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Titanium As Biomaterial
Despite the great numbers of metals and alloys known to man, remarkably few warrant even preliminary consideration for uses as implant materials. The relatively corrosive environment combined with the poor tolerance of the body to even minute concentrations of most metallic corrosion products eliminates from discussion most metallic materials. Of the possible metallic candidates, tantalum and the noble metals do not have suitable mechanical properties for the construction of most orthopedic tools and implants, while zirconium is in general too expensive:

Attempts to use titanium for implant fabrication dates to the late 1930's. It was found that titanium was tolerated in cat femurs, as was stainless steel and vitalium (a CoCrMo alloy). Titanium's lightness and good mechanical and chemical properties are salient features for implant applications. One titanium alloy (Ti6Al4V) is widely used to manufacture implants. The main alloying elements of the alloy are aluminium (5.5 - 6.5%) and vanadium (3.5 - 4.5%). Whilst the strength of the titanium alloys varies from lower than to equal to that of 316 stainless steel, when compared by specific strength (strength per density), the titanium alloys outperform any other implant material. Titanium nevertheless, has poor shear strength, making it less desirable for bone screws, plates and similar applications.

Titanium also tends to seize when in sliding contact with itself or other metal. Titanium-based alloys that have a high co-efficient of friction which can cause problems. Wear particles are formed in a piece of bone if a piece of bone rubs against the implant, or if two parts of an implant rub against one another. Therefore, implants of titanium upon titanium generally are not used as joint surfaces. Titanium derives its corrosion resistance to the formation of a surface oxide film. Under 'in vivo' conditions, the oxide is the only stable reaction product.

More than 1000 tonnes (2.2 million pounds) of titanium devices of every description and function are implanted in patients worldwide every year. Requirements for joint replacement continue to grow as people live longer or damage themselves more in by hard sports play or jogging, or are seriously injured in road traffic and other accidents. Light, strong and totally bio-compatible, titanium is one of few materials that naturally match the requirements for implantation in the human body

Medical grade titanium alloys have a significantly higher strength to weight ratio than competing stainless steels. The range of available titanium alloys enables medical specialists designers to select materials and forms closely tailored to the needs of the application. The full range of alloys reaches from high ductility commercially pure titanium used where extreme formability is essential, to fully heat treatable alloys with strength above 1300 MPa, (190ksi). Shape-memory alloys based on titanium, further extend the range of useful properties and applications. A combination of forging or casting, machining and fabrication are the process routes used for medical products. Surface engineering frequently plays a significant role, extending the performance of titanium several times beyond its natural capability.

'Fit and forget', is an essential requirement where equipment in critical applications, once installed, cannot readily be maintained or replaced. There is no more challenging use in this respect than implants in the human body. Here, the effectiveness and reliability of implants, and medical and surgical instruments and devices is an essential factor in saving lives and in the long term relief of suffering and pain. Implantation represents a potential assault on the chemical, physiological and mechanical structure of the human body. There is nothing comparable to a metallic implant in living tissue. Most metals in body fluids and tissue are found in stable organic complexes. Corrosion of implanted metal by body fluids, results in the release of unwanted metallic ions, with likely interference in the processes of life. Corrosion resistance is not sufficient of itself to suppress the body's reaction to cell toxic metals or allergenic elements such as nickel, and even in very small concentrations from a minimum level of corrosion, these may initiate rejection reactions. Titanium is judged to be completely inert and immune to corrosion by all body fluids and tissue, and is thus wholly bio-compatible.

The natural selection of titanium for implantation is determined by a combination of most favourable characteristics including immunity to corrosion, bio-compatibility, strength, low modulus and density and the capacity for joining with bone and other tissue - osseointegration. The mechanical and physical properties of titanium alloys combine to provide implants which are highly damage tolerant. The human anatomy naturally limits the shape and allowable volume of implants. The lower modulus of titanium alloys compared to steel is a positive facotr in reducing bone resorbtion. Two further parameters define the usefulness of the implantable alloy, the notch sensitivity, - the ratio of tensile strength in the notched vs un-notched condition, and the resistance to crack propagation, or fracture toughness. Titanium scores well in both cases. Typical NS/TS ratios for titanium and its alloys are 1.4 - 1.7 (1.1 is a minimum for an acceptable implant material). Fracture toughness of all high strength implantable alloys is above 50MPam-1/2 with critical crack lengths well above the minimum for detection by standard methods of non-destructive testing.

Bone and Joint Replacement About one million patients worldwide are treated annually for total replacement of arthritic hips and knee joints. The prostheses come in many shapes and sizes. Hip joints normally have a metallic femoral stem and head which locates into an ultrahigh molecular weight low friction polyethylene socket, both secured in position with polymethyl methacrylate bone cement. Some designs, including cementless joints, use roughened bioactive surfaces (including hydroxyapatite) to stimulate osseointegration, limit resorption and thus increase the implant lifetime for younger recipients. Internal and external bone-fracture fixation provides a further major application for titanium as spinal fusion devices, pins, bone-plates, screws, intramedullary nails, and external fixators.

Dental Implants A major change in restorative dental practice worldwide has been possible through the use of titanium implants. A titanium 'root' is introduced into the jaw bone with time subsequently allowed for osseointegration. The superstructure of the tooth is then built onto the implant to give an effective replacement.

Maxillo and Cranio/facial treatments Surgery to repair facial damage using the patients own tissue cannot always obtain the desired results. Artificial parts may be required to restore the ability to speak or eat as well as for cosmetic appearance, to replace facial features lost through damage or disease. Osseointegrated titanium implants meeting all the requirements of bio-compatibility and strength have made possible unprecedented advances in surgery, for the successful treatment of patients with large defects and hitherto highly problematic conditions.

Cardiovascular devices Titanium is regularly used for pacemaker cases and defibrillators, as the carrier structure for replacement heart valves, and for intra-vascular stents. External Prostheses Titanium is suitable for both temporary and long term external fixations and devices as well as for orthotic calipers and artificial limbs, both of which use titanium extensively for its light weight, toughness and corrosion resistance. Surgical Instruments A wide range of surgical instruments are made in titanium. The metal's lightness is a positive aid to reducing any fatigue of the surgeon. Instruments are frequently anodised to provide a non reflecting surface, essential in microsurgical operations, for example in eye surgery. Titanium instruments withstand repeat sterilisation without compromise to edge or surface quality, corrosion resistance or strength. Titanium is non magnetic, and there is therefore no threat of damage to small and sensitive implanted electronic devices.

Titanium also may bio-accumulate in tissues that contain silica, but is not known to play a biological role in humans or animals.

Effects of titanium particle size on osteoblast functions in vitro and in vivo.
Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4578-83. Epub 2005 Mar 8.
Choi MG, Koh HS, Kluess D, O'Connor D, Mathur A, Truskey GA, Rubin J, Zhou DX, Sung KL.
Department of Orthopedic Surgery, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

The formation of titanium (Ti)-wear particles during the lifetime of an implant is believed to be a major component of loosening due to debris-induced changes in bone cell function. Radiographic evidence indicates a loss of fixation at the implant-bone interface, and we believe that the accumulation of Ti particles may act on the bone-remodeling process and impact both long- and short-term implant-fixation strengths. To determine the effects of various sizes of the Ti particles on osteoblast function in vivo, we measured the loss of integration strength around Ti-pin implants inserted into a rat tibia in conjunction with Ti particles from one of four size-groups. Implant integration is mediated primarily by osteoblast adhesion/focal contact pattern, viability, proliferation and differentiation, and osteoclast recruitment at the implant site in vivo. This study demonstrates the significant attenuation of osteoblast function concurrent with increased expression of receptor activator of nuclear factor kappaB ligand (RANKL), a dominant signal for osteoclast recruitment, which is regulated differentially, depending on the size of the Ti particle. Zymography studies have also demonstrated increased activities of matrix metalloproteinases (MMP) 2 and 9 in cells exposed to larger Ti particles. In summary, all particles have adverse effects on osteoblast function, resulting in decreased bone formation and integration, but different mechanisms are elicited by particles of different sizes.

Enhanced bone apposition to a chemically modified SLA titanium surface.
J Dent Res. 2004 Jul;83(7):529-33.
Buser D, Broggini N, Wieland M, Schenk RK, Denzer AJ, Cochran DL, Hoffmann B, Lussi A, Steinemann SG.
Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Berne, Freiburgstrasse 7, PO Box 64, 3010 Berne, Switzerland. daniel.buser@zmk.unibe.ch

Increased surface roughness of dental implants has demonstrated greater bone apposition; however, the effect of modifying surface chemistry remains unknown. In the present study, we evaluated bone apposition to a modified sandblasted/acid-etched (modSLA) titanium surface, as compared with a standard SLA surface, during early stages of bone regeneration. Experimental implants were placed in miniature pigs, creating 2 circular bone defects. Test and control implants had the same topography, but differed in surface chemistry. We created the test surface by submerging the implant in an isotonic NaCl solution following acid-etching to avoid contamination with molecules from the atmosphere. Test implants demonstrated a significantly greater mean percentage of bone-implant contact as compared with controls at 2 (49.30 vs. 29.42%; p = 0.017) and 4 wks (81.91 vs. 66.57%; p = 0.011) of healing. At 8 wks, similar results were observed. It is concluded that the modSLA surface promoted enhanced bone apposition during early stages of bone regeneration.

Characterization of apatite formed on alkaline-heat-treated Ti.
J Dent Res. 2004 Jun;83(6):465-9.
Chosa N, Taira M, Saitoh S, Sato N, Araki Y.
Department of Biochemistry, Iwate Medical University School of Dentistry, Morioka, Iwate, Japan. nchosa@iwate-med.ac.jp

Alkaline-heat-treated titanium self-forms an apatite surface layer in vivo. The aim of the present study was to materialistically characterize the surface of alkaline-heat-treated titanium immersed in simulated body fluid (AHS-TI) and to examine the differentiation behavior of osteoblasts on AHS-TI. SEM, thin-film XRD, FTIR, and XPS analyses revealed that AHS-TI contained a 1.0- micro m-thick, low-crystalline, and [002] direction-oriented carbonate apatite surface. Human osteoblast-like SaOS-2 cells were cultured on polystyrene, titanium, and AHS-TI, and RT-PCR analyses of osteogenic differentiation-related mRNAs were conducted. On AHS-TI, the expression of bone sialoprotein mRNA was up-regulated as compared with that on polystyrene and titanium (p < 0.05). On AHS-TI, the expression of osteopontin and osteocalcin mRNAs was up-regulated as compared with that on polystyrene (p<0.05). The results indicate that the apatite was bone-like and accelerated the osteogenic differentiation of SaOS-2, suggesting that alkaline-heat treatment might facilitate better integration of titanium implants with bone.

Metallic orthopaedic implants and airport metal detectors.
J Arthroplasty. 2002 Jan;17(1):62-5.
Kamineni S, Legge S, Ware H.
Department of Orthopaedics and Biomechanics, Mayo Clinic, Rochester, Minnesota, USA.

Airport security can detect in vivo metallic implants. We hypothesized that a soft tissue shield and fast transit through archway detectors would decrease implant detectability, whereas greater implant mass would increase detectability. Twelve patients with 8 orthopaedic implants in vivo and 60 trauma and arthroplasty implants in vitro were subjected to standard airport security measures at Stanstead Airport (British Airports Authority), including arch and standard and nonstandard hand-held detectors. Archway detectors failed to detect some implants; hand-held detectors detected almost all implants except an ankle arthroplasty. Positive archway detection was related to implant transit speed through the detection field. The implant mass consistently affected detection in stainless steel and titanium implants, and a 1-inch wax shield had no effect. Patients with metallic implants should prepare routinely with documentation of their implant before traveling through security ports.

Evidence for a direct role of cyclo-oxygenase 2 in implant wear debris-induced osteolysis.
J Bone Miner Res. 2001 Apr;16(4):660-70.
Zhang X, Morham SG, Langenbach R, Young DA, Xing L, Boyce BF, Puzas EJ, Rosier RN, O'Keefe RJ, Schwarz EM.
Department of Orthopedics, University of Rochester School of Medicine and Dentistry, New York, USA.

Aseptic loosening is a major complication of prosthetic joint surgery and is manifested as chronic inflammation, pain, and osteolysis at the bone implant interface. The osteolysis is believed to be driven by a host inflammatory response to wear debris generated from the implant. In our current study, we use a selective inhibitor (celecoxib) of cyclo-oxygenase 2 (COX-2) and mice that lack either COX-1 (COX-1-/-) or COX-2 (COX-2-/-) to show that COX-2, but not COX-1, plays an important role in wear debris-induced osteolysis. Titanium (Ti) wear debris was implanted surgically onto the calvaria of the mice. An intense inflammatory reaction and extensive bone resorption, which closely resembles that observed in patients with aseptic loosening, developed within 10 days of implantation in wild-type and COX-1-/- mice. COX-2 and prostaglandin E2 (PGE2) production increased in the calvaria and inflammatory tissue overlying it after Ti implantation. Celecoxib (25 mg/kg per day) significantly reduced the inflammation, the local PGE2 production, and osteolysis. In comparison with wild-type and COX-1-/- mice, COX-2-/- mice implanted with Ti had a significantly reduced calvarial bone resorption response, independent of the inflammatory response, and significantly fewer osteoclasts were formed from cultures of their bone marrow cells. These results provide direct evidence that COX-2 is an important mediator of wear debris-induced osteolysis and suggests that COX-2 inhibitors are potential therapeutic agents for the prevention of wear debris-induced osteolysis.

Particulate wear debris activates protein tyrosine kinases and nuclear factor kappaB, which down-regulates type I collagen synthesis in human osteoblasts.
J Bone Miner Res. 2000 Sep;15(9):1756-65.
Vermes C, Roebuck KA, Chandrasekaran R, Dobai JG, Jacobs JJ, Glant TT.
Department of Orthopedic Surgery, Rush University, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.

Particulate wear debris generated mechanically from prosthetic materials is phagocytosed by a variety of cell types within the periprosthetic space including osteoblasts, which cells with an altered function may contribute to periprosthetic osteolysis. Exposure of osteoblast-like osteosarcoma cells or bone marrow-derived primary osteoblasts to either metallic or polymeric particles of phagocytosable sizes resulted in a marked decrease in the steady-state messenger RNA (mRNA) levels of procollagen alpha1[I] and procollagen alpha1[III]. In contrast, no significant effect was observed for the osteoblast-specific genes, such as osteonectin and osteocalcin (OC). In kinetic studies, particles once phagocytosed, maintained a significant suppressive effect on collagen gene expression and type I collagen synthesis for up to five passages. Large particles of a size that cannot be phagocytosed also down-regulated collagen gene expression suggesting that an initial contact between cells and particles can generate gene responsive signals independently of the phagocytosis process. Concerning such signaling, titanium particles rapidly increased protein tyrosine phosphorylation and nuclear transcription factor kappaB (NF-kappaB) binding activity before the phagocytosis of particles. Protein tyrosine kinase (PTK) inhibitors such as genistein and the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) significantly reduced the suppressive effect of titanium on collagen gene expression suggesting particles suppress collagen gene expression through the NF-kappaB signaling pathway. These results provide a mechanism by which particulate wear debris can antagonize the transcription of the procollagen alpha1[I] gene in osteoblasts, which may contribute to reduced bone formation and progressive periprosthetic osteolysis.