Metastable Zr-Nb alloys for spinal fixation rods with tunable Young's modulus and low magnetic resonance susceptibility.

Good ductility, low magnetic susceptibility, and tunable Young's modulus are highly desirable properties for materials usage as spinal fixation rods. In this study, the effects of niobium content on the microstructure, magnetic susceptibility, and mechanical properties of Zr-xNb (13≤x≤23wt%) alloys were investigated. For the Zr-15Nb and Zr-17Nb alloys, a remarkable increase in Young's modulus was achieved due to the occurrence of deformation-induced ω phase transformation. This was the result of the competition of two factors associated with the Nb content: an increase of the stability of ß phase and a decrease of the amount of athermal ω phase with increasing Nb content. When the Nb content was 15% or 17%, the amount of deformation-induced ω phase was maximum. Moreover, the magnetic susceptibility decreased with the deformation-induced ß→ω phase transformation, and the Zr-17Nb alloy with apparent kink bands exhibited a smaller amount of springback than the Zr-15Nb alloy with {332} 〈113〉 mechanical twins. Furthermore, the ions released from the Zr-xNb alloys in accelerated immersion tests were at a very low level. The combination of low initial Young's modulus, and its remarkable variation induced by deformation, low magnetic susceptibility, good ductility, and smaller springback make the Zr-17Nb alloy a potential candidate for spinal fixation rods. STATEMENT OF SIGNIFICANCE: For the rods of spinal fixation devices, it is important but difficult to lower the springback for bending formativeness while keeping the low initial Young's modulus for biocompatibility and lower the magnetic susceptibility for postoperative examination simultaneously. In this study, Zr-17Nb alloy was successfully developed via deformation-induced ω phase transformation during loading, simultaneously meeting the abovementioned properties for spinal fixation rods.

Bioactive surface modification of Ti-29Nb-13Ta-4.6Zr alloy through alkali solution treatments.

Bioactive surface modification of Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) was performed through three different alkali solution treatments, including the electrochemical (E), hydrothermal (H), and hydrothermal-electrochemical (HE) processes; all of the processes lead to the formation of sodium-contained amorphous titanium oxide layers on TNTZ samples. The TNTZ samples subjected to the E, H, and HE processes exhibit a flat surface, smooth and fine mesh-like structure surface, and rough mesh-like structure surface, respectively. In the bioactive test, namely, simulated body fluid test, apatite inductivity increases as the surface morphology becomes rough. The order of inductivity for the three processes was HE>H>E. The surface chemical composition also affects the apatite induction ability. The surface with fewer niobium species exhibits better apatite inductivity.

Adhesive strength of bioactive oxide layers fabricated on TNTZ alloy by three different alkali-solution treatments.

Bioactive oxide layers were fabricated on Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) by three different alkali solution treatments: hydrothermal (H), electrochemical (E), and hydrothermal-electrochemical (HE). The adhesive strength of the oxide layer to the TNTZ substrate was measured to determine whether this process achieves sufficient adhesive strength for implant materials. Samples subjected to the HE process, in which a current of 15mA/cm(2) was applied at 90°C for 1h (HE90-1h), exhibited a comparatively higher adhesive strength of approximately 18MPa while still maintaining a sufficiently high bioactivity. Based on these results, an oxide layer fabricated on TNTZ by HE90-1h is considered appropriate for practical biomaterial application, though thicker oxide layers with many cracks can lead to a reduced adhesive strength.

Mechanical properties of a medical ß-type titanium alloy with specific microstructural evolution through high-pressure torsion.

The effect of high-pressure torsion (HPT) processing on the microstructure and mechanical biocompatibility includes Young's modulus, tensile strength, ductility, fatigue life, fretting fatigue, wear properties and other functionalities such as super elasticity and shape memory effect, etc. at levels suitable for structural biomaterials used in implants that replace hard tissue in the broad sense (Sumitomo et al., 2008 [4]). In particular, in this study, the mechanical biocompatibility implies a combination of great hardness and high strength with an adequate ductility while keeping low Young's modulus of a novel Ti-29Nb-13Ta-4.6Zr (TNTZ) for biomedical applications at rotation numbers (N) ranging from 1 to 60 under a pressure of 1.25 GPa at room temperature was systematically investigated in order to increase its mechanical strength with maintaining low Young's modulus and an adequate ductility. TNTZ subjected to HPT processing (TNTZHPT) at low N exhibits a heterogeneous microstructure in micro-scale and nano-scale consisting of a matrix and a non-etched band, which has nanosized equiaxed and elongated single ß grains, along its cross section. The grains exhibit high dislocation densities, consequently non-equilibrium grain boundaries, and non-uniform subgrains distorted by severe deformation. At high N which is N>20, TNTZHPT has a more homogeneous microstructure in nano-scale with increasing equivalent strain, εeq. Therefore, TNTZHPT at high N exhibits a more homogenous hardness distribution. The tensile strength and 0.2% proof stress of TNTZHPT increase significantly with N over the range of 0≤N≤5, and then become saturated at around 1100 MPa and 800 MPa at N≥10. However, the ductility of TNTZHPT shows a reverse trend and a low-level elongation, at around 7%. And, Young's modulus of TNTZHPT decreases slightly to 60 GPa with increasing N and then becomes saturated at N≥10. These obtained results confirm that the mechanical strength of TNTZ can be improved while maintaining a low Young's modulus in single ß grain structures through severe plastic deformation.

Heterogeneous structure and mechanical hardness of biomedical ß-type Ti-29Nb-13Ta-4.6Zr subjected to high-pressure torsion.

A novel ß-type titanium alloy, Ti-29Nb-13Ta-4.6Zr (TNTZ), has been developed as a candidate for biomedical applications. TNTZ exhibits non-toxicity and a low Young's modulus close to that of bone (10-30 GPa). Such a low Young's modulus of this alloy is achieved by comprising a single metastable ß phase. Greater mechanical biocompatibility, which implies higher mechanical strength and hardness while maintaining a low Young's modulus, has been aimed for TNTZ. Therefore, strengthening by grain refinement and increasing dislocation density is expected to provide TNTZ high mechanical strength while keeping a low Young's modulus because they keep the original ß phase. In this case, high-pressure torsion (HPT) processing is one of the effective ways to obtain these properties simultaneously in TNTZ. Thus, in this study, the effect of HPT processing on the microstructure and mechanical hardness of TNTZ was systematically investigated at rotation numbers (N) of 1 to 20 under a pressure of around 1.25 GPa at room temperature. On the cross sections of TNTZ subjected to HPT processing (TNTZ(HPT)) after cold rolling (TNTZ(CR)) at any rotation number, a heterogeneous microstructure consisting of a matrix and a non-etched band, which is not corroded by etching solution, can be observed. The thickness of non-etched band increases as rotation number and distance from specimen center increase. Both matrix and non-etched band comprise a single ß phase, but their grain geometries are different each other. Equiaxed grains and elongated grains are observed in the matrix and the non-etched band, respectively. The equiaxed grain diameter, which is ranged from 155 nm to 44 nm, in the matrix decreases with increasing rotation number. Contrastingly, the elongated grains with a length of around 300 nm and a width of 30 nm, which are nearly constant with rotation number, are observed in the non-etched band. The mechanical hardness of TNTZ(HPT) is consistently much higher than that of TNTZ(CR). The mechanical hardness distribution on the surface of TNTZ(HPT) is heterogeneous in the radial and depth directions, while that of TNTZ(CR) is homogeneous; the mechanical hardness is higher in the peripheral region than in the central region on the surfaces of TNTZ(HPT) at all N. Further, the mechanical hardness distribution on the cross sections of TNTZ(HPT) at all N is also heterogeneous in depth direction; the mechanical hardness is higher in the peripheral region than in the central region. The heterogeneous mechanical hardness distribution depending on the position on the surface and cross section of TNTZ(HPT) is considered to be related to grain refinement and imposed strain due to HPT processing.

Titanium-Based Biomaterials for Preventing Stress Shielding between Implant Devices and Bone.

ß-type titanium alloys with low Young's modulus are required to inhibit bone atrophy and enhance bone remodeling for implants used to substitute failed hard tissue. At the same time, these titanium alloys are required to have high static and dynamic strength. On the other hand, metallic biomaterials with variable Young's modulus are required to satisfy the needs of both patients and surgeons, namely, low and high Young's moduli, respectively. In this paper, we have discussed effective methods to improve the static and dynamic strength while maintaining low Young's modulus for ß-type titanium alloys used in biomedical applications. Then, the advantage of low Young's modulus of ß-type titanium alloys in biomedical applications has been discussed from the perspective of inhibiting bone atrophy and enhancing bone remodeling. Further, we have discussed the development of ß-type titanium alloys with a self-adjusting Young's modulus for use in removable implants.

Bone bonding bioactivity of Ti metal and Ti-Zr-Nb-Ta alloys with Ca ions incorporated on their surfaces by simple chemical and heat treatments.

Ti15Zr4Nb4Ta and Ti29Nb13Ta4.6Zr, which do not contain the potentially cytotoxic elements V and Al, represent a new generation of alloys with improved corrosion resistance, mechanical properties, and cytocompatibility. Recently it has become possible for the apatite forming ability of these alloys to be ascertained by treatment with alkali, CaCl2, heat, and water (ACaHW). In order to confirm the actual in vivo bioactivity of commercially pure titanium (cp-Ti) and these alloys after subjecting them to ACaHW treatment at different temperatures, the bone bonding strength of implants made from these materials was evaluated. The failure load between implant and bone was measured for treated and untreated plates at 4, 8, 16, and 26 weeks after implantation in rabbit tibia. The untreated implants showed almost no bonding, whereas all treated implants showed successful bonding by 4 weeks, and the failure load subsequently increased with time. This suggests that a simple and economical ACaHW treatment could successfully be used to impart bone bonding bioactivity to Ti metal and Ti-Zr-Nb-Ta alloys in vivo. In particular, implants heat treated at 700 °C exhibited significantly greater bone bonding strength, as well as augmented in vitro apatite formation, in comparison with those treated at 600 °C. Thus, with this improved bioactive treatment process these advantageous Ti-Zr-Nb-Ta alloys can serve as useful candidates for orthopedic devices.

Experiment study on fracture fixation with low rigidity titanium alloy: plate fixation of tibia fracture model in rabbit.

In order to investigate bone tissue reaction to the low rigidity titanium alloy of TNTZ in bone plate fixation, animal experiment with rabbit was performed with X-ray follow-up and histological observation. Experimental fractures were made in rabbit tibiae, and fixed by different bone plates of SUS316L, Ti-6Al-4V and TNTZ. Although there was no significant difference in fracture healing, bone atrophy was observed in cortical bone especially under the bone plate, which was different in time course among three materials. The bone atrophy under the bone plate was confirmed as porous or poor bone tissue in histological observation. In addition, the diameter of the tibia bone was increased in TNTZ as the result of bone remodeling with a new cortical bone. It is confirmed that the elastic modulus of the bone plate will naturally influence bone tissue reaction to the bone plate fixation according to the Wolff's law of functional restoration.

Fatigue characteristics of bioactive glass-ceramic-coated Ti-29Nb-13Ta-4.6Zr for biomedical application.

A new surface-coating method by which CaP invert glass is used to improve the bioactivity of titanium alloys has been developed recently. In this method, the powder of CaP invert glass (CaO-P2O5-TiO2-Na2O) is coated on the surface of titanium alloy samples and heated between 1073 and 1123 K. With this treatment, a calcium phosphate layer mainly containing beta-Ca3(PO4)2 phase can be coated easily on titanium alloy samples. In the present study, the effect of this coating process on the fatigue properties of Ti-29Nb-13Ta-4.6Zr, a new metastable beta alloy for biomedical applications, has been investigated. The fatigue endurance limit of the coated alloy was found to be about 15% higher than that of uncoated alloy, as a result of the formation of a hard (alpha + beta) layer and a small amount of the omega phase during the coating process. The coating exhibits excellent adhesion to the substrate during the tensile and fatigue tests. Subsequent ageing at 673 K for 259.2 ks greatly improves the fatigue resistance of the coated alloy due to isothermal omega phase precipitation, and does not have obvious detrimental effect on the coating properties.

Formation and growth of calcium phosphate on the surface of oxidized Ti-29Nb-13Ta-4.6Zr alloy.

The bioconductivity of a new biomedical titanium alloy Ti-29Nb-13Ta-4.6Zr achieved by a combination of surface oxidation and alkali treatment is reported in this paper. Oxidation treatment at 400 degrees C for 24 h was found to result in the formation of a hard layer on the surface of the alloy. Immersion in a protein-free simulated body fluid and fast calcification solution led to the growth of calcium phosphate (Ca-P) phase on the oxidized and alkali-treated alloy, and the new bioconductive surface was still harder than the substrate. The surface processes during various treatment and immersion processes were investigated in detail, and the morphology of the calcium phosphate crystals was shown to be determined by the concentrations of Ca and P in the solution.

Cold crucible levitation melting of biomedical Ti-30 wt%Ta alloy.

Recently, titanium-tantalum alloys have been studied as implant materials for dental and orthopedic surgery. However, titanium and tantalum are difficult to mix by common arc melting and induction melting, because of their high melting point and the marked difference between their densities (Ti: 1,680 degrees C, 4.5 g/cm3, Ta: 2,990 degrees C, 16.6 g/cm3). Thus, the Cold Crucible Levitation Melting (CCLM) method was chosen to produce a Ti-30 wt%Ta binary alloy in the present study. The CCLM furnace, with 1 kg capacity, consisted of a water-cooled crucible comprising oxygen-free high purity copper segments and coils wrapped around the crucible and connected to a frequency inverter power supply. A qualified ingot of 1.0 kg of Ti-30 wt%Ta alloy was obtained. The ingot was characterized from the surface quality, chemical composition distribution and microstructure, and finally the melting process was discussed.

Calcium phosphate invert glass-ceramic coatings joined by self-development of compositionally gradient layers on a titanium alloy.

A glass-ceramic layer containing beta-Ca3(PO4)2 crystals could be joined easily with a new type of titanium alloy (Ti-29Nb-13Ta-4.6Zr) consisting of a beta-titanium phase by heating the metal, on which glass powders with a composition of 60CaO x 30P2O5 7Na2O x 3TiO2 were placed, at 800 degrees C in air. Measurement of tensile bonding strength revealed that the joining between the coating layer and the substrate is very strong. Even after the large deformation (e.g., approximately 90 degrees in bending angle) of the titanium alloy, the coating layer was not peeled off from the substrate. A compositionally gradient layer in the TiO2-P2O5-Na2O-CaO system is developed automatically on the titanium alloy during the heating, resulting in the formation of the strong joining. By soaking in simulated body fluid at 37 degrees C, hydroxyapatite phase was formed newly on the surface of the coating layer.

Fatigue characteristics of ultra high molecular weight polyethylene with different molecular weight for implant material.

In order to investigate the effect of molecular weight on fatigue characteristics in the ultra high molecular weight polyethylene (UHMWPE), tension-tension fatigue tests of notched specimens were carried out in the present study. The effects of frequency and stress ratio on the fatigue characteristics were also investigated and fractography was discussed. The fatigue strength does not increase with increasing molecular weight. The fatigue strength might be influenced by the high degree of crystallinity in spite of the decreased tie molecule density in this study. Almost no effect of frequency on the number of cycles to failure can be observed. However, the higher the frequency, the higher the crack tip temperature. The effects of heat and strain rate on the fatigue strength must be considered in polymer materials. At a high stress ratio, the stress-number of cycles to failure (S-N) curves shift to high number cycles to failure side. Both stress amplitude and mean stress influence the fatigue life of UHMWPE.

Klinefelter's syndrome accompanied by mixed connective tissue disease and diabetes mellitus.

We report a rare case of Klinefelter's syndrome (KS) with mixed connective tissue disease (MCTD), diabetes mellitus (DM) and several endocrine disorders. A 57-year-old man presented with polyarthritis and tapering fingers with Raynaud's phenomenon on admission. In addition to a karyotype of 47, XXY, a marked restrictive change in respiratory functional test, a myogenic pattern in electromyogram, the positive tests for anti-RNP antibody indicated that this was a case of KS complicated with MCTD. The patients also presented DM with insulin resistance, hyperprolactinemia, slight primary hypothyroidism and hypoadrenocorticism. The mechanism for these coincidences remains to be elucidated.

Pamidronate treatment in patients with tumor-associated hypercalcemia: pharmacological effects and pharmacokinetics.

The purpose of this study was to investigate the effects of pamidronate, a second generation bisphosphonate, on the change in calcium homeostasis in patients with tumor-associated hypercalcemia. Eight patients with tumor-associated hypercalcemia received intravenous infusion of pamidronate (45 mg) and their high mean serum calcium concentration significantly decreased from 3.56 mmol/L to 2.62 mmol/L7 days after treatment. Serum intact PTH before treatment had been suppressed to below normal in all patients but returned to normal range in six patients within 7 days after treatment. Urinary PTH related peptide (PTHrP) excretion before treatment had been elevated in seven patients and then significantly increased further after pamidronate therapy. The serum bone Gla protein concentration was not apparently changed by the treatment. Pamidronate in serum was rapidly eliminated after the treatment and urinary excretion reached a plateau on the second day (13.8% of the administered dose), suggesting that the major portion of the infused dose had been distributed to the bone and other tissues. These findings suggest that pamidronate has a potent hypocalcemic effect and that PTHrP production in malignant tumors could be affected by pamidronate therapy.

Effect of metyrapone pretreatment on adrenocorticotropin secretion induced by corticotropin-releasing hormone in normal subjects and patients with Cushing's disease.

To examine the influence of endogenous cortisol on the ACTH response to CRH, we compared ACTH secretion during CRH tests before and after metyrapone administration in 9 normal subjects and 12 patients with Cushing's disease. The administration of 4.5 g metyrapone (750 mg, orally, every 4 h) resulted in a decrease in basal (pre-CRH) plasma cortisol levels and an increase in basal plasma ACTH levels in both normal subjects and Cushing's patients. The pretreatment with metyrapone significantly blunted the increase in plasma cortisol levels and markedly enhanced ACTH secretion after iv injection of 100 micrograms human CRH. The peak ACTH levels during CRH test before and after metyrapone administration were 8 +/- 1 and 58 +/- 8 pmol/L, respectively, in normal subjects (P less than 0.01) and 26 +/- 5 and 50 +/- 11 pmol/L, respectively, in Cushing's patients (P less than 0.05). Although the basal and peak ACTH levels as well as delta ACTH (peak ACTH - basal ACTH) during the CRH test before metyrapone administration were significantly higher in Cushing's disease patients than in normal subjects (P less than 0.01), no such difference was observed between the 2 groups after metyrapone administration. The results clearly indicate that the endogenous cortisol levels greatly influence the ACTH response to CRH, and that the CRH test as commonly performed does not allow a correct evaluation of potential responsiveness of normal pituitaries and Cushing's adenomas to CRH.

Neurohypophyseal function in postpartum hypopituitarism: impaired plasma vasopressin response to osmotic stimuli.

We studied neurohypophyseal function in 12 women with postpartum hypopituitarism (Sheehan's syndrome) by measuring plasma arginine vasopressin concentrations during 5% hypertonic saline infusions. All patients had a history of obstetric shock or massive bleeding, and were receiving cortisol and/or L-T4 replacement therapy. None had any symptoms of diabetes insipidus. The mean basal plasma vasopressin level in the patients [0.6 +/- 0.1 (+/- SE) pmol/L] was significantly lower (P less than 0.01) than that in normal adults (2.5 +/- 0.5 pmol/L; n = 12), whereas mean plasma osmolality values were similar in the two groups. During hypertonic saline infusion, the 10 hypopituitary patients had varying degrees of subnormal arginine vasopressin responses to the increase in plasma osmolality. Urine-concentrating ability after dehydration also was lower in the patients, although overt polyuria was absent at the time of this study. These results indicate that the osmoregulation of arginine vasopressin secretion is frequently impaired in postpartum hypopituitarism, suggesting neurohypophyseal damage.

High activity of cyclic 3',5'-nucleotide phosphodiesterase in sera of patient with phaeochromocytoma.

Our previous observations that serum cyclic 3',5'-nucleotide phosphodiesterase activity varied in thyroid disorders and was positively correlated with thyroid function stimulated us to investigate the phosphodiesterase levels in sera of patients with pituitary and adrenal disorders, and the response to glucagon in normal subjects. Both serum cyclic AMP phosphodiesterase (cyclic AMP-PDE) and cyclic GMP phosphodiesterase (cyclic GMP-PDE) activities were measured at a low substrate concentration. Serum cyclic AMP-PDE activity was elevated in five patients with phaeochromocytoma and was not elevated in patients with Cushing's syndrome or acromegaly, compared to the level in normal subjects. Increased enzyme activities returned to normal after resection of the tumours. Intramuscular injection of glucagon to five healthy subjects elevated cyclic AMP levels and cyclic AMP-PDE activity in plasma. These results imply that the increased cyclic AMP level by the activation of cyclase may have induced cyclic AMP-PDE in the target organ and the soluble cyclic AMP-PDE may leak into blood vessels from target organs.

Effect of fusaric acid (a dopamine beta-hydroxylase inhibitor) on phaeochromocytoma.

Fusaric acid, an inhibitor of dopamine beta-hydroxylase, which converts dopamine to noradrenaline, lowered the blood pressure and induced a subjective improvement in patients with phaeochromocytoma. These effects may be due either to an impairment of catecholamine biosynthesis or to a direct action on the blood vessels. The use of this drug in the treatment of patients with inoperable malignant phaeochromocytoma or neuroblastoma may improve symptoms and prolong survival.

Serum cyclic 3',5'-nucleotide phosphodiesterase in patients with various thyroid disorders.

Previous observations that cyclic 3',5'-nucleotide phosphodiesterase activity exists in mammalian sera including human serum prompted us to investigate the phosphodiesterase levels in sera of patients with various thyroid disorders. Both serum cyclic AMP phosphodiesterase (cAMP-PDE) and cyclic GMP phosphodiesterase (cGMP-PDE) activities measured in a low substrate concentration were elevated 3-fold in subacute thyroiditis and slightly in hyperthyroidism, compared to the normal. Slight decreases of these enzyme activities were observed in primary hypothyroidism. PDE activities were positively correlated with the value of T3-RSU and serum thyroid hormone levels in hyper- and hypothyroidism. Altered enzyme activities returned to normal during the course of recovery. Identical results were obtained when plasma was tested. These results suggest that serum PDE activities may be partly related to the thyroid function.