Computational biomechanical study on hybrid implant materials for the femoral component of total knee replacements.

Multifunctional materials have been described to meet the diverse requirements of implant materials for femoral components of uncemented total knee replacements. These materials aim to combine the high wear and corrosion resistance of oxide ceramics at the joint surfaces with the osteogenic potential of titanium alloys at the bone-implant interface. Our objective was to evaluate the biomechanical performance of hybrid material-based femoral components regarding mechanical stress within the implant during cementless implantation and stress shielding (evaluated by strain energy density) of the periprosthetic bone during two-legged squat motion using finite element modeling. The hybrid materials consisted of alumina-toughened zirconia (ATZ) ceramic joined with additively manufactured Ti-6Al-4V or Ti-35Nb-6Ta alloys. The titanium component was modeled with or without an open porous surface structure. Monolithic femoral components of ATZ ceramic or Co-28Cr-6Mo alloy were used as reference. The elasticity of the open porous surface structure was determined within experimental compression tests and was significantly higher for Ti-35Nb-6Ta compared to Ti-6Al-4V (5.2 ± 0.2 GPa vs. 8.8 ± 0.8 GPa, p < 0.001). During implantation, the maximum stress within the ATZ femoral component decreased from 1568.9 MPa (monolithic ATZ) to 367.6 MPa (Ti-6Al-4V/ATZ), 560.9 MPa (Ti-6Al-4V/ATZ with an open porous surface), 474.9 MPa (Ti-35Nb-6Ta/ATZ), and 648.4 MPa (Ti-35Nb-6Ta/ATZ with an open porous surface). The strain energy density increased at higher flexion angles for all models during the squat movement. At ∼90° knee flexion, the strain energy density in the anterior region of the distal femur increased by 25.7 % (Ti-6Al-4V/ATZ), 70.3 % (Ti-6Al-4V/ATZ with an open porous surface), 43.7 % (Ti-35Nb-6Ta/ATZ), and 82.5% (Ti-35Nb-6Ta/ATZ with an open porous surface) compared to monolithic ATZ. Thus, the hybrid material-based femoral component decreases the intraoperative fracture risk of the ATZ part and considerably reduces the risk of stress shielding of the periprosthetic bone.

Advanced Ti-Nb-Ta Alloys for Bone Implants with Improved Functionality.

The additive manufacturing of titanium-niobium-tantalum alloys with nominal chemical compositions Ti-xNb-6Ta (x = 20, 27, 35) by means of laser beam powder bed fusion is reported, and their potential as implant materials is elaborated by mechanical and biological characterization. The properties of dense specimens manufactured in different build orientations and of open porous Ti-20Nb-6Ta specimens are evaluated. Compression tests indicate that strength and elasticity are influenced by the chemical composition and build orientation. The minimum elasticity is always observed in the 90° orientation. It is lowest for Ti-20Nb-6Ta (43.2 ± 2.7 GPa) and can be further reduced to 8.1 ± 1.0 GPa for open porous specimens (p < 0.001). Furthermore, human osteoblasts are cultivated for 7 and 14 days on as-printed specimens and their biological response is compared to that of Ti-6Al-4V. Build orientation and cultivation time significantly affect the gene expression profile of osteogenic differentiation markers. Incomplete cell spreading is observed in specimens manufactured in 0° build orientation, whereas widely stretched cells are observed in 90° build orientation, i.e., parallel to the build direction. Compared to Ti-6Al-4V, Ti-Nb-Ta specimens promote improved osteogenesis and reduce the induction of inflammation. Accordingly, Ti-xNb-6Ta alloys have favorable mechanical and biological properties with great potential for application in orthopedic implants.

Multifunctional Hybrid Material for Endoprosthetic Implants Based on Alumina-Toughened Zirconia Ceramics and Additively Manufactured TiNbTa Alloys.

Aseptic implant loosening after a total joint replacement is partially influenced by material-specific factors when cobalt-chromium alloys are used, including osteolysis induced by wear and corrosion products and stress shielding. Here, we aim to characterize a hybrid material consisting of alumina-toughened zirconia (ATZ) ceramics and additively manufactured Ti-35Nb-6Ta (TiNbTa) alloys, which are joined by a glass solder. The structure of the joint, the static and fatigue shear strength, the influence of accelerated aging, and the cytotoxicity with human osteoblasts are characterized. Furthermore, the biomechanical properties of the functional demonstrators of a femoral component for total knee replacements are evaluated. The TiNbTa-ATZ specimens showed a homogenous joint with statistically distributed micro-pores and a slight accumulation of Al-rich compounds at the glass solder-TiNbTa interface. Shear strengths of 26.4 ± 4.2 MPa and 38.2 ± 14.4 MPa were achieved for the TiNbTa-ATZ and Ti-ATZ specimens, respectively, and they were not significantly affected by the titanium material used, nor by accelerated aging (p = 0.07). All of the specimens survived 107 cycles of shear loading to 10 MPa. Furthermore, the TiNbTa-ATZ did not impair the proliferation and metabolic activity of the human osteoblasts. Functional demonstrators made of TiNbTa-ATZ provided a maximum bearable extension-flexion moment of 40.7 ± 2.2 Nm. The biomechanical and biological properties of TiNbTa-ATZ demonstrate potential applications for endoprosthetic implants.

Reliable and easy-to-use LC-MS/MS-method for simultaneous determination of the antihypertensives metoprolol, amlodipine, canrenone and hydrochlorothiazide in patients with therapy-refractory arterial hypertension.

BACKGROUND: Therapy-refractory arterial hypertension is defined as a blood pressure (BP) in a subset of patients who fail to achieve BP control despite a three-drug regimen (including a diuretic). Various factors have impact on loss of therapy response. Drug-drug-interactions (DDIs) may cause altered pharmacokinetics (PK) of antihypertensive drugs. Upregulation of activity and expression of cytochrome P450 (CYP) enzymes can result in decreased plasma drug levels. Besides these PK considerations a significant problem could be nonadherence to drug therapy. In this regard Therapeutic Drug Monitoring (TDM) is a useful tool for detecting nonadherence. Therefore a LC-MS/MS-method for determination of Metoprolol (MET), Amlodipine (AML), Canrenone (CAN) and Hydrochlorothiazide (HCT) was developed. METHODS: An UHPLC-MS/MS method was developed and validated for simultaneous determination of MET, AML, CAN and HCT in plasma matrix. Extraction of serum samples consisted of simple protein precipitation using acetonitrile. Stable isotope labeled analogues for each antihypertensive were obtained for internal standardization and quantitative analysis ([2H7]-MET, ([13C6]-AML, [2H4]-CAN, [13C6]-HCT). Calibrators and quality controls were prepared in plasma matrix of normal individuals. Sample preparation: protein precipitation with acetonitrile and addition of internal standard-mix. RESULTS: All analytes were eluted within a runtime of 2.5 min. Linearity experiments were demonstrated in plasma over following concentration ranges: MET: 5-750 µg/l, AML: 1-50 µg/l, CAN: 10-500 µg/l, HCT: 5-500 µg/l (R2 > 0.993). Chromatographic separation was achieved using a C18 column (50 × 2.1 mm, 1.9 µm particle size) and an isocratic elution. LC-MS/MS analyses were performed on a triple quadrupole mass spectrometer using positive and negative electrospray ionization in selected reaction monitoring (SRM) mode. Ion transitions monitored for quantitation were m/z 268.2 → 74.1 for MET, m/z 409.1 → 238.0 for AML, m/z 341.2 → 91.0 for CAN and m/z 296.0 → 205.1 for HCT. For all analytes, inter- and intra-day precision (CV, %) varied between 1.7 and 14.0 and inter- and intra-day accuracy values ranged from -2.5 to 7.1%. The lower limits of detection and quantification were: 0.08 and 0.23; 0.05 and 0.15; 2.82 and 8.54; and 0.02 and 0.05 µg/l for MET, AML, CAN and HCT, respectively. Results of stability experiments were within the required range of +/- 15%. CONCLUSIONS: Although the level of recommendation of TDM of antihypertensive drugs in patients with refractory hypertension is not yet established, the present LC-MS/MS-method can serve as an effective tool for detection of PK-alterations/nonadherence and may help to monitor antihypertensive pharmacotherapy.