yield strength, and a low elastic modulus rep- resent the optimal mechanical property characteristics for general use. In certain applications, other mechanical attributes become important, such as wear resis- tance whenever any abrasion is anticipated and superelasticity when recoverable elastic strain is desired as in some orthodontic and fracture fixation applications. It will be shown later in this book that titanium is very satisfactory in this respect. There will be other alloys known to the metallurgist, however, that will have supe- rior absolute mechanical properties than titanium alloys, and certainly many have better wear resistance. The usefulness of titanium is dependent on the combination of these properties with other important characteristics. Turning now to the question of biostability and corrosion resistance, there can be no doubt that if a synthetic material is intended to be implanted in the human body for a long period of time with the intention of replacing permanently a part of the body or the function of that part, the material must be sufficiently resistant to the very hostile environment of the body. Leaving aside those transient applications where degradability might be desirable, maximum corrosion or degradation resis- tance is a prime requisite for a long-term implantable biomaterial. This should take into account all potential mechanisms by which a material might adversely interact with the physiological environment, including conjoint mechanical — environmen- tal phenomena and highly specific biodegradation processes. Thus, with a metallic material, maximal resistance to dissolution / metal ion release, crevice corrosion, pitting corrosion, fretting corrosion, galvanic corrosion, corrosion fatigue, stress corrosion cracking, protein and inflammatory cell induced corrosion, accelerated corrosion and microbiological corrosion are all important. There can be no doubt18 2 Titanium for Medical Applications that if the requirement for inertness is paramount, titanium would be one of the most attractive altematives. With respect to biological safety, adverse events associated with an implantable material (ignoring any adverse events attributed to the physical presence of the device) can be caused by either a surface interaction or a release of some material component. Taking the latter point first, it has already been concluded above that titanium excels in corrosion resistance, including the straightforward metal ion release, and so there are few opportunities for any metal ions to be released in any quantity into the body under normal operating circumstances. It is well known [2.3] that some titanium is released into tissues over a period of time and, indeed, can give rise to a characteristic discoloration of the tissue, but the amounts seem to be very small in most clinical applications. However, this condition is predicated on the stability of the oxide film on the titanium and it is possible, for example under extreme conditions of abrasion or fretting, for the oxide film to be compromised, such that elemental or particulate products are released. The biological activity of titanium ions or compounds, if released has been a matter of some controversy. The vast majority of the evidence {for example 2,4] has indicated that the titanium that is present in the tissue, and associated with this discoloration, has very little effect, a position that is confirmed by abundant in vitro studies [for example 5] that demonstrate an absence of cytotoxic effects, or at least a minimal cytotoxicity in comparison with other metallic elements. I have often referred to titanium as physiologically indifferent, it being tolerated by cells and tissues without being an essential element and, therefore, without any positive effect but also without any negative effect. Some studies have appeared to show a more marked biological response, including a putative immunogenicity but these are in a considerable minority. It must also be mentioned, of course, that with a tita- nium alloy, ions other than those of titanium may be released, and this again has been a source of some controversy. The most commonly used alloy contains 6% aluminium and 4% vanadium. There have been many claims that vanadium is an element with certain toxicological characteristics and that this should be a reason for seeking alternatives. It is true that, although there are undoubted positive roles for vanadium as an essential trace element, cytotoxic effects can be observed with this element under some circumstances, but the evidence would suggest that the risks of such events at the levels likely with the clinical use of the alloy are very low. If anything there should be a greater concern with the aluminium content of the alloy, since this element has clearly identified toxicological characteristics, but unfortunately the aluminium is required to act as the alpha stabilizer and provide the alpha-beta structure that is the basis of the mechanical properties of the alloy. In practice, some marginally better performance mechanically may be achieved by using alternatives to Ti-Al-V, but the toxicological or biocompatibility arguments for change are rather weak. As far as the possibility of a biomaterial causing adverse events through surface reactivity is concerned, there is little reason to assume that a titanium surface has ity of engaging in any specific interactions with cells or proteins that2.3 The Validity of the Concept of Biostability and Biological Safety 19 could cause harmful effects. More will be said of this later in the context of the pos- itive aspects of biocompatibility but few would argue with the premise that, if a smooth surface biomaterial was required for direct contact with either soft tissue or blood, with minimal activation of any biological component (contact phase activa- tion of the clotting cascade, platelet adhesion and activation, complement activa- tion, protein adsorption and denaturation), titanium would be a natural choice, as it is for the frame of many heart valves and the casing of most implantable electronic devices. It has to be concluded from this analysis that, unless specific and unique proper- ties are required, titanium should be considered as the material of choice for any implantable medical device for which the mechanical properties of a metal are deemed necessary and where biostability and freedom from biological risk are required. 2.3 The Validity of the Concept of Biostability and Biological Safety In the light of the above comments, and on the understanding that titanium is a very valuable biomaterial at the present time, it is appropriate to consider the validity of this whole approach so that the future position of titanium can be assessed. The reason that titanium is so useful is that it does not react with the body. We will discuss arguments about bone bonding and so-called osseointegration a little later, but this has to be the underlying rationale for the widespread use of the mate- rial. Titanium is much more corrosion resistant than stainless steel and has there- fore, slowly over the years, replaced it in many areas of surgery. Cobalt~chromium alloys are still used in many situations of course, and display very good corrosion resistance, although not as good as titanium, and has excellent biocompatibility, although again arguably not so good as titanium. In some circumstances these alloys are superior to titanium mechanically, as with some of the bearing surfaces in joint replacement devices, whilst in other situations the elasticity of titanium is preferred, as with bone support or replacement. It is also relevant to point out that the other group of metallic biomaterials that are widely used, although under differ- ent circumstances, are the platinum group metals and these again rely upon biolog- ical inertness and biological safety. If this is true, that titanium is successful because it reacts minimally with the body, we must ask the question of whether this is the best approach. It certainly may be argued that this situation with metallic materials has been replicated else- where with biomaterials, since some of the most successful biomedical polymers and bioceramics have been those that are inert and which display excellent biocom- patibility. PTFE, polyethylene, silicone elastomers, polymethylmethacrylate, pyro- lytic carbon and alumina are all used because they also react minimally with the tissues of the body. Many polyurethanes would be useful as thermoplastic elas-20 2 Titanium for Medical Applications tomers but their lack of biostability compromises their long term suitability, as it does with otherwise useful materials such as certain polyesters and polyamide: The situation is, therefore, that the majority of the implanted medical devices of today rely upon materials chosen for their inertness. It is a consequence of this that these materials do not have any intrinsic capacity to become incorporated into the tissues of the body either physically or biologically and will always have to act as an adjunct to the body, performing such functions as are desired but never being part of the body and always being at risk of a separation from the body at some future time. Heart valves may be made of inert materials, for example a titanium frame, car- bon leaflets and expanded PTFE sewing ring. These materials do not incorporate themselves within the heart muscle but the device is sewn in pace. Tissue ingrowth into the pores of the sewing ring or pannus overgrowth may occur but these are not processes of material induced incorporation. A pacemaker can remain in place without incorporation but its exact location is not important; however, the pace- maker electrode has to be firmly fixed to the heart muscle and there is no hope of achieving this with a metal unless a porous surface is used. Most hip replacements have to be cemented in place because they cannot otherwise be retained. Dental implants achieve stability by protective surgery (i.e. a procedure that minimizes loading on the implant during the early post-operative stages) and a threaded root for mechanical integration. In other words, the search for inertness has led to a group of implantable devices which may function mechanically and may be biologically safe, but which cannot be integrated into the body. This places a serious constraint on the uses of inert materials for reconstructive surgery. We may have some useful devices that save lives, provide pain relief and generally improve the quality of life, but it may prove impossible to extend their performance in terms of reliability and the range of con- ditions these procedures address. It is also true that the search for inertness itself may not ultimately be successful. Many of us have argued that there is no such thing as an absolutely inert biomate- rial, and inertness and biostability have to be considered in relative terms. The fail- ure of most polyurethanes to demonstrate biostability and the corrosion failures of stainless steels testify to the fact that otherwise very good biomaterials may eventu- ally be shown to fail the strictest tests for inertness. Alumina has been shown to loose strength on implantation, polyethylene oxidizes and Dacron hydrolyzes in the presence of lysosomal enzymes. Notwithstanding all of the favorable comments above about the exceptional corrosion resistance of titanium, it can corrode under some conditions. For example, if lessons are not leamt about galvanic and fretting corrosion, the titanium stems of modular hip replacements, in contact with a cobalt alloy surfaced head may well corrode, with disastrous clinical consequences [6]. Thus, it could be argued that not only is inertness a concept of limited applica- bility, it is an aspiration that is extremely difficult to achieve. It may be concluded, therefore, that titanium has provided an extremely good solution to a number of. medical device issues, but that its uses have probably reached a peak, and that2.4 Titanium and Tissue Engineering 21 these are likely to decline in the future as different concepts and different materials ‘emerge. Whether this is correct will depend on a number of factors, concerning first the relationship between tissue engineering and medical devices, and secondly the validity of the theories about the putative bioactivity of titanium surfaces. 2.4 Titanium and Tissue Engineering ‘At the present time, tissue engineering is under intense discussion and scrutiny. According to some sources, tissue engineering could negate the need for implant- able, conventionally engineered devices, in which case the future for titanium, or indeed any other inert biomaterial would be in doubt. What is tissue engineering, and is this likely? I have defined tissue engineering as “the persuasion of the body to heal itself, through the delivery to the appropriate site of cells, molecular signals and supporting structures” [7]. There will be many situations where the ability to address a clinical condition by tissue engineering has no counterpart in conven- tional medical devices since, for the reasons alluded to above, the latter approach has been entirely inappropriate, one example being the treatment of neurodegener- ative diseases such as Parkinson’s Disease. A comparison may be seen, however, in cases of diseases of the skeletal system, where there are implantable prostheses at the moment and where the ability to cause regeneration of bone and cartilage implies rapid progress in the tissue engineering approach. In the latter case, it will be the ability to diagnose cartilage degeneration at an early stage, coupled with the ability to harvest and grow chondrocytes and produce new cartilage that can be implanted into the carly lesion in order to restore joint structure, that is so attrac tive, in which case the total joint replacement, currently used as a last resort with severely damaged cartilage and sub-chondral bone, will largely become redundant. It may well be that scientific, technical, regulatory and logistics hurdles delay the progress in this area, and total joint replacements will still be required for a long time yet, but it does appear that these uses have peaked. The same may be said of heart valves, where it is unlikely that the mechanical valves, already losing ground to the bioprosthetic valve, will be able to compete with tissue engineered or other more natural valve forms in the future. The above definition did indicate that there would still be a need for support sys- tems in some cases. The delivery of cells and biologically active molecules to sites of tissue damage where they are intended 10 effect a regenerative process is not a trivial process. Most scaffolds and matrices are being made of biodegradable poly- mers for the obvious reason that there is usually little point in persuading tissue to repair itself around a permanent un-natural object. In some situations, however, the need to achieve rapid and effective stability with continued support from a stable structure, as in some situations with the treatment of spinal defects, suggests that the most stable and inert of all engineering structures may still have a role along- side tissue engineered bone grafts.22 2 Titanium for Medical Applications 2.5 Bioactivity and Titanium Much of the discussion about titanium performance in the literature during the last decade or so has been focussed on the manner in which titanium interacts with bone. Ever since Branemark and his colleagues demonstrated good success with dental implants made of titanium with respect to attachment to bone, and the so- called osseointegration phenomenon [8] arguments have been put forward, and refuted, about the special qualities of titanium that allowed for a positive interac- tion at the bone titanium interface. Mechanistically there are two issues with respect to the bone-biomaterial interface. First, is it bone that forms at the interface or is ita variable combination of bone and soft tissue. Secondly, if bone does form at the interface without any detectable soft tissue layer, is the material actually bonded to the surface. The conclusions that I draw from the literature and my own observations is that there is a great variability in the way in which bone and soft tis- sue compete for the biomaterial surface after the latter is implanted in a bony site There are some materials that come close to 100% contact with bone and some that develop little or no bone contact. Taking into account the many experimental vari- ables that are involved, such as mechanical stability, surface roughness and so on, it is a clear impression that the extent of bone contact increases with inertness. It is possible to see essentially the same level of bone contact in a transcortical rabbit model with implants made of alumina, high density polyethylene and titanium, with decreasing levels as less and less inert metals, ceramics. composites and ther- moplastics are used. In the vast majority of circumstances, apposition to bone and clinical stability of devices, which is considered by many to be the effective mean- ing of osseointegration, is achieved through the route of maximizing inertness, the lack of reactivity meaning minimal stimulus to inflammation and the resulting soft tissue formation, On the other hand, apposition of a material to bone does not signify adhesion or bonding. There is a clear indication that so-called bioactive materials based on cal- cium phosphates, particularly calcium hydroxyapatite, do actively permit bone bonding, hence their use as coatings on many orthopaedic and dental implants. The coating of titanium implants with hydroxyapatite in order to achieve bone bonding implicitly states that this bonding does not occur so readily or so well with uncoated titanium. Intuitively it is not easy to see why a bond should form between titanium and new bone. As Davies points out [9], the important thing about the interface is that the associated environment permits expression of osteoblast pheno- type. However, these cells should produce a caleium phosphate cement-like sub- stance and if, as shown to be feasible by Hanawa [10], the phosphorus and calcium are adsorbed to a surface such as titanium oxide, a bond could form. It is possible, therefore, that titanium has a little more to offer than exceptional corrosion resis- tance2.6 Conclusions 23 Whether this proves to be the case and provides titanium, in any of its forms (i.e. alloys), with a clinically significant advantage over other conventional biomaterials remains to be seen. 2.6 Conclusions This review has demonstrated that titanium and several of its alloys have been con- firmed as one of the most effective groups of traditional biomaterials and are still the materials of choice for many structural implantable device applications. It has to be recognized, however, that this situation has arisen almost exclusively because titanium has exceptional corrosion resistance in the physiological environment, a characteristic which itself, along with physiological indifference, imparts excellent soft and hard tissue biocompatibility. There is no reason for this position to change in the short, or probably medium term. However, it is necessary to be cognizant of the radical change that is currently underway in reconstructive surgery, with the emergence of tissue engineering and its associated products. On this basis, it may well be that the clinical uses of titanium will peak soon. A great deal will depend on the competitive edge that some titanium alloys may have with respect to overall 's or components will still be performance in those situations where metallic de required irrespective of the developments in tissue engincering, and on the outcome of the controversial aspects of so-called bioactivity of titanium, especially with respect to bone. References 1. Williams DF (1981) Titanium and titanium alloys, In: Williams DF (ed) Biocompatibility of Clinical Implant Materials. CRC Press, Boca Raton 2. Meachim G, Williams DF (1973) Changes in non-osseous tissue adjacent to titanium implants. J Biomed Mater Res 7:555-572 3. Black J, Sherk H, Bonini J, Rostoker WR, Schajowicz F, Galante JO (1990) Metallosis asso- ciated with a stable titanium alloy femoral component in total hip replacement. J Bone Joint Surg 72A (1):126-130 4, Bardos D (1990) Titanium and titanium alloys. In: Williams DF (ed) Concise Encyclopedia of Medical and Dental Materials. Pergamon Press, Oxford New York, pp 360-364 5. Maurer AM, Merritt K, Brown SA (1994) Cellular uptake of titanium and vanadium from addition of salts or fretting corrosion in vitro. J Biomed Mater Res 28:241-246 6. Williams DF (1999) Unpublished observations 7. Williams DF (1999) The Williams Dictionary of Biomaterials. Liverpool University Press, Liverpool 8. Branemark PI, Hansson BO, Adell R, Breine U, Lindstrom J, Hallen ©, Ohman A (1977) Osseointegrated implants in the treatment of the edentulous jaw. Scand J Plast Reconstr Surg. 52:1-13224 2 Titanium for Medical Applications 9. Davies JE, Ottensmeyer P, Shen X, Hashimoto M, Peel SAF (1991) Early extracellular matrix synthesis by bone cells. In: Davies JE (ed) The Bone-Biomaterial Interface, University of Toronto Press, Toronto, pp 214-228 10. Hanawa T (1991) Titanium and its oxide film: a substrate for formation of apatite. In: Davies JE (ed) The Bone-Biomaterial Interface. University of Toronto Press, Toronto, pp 49-613_ Metallurgy and Technological Proper ‘anium and Titanium Alloys Howard L. Freese”, Michael G. Volas, J Randolph Wood Allvac (An Allegheny Technologies Company), Monroe NC, USA Unntrodunction oo... 11. .ccsssrsnescsccssessscsssssssetstsssessssses 26 Corrosion Resistance of Biomaterials... 00. ccee0eeeseeeeeeeseuee 26 General Biocompatibility . ‘Titanium Biomaterials .. Titanium as 4 Biomaterial Osseointegration and «Osseointegratability» .... Titanium Properties and Chemistry zi .31 Chemistry and Structure... ; al Chal loyeil Titans and Alpha Titenbu lioys 33 Beta Titanium Alloys os... cc... se vues 34 Alpha—Beta Titanium Alloys. 34 Processing and Mier Machinability Manufacture of Titanium Metal . Titanium-Containing Ores and Minerals Titanium Sponge Titanium Meltin; Manufacture of Semi-Finished Titanium Mill Products Titanium Ingots and Billets Titanium Bar, Rod and Wire Products Plate, Sheet, Strip and Foil Products . Casting Alloys Powder Metallurgy. Heat Treatment Stress Relieving and Annealing Solution Treating plus Aging . Abbreviations and Symbols ..... 48 References ......sccccccees sees sees cesses esses eee eee WD ructure * To whom correspondence should be addressed. Bahan dengan hak cipta26 3 Metallurgy and Technological Properties 3.1 Introduction Titanium, occasionally referred to as the “wonder metal”, has been utilized in a growing list of specialized applications since the Kroll process made the winning of this material from ores a commercial possibility in 1936 [1]. Titanium is the ninth most common element in the earth’s crust and is recovered from TiOy-rich deposits of rutile, ilmenite and leucoxene that are found on every continent. Since the discovery of titanium in 1794 [2], and up until Kroll's innovative process devel- opment in 1936, there had been no practical method to recover titanium metal from these ores because of its pronounced affinity for oxygen. Modem ore extra beneficiation and chemical processes have since enabled the large-volume manu- facturing of high-grade TiO, an important pigment for paints and commercial products, and of titanium metal for the production of the CP (“Commercially Pure”) titanium grades, titanium-based alloys and other alloys systems. The class of implantable metallic biomaterials can be divided into four sub- groups: stainless steels, the cobalt-based alloys, titanium metals, and miscellaneous others (including tantalum, gold, dental amalgams and other “specialty” metals). Principal requirements for all the biomaterials, including metallics, are presently understood to be [3]: ion, * corrosion resistance * biocompatibility * bioadhesion (bone ingrowth) * biofunctionality (mechanical properties, including fatigue strength and Young's modulus) * processability + availability 3.44 Corrosion Resistance of Biomaterials There is general consensus that the most corrosion-resistant metallic biomaterials are the “special metals” (titanium, niobium, tantalum and their alloys), followed by the cobalt-based alloys, and then the stainless stee! grades [4-6]. Within the tita- nium grades and alloys, there is a fairly broad spectrum of observed corrosion resistances based upon the titanium material chemical composition, including the level of trace elements. Whether in seawater and saline solutions, aggressive chem- ical processes, or the human body, some titanium grades are engineered and manu- factured to have better corrosion resistance than other titanium “recipes”. However, all the commonly-used titanium-based biomaterials have extraordinarily good cor- rosion resistance for extended contact with human bone, synovial fluids, soft tissue and plasma when compared with other metallic biomaterials [7.8]. Mechanisms for corrosion and the general consequences for in vitro or in vivo reaction products3.2 Titanium Biomaterials a7 from the corrosion of metallic biomaterials are well established. For further discus- sion on corrosion see Chap. 6. 3.1.2 General Biocompatibility It is universally agreed that no known implantable material has ever been shown to be completely free of adverse reactions in humans or animals, over a reasonable period of time. Therefore, a cautionary “biocompatibility statement” is now included in every ASTM and ISO biomaterial standard, including the metallics. Black [9] and Williams [10] have considered the host response to the presence of so-called “inert” biomaterials. They conclude that we are generally trying to note, histopathologically, very small changes in difficult-to-observe events over a rather long period of time by examining end points, usually after the human or animal host is dead. Since total inertness is never achieved in metallic, polymeric, ceramic or com- posite biomaterials, some measurable host responses to the presence of the bioma- terial are to be expected and must be considered in the material's selection, the device design and the implant application. A workable definition of biocompatibil- ity has been proposed by Williams: “. . . the ability to perform with an appropriate host response in a specific situation” [11]. Most clinicians, materials scientists, and medical-device design engineers favor the family of titanium-based biomaterials as being generally more inert, more corrosion resistant and more biocompatible in more implant applications than the other two major groups of metallic biomateri- als: cobalt-based alloys and stainless steels. General biocompatibility, such as cor- rosion resistance, is very good for titanium and its alloys; differentiation between grades is fundamentally determined by the differences in their chemical composi- tions. For further detailed discussion on concepts of biocompatibility the reader is referred to Chaps. 1 and 2. 3.2 Titanium Biomaterials 3.2.1 Titanium as a Biomaterial The earliest applications of titanium as a material for medical, surgical and dental devices were based on the post-World War IT advances in titanium manufacturing processes for aerospace and military requirements. Thus, the earliest ti materials were commercial aerospace “hand-me-downs” because the volume requirements represented by that industry, as it grew throughout the early 1960's, overwhelmed all other research and industrial applications for titanium combined. The four CP titanium grades (ASTM F 67), Ti-6AI-4V ELI (ASTM F 136), and nium bio-28 3 Metallurgy and Technological Properties “standard” Ti-6AI-4V (ASTM F 1472) were the first titanium biomaterials intro- duced in implantable components and devices. The issues of corrosion resistance and biocompatibility for those titanium grades were studied and documented, and interest ws generated in new “non-aerospace” titanium grades that were more suitable to the needs of the manufacturers of medi- cal, surgical and dental devices [12]. As device manufacturers investigated the potential advantages of titanium, new devices and improved versions of older devices were created that utilized the properties of titanium. This stimulated the need for better understanding of existing titanium formulations, and initiated research into improved titanium biomaterials more suited to the specific needs of dental applications, total joint replacement systems, medical fasteners and fracture- fixation devices (Fig. 3.1 to 3.4). Fig. 3.1. Titanium total hip arthroplasty. Fig. 3.2. Titanium porous hip stems Prospective multi-center clinical studies conducted in the USA, Sweden and elsewhere measure the survivability and efficacy of medical implants with patient follow-up surveys, interviews and radiographic examinations. Results of large- scale clinical studies that are reported in professional association journals suggest improvements or failures in materials performance, device design and physician technique. Materials issues such as bearing surface wear from articulating implants, or fret- ting wear from micro-motion in multi-component constructs have become major concerns for all metallic biomaterials. Device retrievals, from revisions and from autopsies when the patient dies or the laboratory animal is harvested, have enabled clinicians and materials experts to characterize the wear debris and to comment on the condition of the host's nearby and remote tissue and organs. Transport of3.2 Titanium Biomaterials 29 released metal ions and undisturbed metal particles in the vicinity of the implant are the subject of many studies, and the histopathological responses of the host are being better understood by the application of modem analytical techniques. All of this has driven the development of the newer titanium biomaterials, including beta titanium alloys that were invented specifically for chemical and mechanical proper- ties better suited for medical devices [13,14]. For the formation and medical conse- quences of wear particles and corrosion products the reader is referred to Chaps. 22, 21,7 and 6. Re) f Fig. 3.3. Combination titanium implant system for fractured femur and hip. Color version of this figure (left part): see Appendix A in Part VI of the book. SSS 7.0 mm Cannulated Screw —_—awee 4.5 mm Cannulated Screw ere 3.5 mm Cannulated Screw Fig. 3.4, Titanium screws for fracture fixation.30 3 Metallurgy and Technological Properties Titanium biomaterials in general rely upon the formation of an extremely thin (about 5~20 nm thick), hard, adherent, protective titanium-oxide film that is princi- pally TiO, (reference: Chap. 7). The extent to which alloying elements or trace ele- ments can cither enhance or interfere with this adherent TiO film determines whether the alloys have improved or more limited general corrosion resistance and, perhaps, general biocompatibility than do the CP titanium grades [15] (reference: Chap. 6). Some newer biomaterials that have been developed are metastable beta titanium alloys that incorporate the more noble beta stabilizing elements. These alloys claim improved in vivo material properties including: corrosion resistance, biocompatibility, lower modulus, ductility and formability [16-22]. 3.2.2 Osseointegration and «Osseointegratability» Brinemark selected titanium for dental implant applications, and coined the term osseointegration to describe the condition and the process for having a stable, loaded implant in direct contact with bone [23]. Integration of a foreign substance, a metallic implant, into bone or soft tissue of a living host involves many complex physiological and biological reactions, and these forces are prominent at the inter- face between the host and the device. For example, corrosion is essentially a chem- ical reaction that takes place on the implant surface, on the surface of wear debris, or between surfaces of two components of a device construct that are in contact with each other. Biochemical reactions also take place at these sites, and the ionic by-products of corrosion and wear can trigger other biochemical responses within the host, both at the metallic surface and beyond. The chemistry of the base metal from which the implant is made is important, as is the surface chemistry and the make-up of any coating, deposition, film or surface treatment that remains after implantation. Compatibility of metallic devices in their implanted condition with the bone, tissue and body fluids of the host is an important factor to be considered in the safety and efficacy of the implant over its useful life [24,25]. (See Part IV, Biological Performance, and Part V, Medical Applications). For human or animal cells to attach and proliferate on an implant surface during the critical weeks and months just after implantation, the biomaterial must be “osseointegratable”. Alternatively, a “cemented” hip stem has two interfaces: stem- cement, and cement-bone. In this case, the cement would need to possess “osseoin- tegratibility” as one of its important properties. Should the cement crack, corrode, wear or deteriorate, the biocompatibility and osseointegratibility of the implant remains important to the efficacy of the procedure. There are only a few biomaterials in wide use today that seem to have excep- tional osseointegratibility: CP titanium (with low interstitial iron content), CP tan- talum, and calcium hydroxyapatite (HA). The work of Branemark and his associates in the pioneering field of dental implants has resulted in a deepened understanding of the integration of, and the host response to, loaded, coated CP titanium implants [26]. Studies of retrieved dental implants, failures and long-lived3.3 Titanium Properties and Chemistry 31 successes, have shown the importance of the appropriate material selection for the device, the proper implant design, and the successful procedure by a skilled medi- cal or dental professional. Whether the implant is cemented, cement-less press-fit, or depends upon osseointegration for fixation, the need for new titanium grades with improved chemical, mechanical, wear, biocompatibility and osseointegratibil- ity properties has been made clear [27]. 3.3 Titanium Properties and Chemistry 3.3.1 Chemistry and Structure ‘Titanium is an allotropic element, which means that it can exist in more than one crystallographic form. The hexagonal close-packed crystal structure (hep), also called the alpha phase, exists at room temperature. A transformation to the body- centered cubic (bec) structure, or beta phase, takes place when titanium solidifies from a liquid or when solid titanium is heated to temperatures above 1,621 °F (883 °C). These two crystal structures are the basis for naming the three generally accepted classes of titanium alloys: “alpha”, “alpha-beta” and “beta” [28,29]. By alloying titanium metal with other elements, either crystal structure can be selectively stabilized at room temperature, thus making it possible to manufacture stable alpha, alpha-beta and beta alloys. Fig. 3.5 illustrates the stabil ence of these various alloying additions and how material behavior characteristics are affected [30]. Common alloying elements used to stabilize the alpha phase include aluminum, tin and oxygen, while those used to stabilize the beta phase include niobium, molybdenum, tantalum, chromium, iron and vanadium. Many alloys combine a carefully chosen combination of the two types of elements, and these are classified as “alpha-beta” alloys. Important properties of those titanium alloys used most widely in industry are reported in the ASM International publication, “Materials Properties Handbook: Titanium Alloys” [31]. Representative chemical properties of some frequently used titanium biomaterials are presented in Table 3.1, along with data on some of the newer titanium alloys that have been specifically developed for medical and surgi- cal devices.32 3 Metallurgy and Technological Properties Alpha-stabilizing Beta-stabilizing elements elements For example: For examp! aluminum molybdenum oxygen iron nitrogen vanadium chromium manganese Increasing quantities of alpha stabilizers promote alpha phase. «< < ~< ~=— —<. Increasing quantities of beta stabilizers promote beta phase. —_—> > Near- Mixed Near- Alpha alpha alpha-beta beta Beta structure | (some beta) | structure | (some alpha) | Stucture Unalloyed Te Ti 9 Te Tk Te Te Te Ti Ti SAL 6AL GAL GAl- 6A 8Mn —8Mo_11.5Mo- ™ 6Sn- 2Sn- 4V 6V- 2Sn- 8V- 6Zr- a Wr 4Zr- 2Sn 4Zr- 2Fe- 4.5Sn eae 1Mo- 2Mo 6Mo- 3Al 2.58n 0.2Si Te Tie 1BV- 8AL Cr. 1Mo- 3Al 1V Higher density —________» Increasing heat-treatment response ———> Higher short-time strength ——————_> ~<—_—__— Higher creep strength Increasing strain rate sensitivity __p»> << Improved weldability Improved fabricability —————>- Fig. 3.5. Effecis of alloying elements on titanium alloy structure. (Reproduced by permission of ASM International, Metals Park OH, USA),3.3 Titanium Properties and Chemistry 33 Table 3.1. Chemical composition and standards for selected titanium biomaterials. ‘Grade Name UNS ASTM 1S0 ] Chemical Composition and Type Number [Standard {Standard |Nominal Weight % Tit 50250 [ASTM F67 [180 sea2-2 [EOE mes Fe 020 max HOOIS max TicP2 9.2 [E010 max Fe0.30max 1001S max (Alpha) R50400_ [ASTM F 67 | ISO 5832-2 |N0.03 max O035maxTirem apa. ASTM P67 _|1S0 5832.2 0 wey BOD2 aN TiCP-4 ‘Fe Iso 0.10 max Fe 0.50 max H0.015 max (abo _|Rso700_|asTMF 67 |180 5832-2 |Noos mur O odo max Them TOMA (somo ER | ThSAL2.5#e TAL5.0 C 003 max Fe 25 HO.013 max (AlphavBeta) |= ISO 5832-10 |N0.05 max 00.25 Ti rem TERA, soe striae [apg aBma Re gag Ti-6AL-4V ELI 5 ‘AL6.0 C 0.10 max Fe 0.20 HOOI5 max (Alpha/Beta) RSGIOI ASTM F 136 | 180 5852-3 'N0.03 60.13 max Tirem V 40 Tigalans, [rio [asta Fs] so suns / Aeon O82 HO Tic|5Mo €0.05 max Fe 0.1 H 0.015 max Bea) __|R58150_|ASTM F 2066 |-— Mo 150 N00! 00.15 Tirem Ti-[3Nb-13Zr | €0.08 max Fe 0.1 H 0.02 max Nb 130 Waa} 88130 ASTM F 1713 | Noor Outten ze 130 Ti |6Nb-10HF _ r . [C005 max Fe0.05 H 0015 max HEO.S (Bea - ~ Nb 160 N0.002.00.1 Ti rem “Ti-13Mo-2.8ND-0.25i) (€0.02 max Fe 0.2 0.02 mex Mo 150 (Beta) {> C7 = N0.01 00.18 Ti rem Nb 28Si0.2 TuaNostar Tessi20 €0.02 max Fe 2.0 H.0.02 mex Mo 12.0 Bex) = - N0.01 00.18 Tirem Zr 6.0 Ti-[2Mo-SZr-58a €0.02 max Fe 0.2 H 0,02 mex Mo 12.0 (Beta) | ia N001 00.18 Tirem Zr 5.05050 "Tie I5Mo-5Z-3AL ‘AL 3.0 002 max Fe 02 40.02 max (Bea) = - Mo 15.0 NO.01 00.18 Ti rem Zr 5.0 Ti.30Ta 0.05 max Fe 0.1 H0.015 max Beta) z | N 0.01 0 0.15 Ti rem Ta 30 ‘Ti-4SNb 2 |. 0.04 max Fe 0.1 H.0.003 max Bewa) ReeAs0, [AMS 4982 |= Nb4SSNOOLOOITi rem 10.05 max Fe 0.05 0015 max Nb 105 Ti 35Zr 1ONb Gea) - a |N000200.1 Tirem Zr 352 TiASNbZSTa _swiso "Task Force ‘C005 max Fe 0.05 H10015 max Nb355 Bea) = [858350 _|F94.1225 |= No020015TaS7TiremZr13 TESA ASTM F 2063 Gntermealig - LNi558N001 0005 Tire 3.3.2 Unalloyed nium and Alpha Titanium Alloys Unalloyed titanium grades and alloys of titanium with alpha stabilizing elements maintain their hep crystallographic structures at room temperature and hence are classified as alpha titanium grades. These grades exhibit good elevated temperature creep properties, are weldable, and are used in cryogenic applications since hep phase materials do not exhibit ductile-brittle transformation. Strengthening effects in alpha alloys are achieved by solid solutioning of the alloying elements34 3 Metallurgy and Technological Properties 3.3.3 Beta Titanium Alloys ‘Most beta titanium alloys contain small amounts of alpha stabilizers which permit second phase strengthening to high levels at room to moderate temperatures. The bee beta phase is ductile, and therefore beta titanium alloys are easily cold form- able. Beta alloys are prone to ductile-brittle transformation, and thus are not used for cryogenic applications. The major alloying elements for beta alloys ~ molybde- num, niobium and tantalum — are also the elements that are considered to be very biocompatible, more so than the alpha stabilizing clements like aluminum and tin. Beta alloys may be strengthened by the solid solutioning effect of the beta stabi- lizer additions, but large strength increases also result from small volume (typically < 5%) second phase precipitation during heat treatment. Because of attractive hot and cold workability properties, much effort has been devoted to creating special- ized beta titanium alloys for specific applications. Even though the interest in, and the manufacture of, beta titanium grades is growing, the total worldwide output of titanium mill products includes only a few percent of beta titanium alloys by weight 3.3.4 Alpha-Beta Titanium Alloys Those alloys that combine the metallurgically balanced amounts of both alpha and beta stabilizers are typically used in applications where optimum levels of compet- ing characteristics are desired. This balancing of desired properties can be: high tensile strength versus fracture toughness, good creep resistance versus low cycle fatigue, high tensile strength versus high cycle fatigue. The properties of these two- phase alpha-beta titanium alloys can be tailored by heat treating and processing to adjust the microstructure and precipitation states of the beta phase to suit the metal temperature(s) for the end use application. Table 3.2 tabulates strength and ductility properties of most of the titanium bio- materials used and being considered by manufacturers of medical devices. Although some of these alloys have undergone different heat treatments, the heat treatments listed are in common use, and rather wide ranges of strength and ductil- ity can be achieved as shown by these data, Tensile strengths from 35 ksi. (242 MPa) to 145 ksi. (1000 MPa) can be tailored in the alpha grades by utilizing differ- ent elements of solid solution strengthening. Beta and alpha-beta alloys are shown to exhibit strengths upwards of 170 ksi (1173 MPa). The molybdenum containing beta and alpha-beta alloys can be cold drawn and direct aged to strength levels of over 220 ksi. (1518 MPa) with reasonable ductility properties3.3 Titanium Properties and Chemistry 35 Table 3.2. Mechanical properties of selected titanium biomaterials, Grade ‘Metallurgical ~] Tensile 02% Vield [Elon [Reduction [Typicar Designation Condition [Strength Strength _|gation jin Area’ [Hardness and Type | Gootnote) _|ksi. (MPa) [ksi (MPa) |% |S (Rockwell) tain fea Go 35241) 25722430 110 HRB 4 1 = aa teary 50845) 40276) [2030 80 HRB oe s@ (S448) ssa7) fis 50 HRB (alpha) 1) 80 (552) 70483) fis. as 100 HRB TisalZsy 130077 Tioo eno) asst6) fis, asain TTiSAL25Fe _ ~ - ~ & (Aiphaiieta} tae Fania 13531) 125(862)-|1s_— 30. 36 HRC ___| anneal - L — Catto lameatgy (1250862) fuss fos 32 HRC TT GALING aoa 125 62) 115(793) 10 as ho ure Teme WD 11593) oss) [2 eo ‘24 HRC 125 (860) |105(725) 8 IS L- 1560°F + ae aterquench @ 85486 [40@76) 16 f~ | eae eNO 8 Ae 115793) 95655) |22 Joo 24 HRC FepMocerare: [LAO 145 (1,000) |140(965) [15 33 HRC “Tel2Mo-Szr5Sn | - [ o - _ (Bea) 7 i = - Asdrawn "70 483) [osa4s) 12 HorRolled 130897) |90(621) 16 | Ge 12027) [115(793) 205s 35 HRC Ti-55.8Ni 1475 °F - TaN 5 tunel te) [130.08 [50085 20 f- = HRB = Hardness, Rockwell B Scale. HR Hardness, Rockwell C Scale. a: approx. 700 °C b: approx. 940°C c: approx. 800°C. d: approx. 850°C. e: approx. 760°C.36 3 Metallurgy and Technological Properties 3.3.5 Processing and Microstructure Along with chemistry, microstructure plays a major role in determining material properties of titanium biomaterials. Desired microstructures are obtained through thermo-mechanical (= combination of deformation and thermal treatment) process- ing and heat treatment operations. Except for the small volume of a second phase used to strengthen the beta alloys, alpha and beta alloys are primarily single-phase systems. Thermo-mechanical work will either produce a dynamically recrystallized equiaxed structure, or a structure that consists of elongated grains in the direction of working. Most semi-finished mill product is delivered with a final heat treat that statically recrystallizes the elongated structure into an equiaxed structure. Fig. 3.6 (left and middle) illustrate an elongated structure resulting from hot and cold working in a “long” product, such as bar or wire. Fig. 3.6 (right) illustrates the equiaxed structure resulting from an anneal recrystallization of the same or a simi- lar product after the thermo-mechanical working has been completed. “As-worked” structures exhibit higher anisotropic tensile strengths, typical of the types of pro- cessing that have been performed, and lower ductilities. On the other hand, recrys- tallized equiaxed structures exhibit lower non-directional strengths but have higher levels of ductility. 200 um Fig. 3.6. Microstructures for beta titanium alloy with different processing conditions: eft: hot-rolled condition; middle: cold drawn condition; right: recrystallized during final anneal. Microstructural manipulation can be achieved in alpha-beta alloys to improve or customize biomaterial properties. Typically, processes are chosen that generate ran- domly oriented grains of equiaxed alpha, which have been dynamically recrystal- lized during thermo-mechanical conversion, amidst a matrix of transformed alpha and retained beta. This structure is commonly referred to as a bimodal structure. The equiaxed alpha is used to resist crack initiation while the wansformed alpha is used to resist crack propagation. Other factors such as size, shape and spacing of the transformed alpha dictate other material behavior. The two prime processing variables responsible for trans- formed alpha size, shape and spacing are the annealing temperature and the rate of cooling to ambient temperature. Holding the metal temperature close to the beta transus temperature will “solution” most, if not all, of the equiaxed alpha devel-3.3 Titanium Properties and Chemistry 37 oped during thermo-mechanical work, while exposures close to the alpha tempera- ture will permit most or all of the equiaxed alpha to remain. The nature of the remaining transformed alpha develops during the cooling process from the solution anneal temperature to room temperature. Fast cooling rates develop narrow, closely spaced, randomly oriented platelets of alpha phase, commonly referred to as a Wid- manstatten structure. Fig. 3.7 shows the typical equiaxed and transformed micro- structures that are found in @, o-B, and £ titanium alloy semi-finished mill products. Table 3.3 illustrates how material behavior changes according to the vari- ous morphologies of the phases present in some a—falloys [32]. Fig. 3.7. Typical microstructures for cf, af, and f titanium alloys: a. equiaxed « phase in unal- Joyed titanium (after 1h/1 290 “F); b. equiaxed of e.acicular act B in TI-GAI-4V; d.cquianed in Ti-13V-I1Cr-3AL. (Reproduced by permission of ASM International, Metals Park OH, USA) Table 3.3 Typical fracture-toughness values for high-strength alphe-beta titanium alloys. (Reproduced by permission from ASM International, Metals Park OH, USA). Alloy Alpha Yield strength —_—_—Fracture toughness, Kj. morphology [ksi] [MPa] [ksiin.] [MPa-m] Ti-6AL4V Equiaxed 130910 40-60 44-66 Transformed = 125.875 80-100 88-110 Ti-6AL-6V-2Sn Equiaxed 155 1085-30-50. 33-55 Transformed (140980 350-70 55-77 Ti-6AL-2Sn-4Zr-6Mo — Equiaxed 165 1155-20-30 22-33 ‘Transformed = 160, 1120, 30-50 33-5538 3 Metallurgy and Technological Properties Fast cooling from the solution annealing temperature facilitates another micro- structural control aspect of titanium alloys. A fast cooldown generates a non-equi- librium, metastable, beta phase. This metastable beta phase, which is not stable at elevated temperatures, is “trapped and frozen” by the rapid quenching of the hot metal. This non-equilibrium phase makes it possible to precipitate small equilib- rium amounts of alpha phases in subsequent aging treatments, thus providing an inexpensive and reliable method for improving the tensile and yield strengths of the component. Further information on processing, in particular on forging, is given in Chap. 21. 3.3.6 Machinability Titanium is one of the more difficult metals to machine, but current industry metal- working practices have advanced so that reasonable production rates with excellent surface finishes are possible, when taking the unique characteristics of this material into consideration. For example, the @-B titanium alloy Ti-6Al-4V ELI (ASTM F 136) has a low modulus of elasticity, 15 msi. (104 GPa) versus 30 msi. (207 GPa) for steels and nickel grades. This lower modulus may cause greater “spring back” and deflection of the workpiece. Therefore, more rigid setups and greater clear- ances for tools are required. Titanium is chemically reactive, particularly at higher temperatures caused by friction, and there is a tendency for titanium to “weld” to tool bits during machining operations. Because titanium has a relatively low coeffi- cient of thermal conductivity, more heat can build up locally and this can further increase the temperature at the tool-to-workpiece interface. The following guidelines are suggested to machine titanium efficiently: * use low cutting speeds, © maintain high feed rates, * use a generous quantity of cutting fluid, * use and maintain sharp tools, * use rigid setups, and * never interrupt a cut ‘A dramatic loss of mechanical properties and the desired performance of the workpiece can result if these precautions are not taken. Surface cracks and other discontinuities might lead to the development of notch sensitivities that signifi- cantly decrease ductility and fatigue properties. Over-heating of the surface can result in interstitial pickup of oxygen and nitrogen, which will produce a hard and brittle alpha case. Two other concerns should be given attention when machining titanium. Chlori- nated cutting fluids are not recommended for components that will be applied in elevated temperature services. Titanium can be susceptible to stress corrosion fail- ures in the presence of chlorine. Fine particles and turnings produced by machining can be pyrophoric, and might create environmental hazards in manufacturing facil- ities. The rate of oxidation of titanium is extremely rapid, and spontaneous com-3.4 Manufacture of Titanium Metal 39 bustion can occur when titanium and its alloys are exposed in air with high metal surface area to metal volume ratios as in titanium “fines”. 3.4 Manufacture of Titanium Metal 3.4.1 Titanium-Containing Ores and Minerals Titanium is the fourth most abundant structural metal on Earth, exceeded only by aluminum, iron and magnesium. The predominant ores containing titanium are found all over the world in alluvial and volcanic deposits. The most attractive ores for extracting titanium are rutile, which contains about 95% titanium dioxide (TiO), and ilmenite, which contains from 50 to 65% TiO. Although these ores are plentiful, the high reactivity of titanium with hydrogen, oxygen and nitrogen requires sophisticated and costly handling and processing techniques to extract pure titanium metal from the ore. Most of the titanium ore mined is for the produc- tion of pure TiO, which is used extensively as paint pigment because of its bright white color and high opaqueness. Only about 5% of the titanium ore is used for the production of titanium metal [33]. 3.4.2 Titanium Sponge The winning of titanium metal from the ore involves a carbo-chlorination process that converts the TiO to titanium tetrachloride (TiCl4), followed by a chemical reduction of the TiCly to clemental titanium which is known as titanium sponge because of its highly porous, spongelike nature. The most common method of tita- nium reduction is the Kroll process, which involves the reaction of TiCl, with liq- uid magnesium (Mg) at high temperatures in large, airtight vessels in argon to avoid contamination of the titanium from air or moisture. The resultant titanium sponge has residual magnesium and magnesium chloride salts entrapped in the pores after the reduction process and must be further purified by crushing into small particles followed by acid leaching or vacuum distillation to produce com- mercially pure (99.9%) titanium. The energy required to produce a ton of titanium sponge from its ore is approxi- mately 16 times that needed to produce a ton of steel and twice that needed to pro- duce a ton of aluminum [34]. These high processing costs contribute to the relatively high cost of titanium metal compared with that of steel and aluminum.40 3 Metallurgy and Technological Properties 3.4.3 Titanium Melting Titanium sponge (Fig. 3.8) is converted into useful product forms by consolidation and melting into conventional ingots. Titanium sponge is processed without further alloying to make CP titanium ingots and mill products. Titanium alloys are pro- duced by mixing the titanium sponge with various metallic elements such as alumi- num, vanadium, iron, tin, niobium, molybdenum, chromium and zirconium to produce a wide range of titanium alloys with varying physical, chemical and mechanical properties. Fig. 3.8. Titanium sponge and 16" (406 mm)-diameter titanium alloy compact. For alloys that contain high melting refractory elements vanadium, niobium, and molybdenum, master alloys have been developed with aluminum which lower the melting point of the refractory elements in order to assure dissolution in a titanium alloy ingot. Primary melting and refining methods include consumable-electrode vacuum are melting (VAR), electron beam melting (EB) under vacuum, plasma arc melting (PAM) under inert gas and induction skull melting (ISM). Titanium sponge, alloying elements, master alloys and, in some cases, clean recycled scrap chips are blended in the proper proportions to develop a composite chemistry for3.4 Manufacture of Titanium Metal 41 the alloy of interest. These ingredients are mechanically compacted by cold press- ing into briquettes or compacts weighing from 5 to 150 Ib. (2.3 to 68 kg), which are used as feed stock for the first melting operation. feat Retning Hearn? continuotsly Cast ingot s Fig. 3.9. Plasma arc furnace for primary Fig. 3.10. Schematic of plasma are furnace for melting of titanium alloys. melting titanium alloys. Color version of this figure: see Appendix A in Part VI of the book. Compacts are welded together by consumable arc or plasma welding in an inert atmosphere to make a long, cylindrical, “consumable electrode” for the VAR pro- cess. This primary melting step consists of melting under vacuum in a water-cooled copper crucible to produce a round, first stage ingot. Alternatively, large bulk serap pieces can be welded together, with or without compacts, to produce a primary electrode for melting by VAR. First stage melted ingot/electrodes are then vacuum arc remelted one or two more times to produce a double or triple melted VAR ingot. The majority of titanium alloys is produced by the VAR process. Ingots typically range in size from 24 to 42 in. (588 to 1066 mm) diameter, and in weight from 6,000 to 36,000 Ib. (2730 to 16360 kg). The VAR melting method is not capable of producing a rectangular ingot; however, by means of press forging or extrusion, rectangular billets can be made from round ingots for flat product applications [35]. In the EB and PAM furnace systems, compacts and/or bulk scrap are fed into a horizontal water-cooled copper hearth and melted by high intensity electron beams (in the EB process) or inert gas plasma torches in the PAM process (Fig. 3.9 and 3.10). The liquid pool of molien titanium is poured down into a water-cooled cop- per crucible, to produce a round or rectangular ingot. When hearth melting is uti- lized, titanium alloys are generally produced as round ingots up to 30 in. (762 mm) diameter [36]. These ingots are usually remelted by the VAR (Fig. 3.11) process for optimum homogeneity to produce long, round products such as billet, bar, rod and42 3 Metallurgy and Technological Properties wire. CP titanium grades are generally hearth melted into both round and rectangu- Jar ingots, which can be fabricated directly into round and/or flat products, without the need for VAR processing. Hearth-melted rectangular ingots have been produced in sizes as large as 20 x 60 in, (508 x 1524mm) and 40,000 Ib. (18180 kg) [37]. Water in Fig. 3.11. Schematic of Vacuum Arc Remelt (VAR) Furnace. In the ISM process, titanium compacts and scrap are fed into a water-cooled seg- mented copper crucible, induction melted under vacuum or inert gas atmosphere and poured into ingot molds or investment cast shapes. The current technology is limited to a small crucible size, and heats are on the order of 180 Ib. (82 kg) or less. ‘The melting process is fast, with quick turnaround times between heats, and is therefore suited to small lot sizes and to investment cast shapes [38].aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.3.6 Heat Treatment 47 3.5.4 Casting Alloys Titanium castings are produced by the well-known investment casting process, using ceramic molds and special coatings to minimize surface contamination. Starting stock may be in the form of small diameter ingot or billet material for the VAR process, or scrap/virgin raw material for the ISM process. In either method, the molten metal is poured directly into molds of the final part shape. Most castings are hot isostatically pressed (“HIP”-ed) to heal internal shrinkage porosity, and the HIP operation is followed by stress relief annealing and pickling to remove any possible surface contamination. Castings may be further heat-treated depending upon the alloy, the customer's specification, and any other finish part requirements. 3.5.5 Powder Metallurgy Titanium powder metallurgy products are produced by either of two processes. One method is the blended elemental (BE) process in which titanium sponge fines, mas- ter alloys and other desired additions are thoroughly mixed in the proper propor- tions to yield the alloy composition. The other method is the pre-alloyed (PA) process in which a conventionally melted homogenous ingot or billet is made into powder by consumable melting and gas atomization into a fine powder. As a varia- tion of this second method, a hydride/dehydride process can be employed wherein an ingot or billet is heated ina hydrogen atmosphere. This introduces hydrogen to embrittle the titanium alloy which is then crushed into a powder and is finally vac- uum degassed to remove virtually all of the hydrogen introduced earlier. Either the BE or PA-produced powder is cold pressed into the desired final shape and is hot sintered in vacuum to consolidate and bond the powders (thus the chem- istry is “homogenized”). A post-sintering HIP process may be employed to further densify the part made from powder. Finished parts are usually annealed or heat treated, depending upon the specification requirements. 3.6 Heat Treatment Titanium and titanium alloys are heat treated to develop specific microstructures and mechanical properties for a particular application [41]. Heat treatments may also be combined with special thermo-mechanical processing sequences to further enhance or to optimize microstructures and properties of a desired component or device, ‘The response of titanium alloys to heat treatment depends on the composition of the particular alloy, and the effects of alloying elements on the alpha-beta phase balance. Heat treatments that are generally applicable to all titanium alloys are stress relieving, mill annealing and solution treating plus aging [4248 3 Metallurgy and Technological Properties 3.6.1 Stress Relieving and Annealing Stress relieving is a low-temperature treatment, typically in the range of 900 to 1,300 °F (482 to 704 °C), followed by air or controlled cooling. This process relieves internal stresses that occur during fabrication such as forging, rolling, welding, machining etc. Mill annealing, also known as “process” or “full” anneal- ing, is similar to stress relieving except that it is accomplished at higher tempera- tures, typically 1,200 to 1,500 °F (649 to 816 °C) followed by air cooling. This treatment tends to minimize hardness and maximize ductility so as to enhance fab- ricability, machinability and dimensional stability of the mill product. Many fin- ished parts are put into service in the “fully annealed” condition because a good combination of properties is achieved for most applications. 3.6.2 Solution Treating plus Aging Solution treating plus aging is a higher-temperature treatment with a rapid cool, followed by a low-temperature aging treatment that produces the highest tensile strength and moderate ductility combined with a good fatigue strength, fracture toughness, creep resistance etc. for the intended application. The range of tempera- tures and times for solution treating plus aging can be quite broad, depending upon the specific alloy. Not all titanium alloys are heat treatable by solution treating plus aging because of differences in composition and microstructure, which define the “physical met- allurgy” of the system. Some alpha alloys and the CP titanium grades are generally considered to be non-heat treatable because they consist of the single-phase alpha structure. Therefore, they are usually used in the annealed condition only. Alpha- beta alloys are typically heat treatable, and have moderate strengthening capal ties. Beta and “near-beta” alloys are highly heat treatable, and are capable of achieving very high strengths. The type of heat treatment employed depends upon the intended application, and is dictated by the finish part specification. Abbreviations and Symbols ASTM American Society for MPa mega-Pascal (10° Pa) Testing and Materials PAM plasma are melting (West Conshohocken, UNS Unified Numbering System Pa, USA) (Warrendale, Pa, USA) EB electron beam melting VAR vacuum arc melting HA hydroxyapatite 1SM induction skull melting Iso Intemational Organization for Standardization (Geneva, Switzerland)References 49 References 1, Imam MA, Fraker AC (1996) Titanium alloys as implant materials. In: Brown SA, Lemons JE (eds) Medical Applications of Titanium and its Alloys: The Material and Biological Issues. ASTM Special Technical Publication STP 1272 (Proceedings of a symposium held on 15 and 16 Nov 94 in Phoenix AZ., USA). Wes! Conshohocken PA, USA, p 4 2. Collings EW (1984) The Physical Metallurgy of Titanium Alloys. American Society for Met- als, Metals Park, OH 3. Breme J, Biehl V (1998) Metallic biomaterials. In: Black J, Hastings G (eds) Handbook of Biomaterial Properties. Chapman & Hall, London, Part Il, Sect. 1, p 135 4. Black J, Hastings G. ibid. p 137 5. Fontana MG (1970) Perspectives on corrosion of materials, Metallurgical transactions Vol. 1, The 1970 Campbell Memorial Lecture, ASM, pp 3251-3266 6. Steinemann SG (1987) Corrosion of titanium and titanium alloys for surgical implants. In: Lutjering G, Zwicker U, Bunk W (eds) Proceedings of the Sth International Conference on Titanium (Munich FRG, 10-14 Sep 1984). Deutsche Gesellschaft fur Metallkunde, pp 1373 1379 7. Zitter H, Plenk H (1987) The electrochemical behavior of metallic implant materials as an indicator of their biocompatibility. J Biomed Mater Res 21:881 8. Steinemann SG, Maiusli PA (1988) Titanium alleys for surgical implants; biocompatibility from physiochemical principles. In: Lacombe P, Tricot R, Beranger G (eds) Proceedings of the 6th International Conference on Titanium (Cannes France, 06-09 Jun 88). Les Editions de Physique, pp 535-540 9. Black J (1984) Systematic effects of biomaterials. Biomaterials 5:11-18 10. Williams DF (1998) Handbook of Biomaterial Properties. Black J and Hastings, ibid, Part III, Sect. 1, General concepts of biocompatibility, pp 481-489 11, Williams DF (1987) Definitions in Biomaterials. Elsevier, Amsterdam, pp 49-59 12. Steinemann SG, Perren SM (1984) Titanium alloys as metallic biomaterials. In: Lutjering G, Zwicker U, Bunk W (eds) Proceedings of the 5th International Conference on Titanium (Munich FRG, 10-14 Sep 84). Deutsche Gesellschaft fur Metallkunde, pp 1327-1334 13. Semlitsch M (1986) Classic and new titanium alloys for production of artificial hip joints. Proceedings of the technical program from the 1986 International Conference. Titanium Development Association, Dayton OH, USA, pp 721-740 14, Wang K, Gustavson L, Dumbleton J (1993) The characterization of Ti-12Mo-6Zr-2Fe ~ a new biocompatible titanium alloy developed for surgical implants. In: Eylon D, Boyer RR, Koss DA (eds) Beta Titanium Alloys in the 1990's. The Minerals, Metals and Materials Soci- ety (Proceedings of a Symposium held 22-24 Feb 93 in Denver CO, USA), Warrendale PA, USA, pp 49-60 15. Schutz RW (1993) An overview of bets titanium alloy environmental behavior. Beta Titanium Allloys in the 1990's, ibid, pp 75-91 16. Wang K, Gustavason J, Dumbleton JH (Aug 28, 1990) Method of making high strength, low modulus, ductile, biocompatible titanium alloy. US Patent Number 4,952,236 17, Wang K, Gustavason J, Dumblcton JH (Aug 15, 1989) High strength, low modulus, ductile, biocompatible titanium alloy. US Patent Number 4,857,269 18. Paris WM, Bania PJ (Dec 25, 1990) Oxidation resistant titanium based alloy. US Patent Number 4,980,127. Registered trademark of Titanium Metals Corporation, Denver, CO 19, Davidson JA, Kovacs P (Dec 8, 1992) Biocompatible low modulus titanium alloy for medical implants. US Patent Number 5,169,597 20. Zardiackas LD, Mitchell DW, Disegi JA (1996) Characterization of Ti-15Mo beta titanium alloy for orthopedic implant applications. In: Brown SA, Lemons JE (eds) Medical Applica-aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.References 51 41. Froes FH, Allen PG, Niinomi M (eds) Non-aerospace applications of titanium. The Minerals, Metals and Materials Society (Proceedings of a symposium held 16-19 Feb 98 in San Anto- nio TX, USA), pp 171-186 42. Wood JR, Russo PA (1997) Heat treatment of titanium alloys. Industrial Heating, April issue, pp5i-554 fanium-Nickel Shape Memory Alloys Medical Applications Peter Filip Southern Illinois University at Carbondale, Materials Technology Center, Carbondale IL, USA Introduction Fundamentals and Terminology of Shape Memory Phenomena . Martensitic Transformation in Shape Memory Ale Shape Memory Effect . Pseudoclasiciny or Superelasticiy Two-Way Shape Memory Effect ‘TiNi Shape Memory Alloys . . . Phase Diagram of TiNi Structure-Properties Relationship . Product Design . Medical Applications of TiNi Shape Memory Alloys Biocompatibility and Biaghanctionaliy dpe of TiNi . Applications in Dentisiry . 69 Vascular Applications and Stents 70 Medical Instruments 2... a Applications of TiNi in Orthopedics ......... 72 ‘A Case Snedp-Application of HN: ix Osieoxprthesis... a Future Trends in Medical Applications of TINi 78 Abbreviations and Symbols... + 80 References54 4 Titanium-Nickel Shape Memory Alloys 41 Introduction Shape memory alloys (SMAS) are special metallic materials, which spontaneously recover shape after being subjected to macroscopic deformation higher than their elastic limit. Recovery of shape may occur after heating or after release of loads. Applied deformation can be quite complex. Combinations of different deformation sequences are as readily recoverable as simple tension or compression. Numerous alloy systems, polymers, and ceramics have been found to exhibit shape memory behavior [1-10]. Titanium-nickel is a stoichiometric compound of Ti and Ni. This intermetallic compound is extraordinary due to excellent memory parameters and because its ductility is comparable to most ordinary alloys. It is often called NITINOL; Ni for Nickel, Ti for Titanium and NOL for Naval Ordnance Laboratory, the place where Buehler and his coworkers discovered this alloy. Other terms are NiTi alloy, which respects the metallurgical terminology of solid solutions with 55 wt% of Ni and 45 wt% of Ti, or TiNi alloy, which respects the chemical terminology, the TiNi being titanium nickelide. Research related to application of TiNi alloys in medicine started in the late si ties [11]. TiNi alloys became attractive for medical applications particularly because of memory properties. Ability of TiNi elements to recover an original shape after being deformed up to almost 10 % offers a considerable improvement during numerous medical treatments. For instance a tailored compressive fixation of bone fragments (e.g., fragments of small bones, broken jaws, cranial fractures) can be easily performed using recoverable deformation. Anchoring of implants (e.g. tooth roots, joint implants) and dentures to the living tissues as well as posi- tioning of tissues (e.g., shifting of misaligned teeth or vertebra, opening of nar- rowed veins or urethral tracts) is easily achievable using TiNi articles exhibiting shape memory behavior. Forces generated by memory elements can be controlled and invasive interventions can be minimized. Actuating ability of shape memory articles allows replacement or support of damaged muscles and tendons. Unique memory properties allow designing unique medical instruments with excellent steerability and flexibility (e.g., endoscopes). In addition to memory properties, TiNi shape memory alloys exhibit significantly better mechanical compatibility with tissues compared to other alloys and ceramics used in medicine. TiNi alloys exhibit excellent corrosion resistance, wear resistance, mechanical damping capac- ity, MRI visibility and sufficient radio-opacity. Great interest has been devoted to nickel release from TiNi biomaterials, since Ni hypersensitivity represents a signif- icant problem. Itis accepted now that the proper surface treatment and formation of a passivity layer is required for clinical applications without adverse effects. How- ever, because of high nickel content, it is necessary to be cautious regarding the clinical use of TiNi shape memory alloys and to make sure that relevant prope are under control. According to Andreasen, the first clinical application of a TiNi alloy in orthodontics dates to 1972 [12]. Numerous successful medical applicationsaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.4.4 Medical Applications of TINi Shape Memory Alloys 69 affected by surface preparation and also by structure state (cast, wrought, austenite, martensite) of the TiNi material [86,97]. The surface of TiNi alloy may change dur- ing exposure to a bioenvironment and the response of human cells differs from the response of animal cells [86]. Acceptable limits of nickel release and mechanisms of nickel interaction with tissue cells are not well understood. 4.4.2 Applications in Dentistry Fig. 4.6. An example of pseudoelastic TiNi arch wire utilization in orthodontics. Dental arch wire is one of the most successful applications of TiNi shape memory alloys. Resilience of work hardened TiNi martensitic structure (without shape memory) was used in the original application proposed by Andreasen [12]. The most effective solutions usually exploit pseudoelastic behavior. Shape memory effect is also applied to a certain extent. Fig. 4.6 shows a clinical example of orth- odontic treatment using a PE TiNi arch wire. An “ideal shape” is given to the mate- rial at elevated temperature (400 to 600 °C). During insertion into mouth a PE arch wire must be deformed in order to be fixed to the misaligned teeth. Since the arch wire tends to remember its original (an ideal arch) shape it acts by applying a force on a misaligned tooth. Schematic comparison of bending deformation characteristics of stainless steel (SS), work hardened TiNi (WH TiNi) and pseudoelastic TiNi (PE TiNi) wire is given in Fig. 4.7. The relevant portion of the curve is the unloading phase. Pseu- doelastic TiNi material provides the largest effective strain for tooth movement in an optimal stress zone. A treated tooth can move over a wide range and the PE TiNi arch wire will still generate the required stress. A nearly constant opposing force is70 4 Titanium-Nickel Shape Memory Alloys acting over a large reversible deformation span in case of PE TiNi. Work hardened ‘TiNi has shorter effective strain than PE TiNi but significantly higher than stainless steel (SS). Work hardened TiNi does not recover the deformation completely but has the advantage that a physician can adjust its shape. A physician can only adjust the PE TiNi if heated (temperature typically 400 to 600 °C), which may degrade the material if not performed properly. Stainless steel materials are easily adjustable but a rapid decrease of required stress related to a very low effective strain repre- sent significant disadvantages in treatment. Strain —> Fig. 4.7. Bending characteristics of pseudoelastic (PE TiNi), work hardened (WH TiNi), and stainless steel (SS). Treatment using TiNi dental wires and arch wires diminishes the risk of root hyalinization, shortens the time required for tooth rotations and leveling, requires significantly less chair time, as well as frequency of patient visits, and produces less patient discomfort 4.4.3 Vascular Applications and Stents Flexible TiNi stents have been used in the surgical treatment of various strictures such as constricted arteries, recurrent urethral obstructions, biliary obstructions, and malignant esophageal stenosis [102-108]. Helical wire or strip coils, woven or braided wire cylinders, laser cut tubing, and welded wire structures are used with varying success [77,105,107,108]. Difficulty with accurate positioning is a typical characteristic for helical coils. Woven stents frequently have trouble with fretting due to overlapping wire. Welds are inherently more susceptible to stress corrosion cracking and fatigue. Stents made from cut tubing exhibit the best performance, however, the diameter is limited to approxi- mately 5 mm. Pseudoelastic “self-expanding” stents are delivered to a lesion using a catheter stent delivery system. Before placing into a catheter, the stent is4.4 Medical Applications of TiNi Shape Memory Alloys 71 deformed to a minimum diameter. This deformation is related to SIM. The delivery system requires only a small opening or incision and the stent is deployed after positioning. Upon release from the catheter constraint, reverse transformation ‘occurs and the stent expands freely until it makes contact with the vessel wall. Expanding of vessel diameter follows and an equilibrium with vessel clastic stress is achieved. If the vessel should collapse the stress required for deformation of the TiNi stent increases steeply whereas the chronic force, trying to open the vessel, remains small. This behavior is not possible in conventional metals. Because of pseudoelastic character at body temperatures, very large expansion compared to stainless steel can be achieved (an analogy with dental wire shown in Fig. 4.7). If the chronic outward stress is too great, the smooth muscle layer may be damaged. Shape memory effect may be also utilized and the stent with a proper size is cooled and deformed in the martensitic state. After deploying into a vein or a stric- ture, heating to body temperature leads to recovery of desired size. Shape memory can also be used for temporary stenting. In this case, the stent remains in the mar- tate after placement in the target tissue and removal from the catheter. tensiti Using a balloon catheter, the stent is easily expanded (in martensitic state) to the required shape. Upon removal the stent is heated above Ag temperature and recov- ers to the non-expanded form shrinking onto the catheter. The catheter is removed with the stent attached [109]. Vena cava filters represent other examples of SME application. The filter is inserted easily into a vein and body heat changes its shape, creating a sieve, pre- venting blood clots from entering the lungs or heart [110]. 444 Medical Instruments TiNi alloys create significant potential for minimally invasive surgical instrumenta- tion [111-114]. TiNi PE guidewires and tubing are used for the introduction of var- ious therapeutic and diagnostic devices. A TiNi guidewire and tubing diminishes the complications, which may occur after a permanent kink of steel. It is difficult to remove a deformed steel instrument from the patient without causing further injury. Pscudoelastic TiNi wire can be easily bent without the risk of kink formation (again an analogy with dental wire shown in Fig. 4.7). Also increased steerability is very important. TiNi PE wire and tubing is able to translate twist at one end of the guidewire to nearly identical torsion at the other end [115,116]. More sophisticated active endoscopes consist of joints which are actuated by shape memory elements which allow flexible and controllable insertion into complicated and narrow regions. A computer can memorize the path and position of the first joint and fol- lowing joints are controlled in order to accommodate the whole shape of the endo- scope to the shape of the path [10,114,117,118]. TiNi PE spatulas, forceps or scissors on wire with variable curvature can be easily introduced into the human body through a small diameter cannula and, when extruded, assume significantly higher radius of curvature compared to steel instruments [14,1 11]. Another inter-aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.image not availableaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.References 81 7. Pelton AR, Hodgson D, Duerig T (eds) (1995) Proc of Conf on Shape Memory and Super- elastic Technologies 94 (SMST-94). International Organization on Shape Memory and Superelastic Technologies (SMST), Pacific Grove CA. 8. Gotthardt R. Van Humbeeck J (eds) (1995) Proc Int Conf on Martensitic Transformation (ICOMAT’95). Journal de Physique IV Volume 5, Colloque C8, Supplement au Journal de Physique III, n° 12 9. Pelton AR, Hodgson D, Russel S, Duerig T (eds) (1997) Proc of Conf on Shape Memory and Superelastic Technologies 97 (SMST-97). International Organization on Shape Memory and Superelastic Technologies (SMST), Pacific Grove CA 10, Otsuka K, Wayman CM (eds) (1998) Shape Memory Materials, University Press, Cambridge 11, Castelman LS, Motzkin SM (1981) The biocompatibility of nitinol. In; Williams DF (ed) Biocompatibility of Clinical Implant Materials, vol 1, pp 129-154 12. Andreasen GF, Morrow RE (1978) Laboratory and clinical analyses of nitinol wire, Ameri- can J Orthodontics 73:142-151 13, Proceedings of the International Conference on Medical Applications of Shape Memory Alloys (1990). Shanghai Iron and Steel Research Institute, Shanghai 14. Gyunter VE, Dambaev GC, Sysoljatin PG et al (1998) Medicinskie materialy i implantaty s pamjatyu formy (Medical materials and implants with shape memory), Izdatelstvo ‘Tom- skogo Universiteta, Tomsk 15. Gjunter VE (1999) private communication 16. Bensman G (1999) private communication 17. Lu S (1990) Medical applications of Ni~Ti alloys in China. In: [6], pp 445-451 18. Jia-long X, Jin-ling J (1990) Investigation and development of SMA in Shanghai Iron and Steel Research Institute. In [13], pp 2-12 19. Ming Z, Jinfang G, Xujun M, Guansen Y (1994) Medical applications of SMA in Beijing General Research Institute for Non-Ferrous Metals. Proc of Int Symp Shape Memory Mate- rials’94. International Academic Publishers, Beijing, pp 602-607 20. Ricart O (1997) The use of a memory shape staple in crevical anterior fusion. In [9], pp 623— 626 21. Musialek J, Filip P, Nieslanik J (1998) Titanium-nickel shape memory clamps in small bone surgery. Archives of Orthopaedic and Trauma Surgery 117(6/7):341-344 22. Olson GB, Owen WS (eds) (1992) Martensite. ASM Intemational, USA 23. Ortin J, Planes A (1988) Thermodynamic analysis of thermal measurements in thermoelastic martensitic transformations. Acta metall 36:1873-1889 24. Krishnan M (1998) The self-accommodating martensitic microstructure of Ni~Ti shape memory alloys. Acta materialia 46:1437-1455 25. Christian JW (1982) Deformation by moving interfaces. Metall Trans A13:509-S38 26. Nishida M, Yamauchi K,, Itai I, Ohgi H, Chiba A (1995) High resolution electron microscopy studies of twin boundary structures in B19" martensite in the Ti-Ni shape memory alloy. Acta metall mater 43:1229-1234 27. Zheng YF, Cai W. Zhang JX, Zhao LC, Ye HQ (2000) Microstructural development inside variant in a Ti-Ni-Nb shape memory alloy. Acta materialia the stress induced martensit 15:1409-1425 28. Wayman CM, Shimizu K (1972) The shape memory (marmem) effect in alloys. Metal Sci- ence Journal 6:175-183 29, Miyazaki $, Otsuka K, Wayman CM (1989) The shape memory mechanism associated with the martensitic transformation in Ti-Ni alloys — Part I: Self-accommodation. Acta Metall 37:1873-1884aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Reterences 85 99, Ryhiinen J, Niemi E, Serlo W, Niemela E, Sandvik P, Pernu H, Salo T (1997) Biocompatibil- ity of nickel-titanium shape memory metal and its corrosion behavior in human cell cultures J Biomed Mater Res 35:451-457 100. Putters ILM, Kaulesar Sukul DMKS, de Zeeuw GR, Bijma A, Besselink PA (1992) Compar- ative cell culture effects of shape memory metal (Nitinol), nickel and titanium: a biocompat- ibility estimation. Eur Surg Res 24:378-382 101. Assad M, Yahia LH, Rivard CH, Lemieux N (1998) In vitro biocompatibility assessment of a nickel-titanium alloy using electron microscopy in situ end-labeling (EN-ISEL). 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Trowers BA, Dar S, Hodges D (1997) Tandem expandable stent technique for a fractured nit- inol stent, Gastrointestinal endoscopy 45(2):217-218 109. Bramfitt JE, Hess RL (1995) A novel heat activated recoverable temporary stent (HARTS: System). In [7], pp 435-441 110. Simon M, Kaplow R, Salzman E et al. (1977) A vena cava filter using shape memory alloy. Experimental aspects Radiology 125(1):87-94 111. Meltzer A. Stickel D (1995) Performance improvement of surgical i the use of Ni~Ti materials. In [7], pp 401-410 112. Moran SS (1995) Flexible instruments in minimal access surgery. In [7], pp 411-415, 113. Frank TG, Xu W, Cushieri A (1997) Shape memory applications in minimal access surgery- The Dundee experience. In [9], pp 509-514 114, Ryklina EP, Morozova TV, Khmelevskaya et al. (1997) New devices for endosurgery based on shape meory and superelasticity. In [9], pp 539-541 115. Zadno R, Simpson JW (1997) The effect of material selection on torquability of guidewires. 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Kuo PP, Yang PJ, Zhong YF, Yang HB, Yu YF, Dai KR, Hong WQ, Ke MZ, Cai TD, Tao JC (1989) The use of nickel-titanium alloy in orthopaedic surgery in China. Orthopaedics 12:116-126 129, Schmerling MA, Wilkoy MA, Sanders AE (1976) Using the shape recovery of nitinol in the ‘Harrington rod treatment of scoliosis. J Biomed Mater Res 10:879-892 130. Haasters J, von Selis-Soglio G, Bensmann G (1990) The use of Ni~Ti as an implant material in orthopedics. In [6], pp 426-4445 Characterization of Titanium Surfaces Janos Vérds!, Marco Wieland?, Marcus Textor!”, Donald M. Brunette” aurence Ruiz~Tayl ! Swiss Federal Institute of Technology (ETH), Department of Materials, Lab land 2 University of British Columbia, Faculty of Dentistry, Vancouver, BC, Canada 3 Zyomyx Inc., Hayward, CA, USA -y for Surface Science and Technolo; Introduction een E Eee ETON SS Surfaces of Biomaterials ..... Surface Characterization Techniques . Overview Techniques for the Analysis of Chemical Composition .......0.00020064 98 Techniques and Methodology for Determining Topographical Properties of Surfaces .. Techniques for in situ, Real Time Monitoring of Surface Reactions . ‘Application to Titanium Surfaces. . Chemical Composition of the Surface Topographical Characterteation of Rough Titanium Surfaces . Monitoring Biomolecule Adsorption . Conclusions .......+.++ Abbreviations and Symbols References .......... 6.0. e cee eee ee ere ere eer Peereree rere ers . 140 107 ws 121 121 125 * To whom correspondence should be addressed.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.5.2 Surfaces of Biomaterials ot be represented by a number of monolayers of a different solid or liquid film at the surface with an abrupt change of composition at the interface to the underlying bulk substrate. The term surface has also been used for much more extended zones such as anodized surfaces with a thickness of the oxide film of several tens of nanometers to micrometers, although the term surface layer would be more appro- priate in such a case. Table 5.1. Properties and required information to describe surfaces. Property ‘Type of physico- ‘Typical information needed in applications chemical information Chemical Atomic (elemental) ‘Type of inorganic compounds composition Structure/ Order Disorder Morphology Texture Roughness Form Surface energetics Electric and magnetic properties, Optics Mechanics Surface dynamics composition Chemical state of ele- ments Molecular composition Functional groups Crystallinity Inclusions ‘Vacancies Crystal boundaries Molecular adlayers ‘Two- (2D) or three- dimensional (3D) form of surface features Specific surface area Porosity Wettability Adsorptivity Surface energy Electric and magnetic fields Optical properties Mechanical properties Mobility Oxidation states of elements Molecular structure of organic compounds Distribution parallel to surface (lateral distrib.) Distribution perpendicular to surface (depth pro- file) Size and distribution of crystallites or grains Orientation of crystallites at surface Structure and order of molecular assemblies, phase separation in heterogeneous systems ‘Type and distribution of morphological features Size and distribution of open or closed porosity 2D and 3D parameters describing the surface roughness, waviness and form ranging from the atomic or nanometer (nm) to the micrometer (jem) to the mm or em scale Wettability by polar/nonpolar solvents Hyérophilic/hydrophobic and. lipophilic/lipophobic properties Surface potentials, surface charges Direction and distribution of electric and mag- netic field strength at surface Dielectric constant, optical reflection and absorp- tion properties Elasticity/plasticity of surface layers ‘Tensile and compressive forces in surface layers Mobility of atoms and molecules at surfaces (across the surface and perpendicular towards the bulk substrate) In most cases, the amount of material that forms the surface is rather small in comparison to the whole sample or device. Taking the example of a small titanium92 5 Characterization of Titanium Surfaces implant, assuming that its weight is 0.2 g and its surface 1 cm’, the following val- ues may be typical and illustrate how sensitive the analytical techniques have to be in order to determine qualitatively or quantitatively the amount of material forming the surface: Total area of device: =1em? Total mass of device: =02g Mass of the surface oxide film: = 10%, Mass of the adventitious contamination film: = 10-8 g There are a number of surface properties that are used to describe surfaces and changes they undergo as a consequence of surface modifications or as function of the time of exposure to a particular environment (Table 5.1). Many of these proper- ties are believed to be (potentially) important in influencing the behavior of a par- ticular surface in a given biological environment, although in most cases the interactions and their underlying mechanisms are not known in sufficient detail. A number of techniques have been developed to an extent that allows the surface scientist to measure qualitatively or quantitatively various surface properties. A selection of the more important and useful techniques in the context of the bioma- terial field is summarized in the next section. This short compilation includes tech- niques that are suitable for the study of static properties as well as for monitoring the dynamics of surface processes, in particular adsorption and desorption at sur- faces when in contact with fluidic (or gaseous) media. ‘Table 5.2. Typical applications of surface analytical tools in the biomedical field, Applications Examples of tasks Research & Control of new surface modification processes (product and process Development development) Monitoring of interactions between surface and biological environment in vitro Adsorption and conformation of biomolecules such as proteins at bioma- terial surfaces Evaluating specific recognition between antibodies or cell receptors and. surface-adsorbed or surface -immobilized proteins Analysis of retrieved implants Correlation between biological performance and surface properties Quality Control of surface composition and topography of implant surfaces Assurance Shelf life stability Tracing back contamination to sources in the fabrication process Reproducibility of fabrication Marketing Regulatory issues (FDA approval, ete.) Analysis of competitor's products5.3 Surface Characterization Techniques 93, 5.3 Surface Characterization Techniques Surface analysis has become an important tool in the development and quality con- trol of biomaterials and biomedical implants. Typical applications are summarized in Table 5.2. Surface characterization is useful in the biomaterial area for more than one rea- son: 1. It allows one to control the surface properties of the test sample or device before biological evaluation is performed. Particularly in cases where the aim is to study the influence of specific surface chemistries and/or topographies, a careful control of the surface properties and quality is essential for the later correlation of biological performance and surface data. Any of the surface characterization techniques used in general may be useful for this purpose as it helps to define the state of the surface before contact with the biological environment, whether this is in vitro or in vivo. 2. Often one would like to know more specifically the properties of a biomaterial surface in contact with a biological environment. This is a difficult task since many of the commonly-used techniques are performed under high vacuum con- ditions. Such conditions may lead to experimental results significantly different from the more relevant situation where the surface is in contact with an aqueous fluid. Table 5.3 lists some of the particular difficulties in achieving results that are meaningful for defining interfacial properties in the biomaterial area. There are techniques such as scanning probe techniques [e.g. atomic force microscopy (AFM)]! or infrared techniques (such as FTIR) that can be performed under ambient conditions (in air or under fluids). Also, specialized preparation tech- niques have been developed, such as freeze drying, allowing one to preserve the state of the surface in contact with aqueous fluids (“frozen state”) for subsequent surface characterization using techniques that need high-vacuum conditions dur- ing analysis [5]. 3. To follow the development of the surface properties in a given situation is obvi- ously of great interest. There are ex situ techniques that only allow one to define the state at a particular point in time having removed the sample from the corre- sponding environment. Typical examples are all surface-analytical techniques requiring vacuum conditions during analysis such as X-ray photoelectron spec- troscopy (XPS) and secondary ion mass spectrometry (SIMS) or roughness measurement techniques such as mechanical stylus profilometry (MSP), non- contact laser profilometry (LPM) or interference microscopy (IM). On the other hand, techniques have been developed that enable the scientist to study surface processes in situ and in real time (“on line”) with high sensitivity. Examples of such processes are mineralization of the surface in simulated body fluid, protein ' For abbreviations: see “Abbreviations and Symbols” at the end of the chapter.