Nitinol Release of Nickel under Physiological Conditions: Effects of Surface Oxide, pH, Hydrogen Peroxide, and Sodium Hypochlorite.

Nitinol is a nickel-titanium alloy widely used in medical devices for its unique pseudoelastic and shape-memory properties. However, nitinol can release potentially hazardous amounts of nickel, depending on surface manufacturing yielding different oxide thicknesses and compositions. Furthermore, nitinol medical devices can be implanted throughout the body and exposed to extremes in pH and reactive oxygen species (ROS), but few tools exist for evaluating nickel release under such physiological conditions. Even in cardiovascular applications, where nitinol medical devices are relatively common and the blood environment is well understood, there is a lack of information on how local inflammatory conditions after implantation might affect nickel ion release. For this study, nickel release from nitinol wires of different finishes was measured in pH conditions and at ROS concentrations selected to encompass and exceed literature reports of extracellular pH and ROS. Results showed increased nickel release at levels of pH and ROS reported to be physiological, with decreasing pH and increasing concentrations of hydrogen peroxide and NaOCl/HOCl having the greatest effects. The results support the importance of considering the implantation site when designing studies to predict nickel release from nitinol and underscore the value of understanding the chemical milieu at the device-tissue interface.

Temperature dependence of nickel ion release from nitinol medical devices.

Nitinol exhibits unique (thermo)mechanical properties that make it central to the design of many medical devices. However, nitinol nominally contains 50 atomic percent nickel, which if released in sufficient quantities, can lead to adverse health effects. While nickel release from nitinol devices is typically characterized using in vitro immersion tests, these evaluations require lengthy time periods. We have explored elevated temperature as a potential method to expedite this testing. Nickel release was characterized in nitinol materials with surface oxide thickness ranging from 12 to 1564 nm at four different temperatures from 310 to 360 K. We found that for three of the materials with relatively thin oxide layers, ≤ 87 nm nickel release exhibited Arrhenius behavior over the entire temperature range with activation energies of 80 to 85 kJ/mol. Conversely, the fourth ''black-oxide'' material, with a much thicker, complex oxide layer, was not well characterized by an Arrhenius relationship. Power law release profiles were observed in all four materials; however, the exponent from the thin oxide materials was approximately 1/4 compared with 3/4 for the black-oxide material. To illustrate the potential benefit of using elevated temperature to abbreviate nickel release testing, we demonstrated that a > 50 day 310 K release profile could be accurately recovered by testing for less than 1 week at 340 K. However, because the materials explored in this study were limited, additional testing and mechanistic insight are needed to establish a protective temperature scaling that can be applied to all nitinol medical device components.

FDA public workshop: Orthopaedic sensing, measuring, and advanced reporting technology (SMART) devices.

Traditional orthopaedic devices do not communicate with physicians or patients post-operatively. After implantation, follow-up of traditional orthopaedic devices is generally limited to episodic monitoring. However, the orthopaedic community may be shifting towards incorporation of smart technology. Smart technology in orthopaedics is a term that encompasses a wide range of potential applications. Smart orthopaedic implants offer the possibility of gathering data and exchanging it with an external reader. They incorporate technology that enables automated sensing, measuring, processing, and reporting of patient or device parameters at or near the implant. While including advanced technology in orthopaedic devices has the potential to benefit patients, physicians, and the scientific community, it may also increase the patient risks associated with the implants. Understanding the benefit-risk profile of new smart orthopaedic devices is critical to ensuring their safety and effectiveness. The 2018 FDA public workshop on orthopaedic sensing, measuring, and advanced reporting technology (SMART) devices was held on April 30, 2018, at the FDA White Oak Campus in Silver Spring, MD with the goal of fostering a collaborative dialogue amongst the orthopaedic community. Workshop attendees discussed four key areas related to smart orthopaedic devices: engineering and technology considerations, clinical and patient perspectives, cybersecurity, and regulatory considerations. The workshop presentations and associated discussions highlighted the need for the orthopaedic community to collectively craft a responsible path for incorporating smart technology in musculoskeletal disease care.

Quality attributes and evaluation of pharmaceutical glass containers for parenterals.

Pharmaceutical containers for parenterals have been predominantly manufactured using glass as a packaging material of choice, especially Type-I glass, since it has been regarded as a chemically inert and an effective container closure system (CCS). Nevertheless, there have been reports and recalls related to glass quality issues, such as breakage, flakes, and particles observed in marketed products. The novelty of this research is based on the knowledge gathered from our previously conducted risk assessments and establishing a comprehensive testing platform focused on risk factors for glass container failure modes and applicability to other types of pharmaceutical containers. The evaluation of container quality attributes was performed for three model glass vials using a mechanical and chemical durability testing platform: freeze-thaw, lyophilization, compression, scratch tests; visual inspection, pH, particle size analyses, extractable, leachable and imaging studies that were conducted under normal (4 and 25 °C), and stress condition (60 °C), respectively. The performance between the glass containers tested under certain stress conditions (failure modes) were variable and differentiated. The systematic platform testing approach shows the importance of lab-based risk evaluation in assessing common failure modes of pharmaceutical containers, since the quality attributes for injectable products are complex and can impact final product quality.

Comparison of ASTM F2129 and ASTM F746 for Evaluating Crevice Corrosion.

Crevice corrosion is one of the major mechanisms that drives implant failure in orthopedic devices that have modular interfaces. Despite the prevalence of crevice corrosion in modular interfaces, very little is known with regards to the susceptibility of different material combinations to participate in crevice corrosion. In this study, we compare two electrochemical methods, ASTM F2129, Standard Test Method for Conducting Cyclic Potentiodynamic Polarization Measurements to Determine the Corrosion Susceptibility of Small Implant Devices, and a modified version of ASTM F746, Standard Test Method for Pitting or Crevice Corrosion of Metallic Surgical Implant Materials, in their ability to induce crevice corrosion. Four commonly used metals, 316 stainless steel, commercially pure titanium (Ti grade 2), Ti-6Al-4V (Ti grade 5), and cobalt-chromium-molybdenum per ASTM F1537, Standard Specification for Wrought Cobalt-28Chromium-6Molybdenum Alloys for Surgical Implants (UNSR31537, UNSR31538, and UNSR31539), were used to form crevices with a rod and washer combination. As a control, the metal rod materials were tested alone in the absence of crevices using ASTM F2129 and the modified ASTM F746 method. As another control to determine if crevices formed with polymeric materials would influence crevice corrosion susceptibility, experiments were also conducted with metal rods and polytetrafluorethylene washers. Our results revealed more visible corrosion after ASTM F2129 than ASTM F746. Additionally, ASTM F746 was found to falsely identify crevice corrosion per the critical pitting potential when visual inspection found no evidence of crevice corrosion. Hence, ASTM F2129 was found to be more effective overall at evaluating crevice corrosion compared to ASTM F746.

The effects of surface processing on in-vivo corrosion of Nitinol stents in a porcine model.

A major limitation with current assessments of corrosion in metallic medical devices is the lack of correlation between in-vitro and in-vivo corrosion performance. Therefore, the objective of this study was to elucidate the relationship between pitting corrosion measured by breakdown potentials (Eb) in ASTM F2129 testing and corrosion resistance in-vivo. Four groups of Nitinol stents were manufactured using different processing methods to create unique surface properties. The stents were implanted into iliac arteries of minipigs for six months and explanted for corrosion analysis. Scanning electron microscopy and energy dispersive X-ray spectrometry analyses indicated that stents with a thick complex thermal oxide (420nm) and high corrosion resistance in-vitro (Eb=975±94mV) were free from detectable corrosion in-vivo and exhibited no changes in Ni/Ti ratio when compared to non-implanted controls. This result was also found in mechanically polished stents with a thin native oxide (4nm; Eb=767±226mV). In contrast, stents with a moderately thick thermal oxide (130nm) and low corrosion resistance in-vitro (Eb=111±63mV) possessed corrosion with associated surface microcracks in-vivo. In addition, Ni/Ti ratios in corroded regions were significantly lower compared to non-corroded adjacent areas on explanted stents. When stents were minimally processed (i.e. retained native tube oxide from the drawing process), a thick thermal oxide was present (399nm) with low in-vitro corrosion resistance (Eb=68±29mV) resulting in extensive in-vivo pitting. These findings demonstrate that functional corrosion testing combined with a detailed understanding of the surface characteristics of a Nitinol medical device can provide insight into in-vivo corrosion resistance. STATEMENT OF SIGNIFICANCE: Nitinol is a commonly used material in the medical device industry. However, correlations between surface processing of nitinol and in-vivo corrosion has yet to be established. Elucidating the link between in-vivo corrosion and pre-clinical characterization can aid in improved prediction of clinical safety and performance of nitinol devices. We addressed this knowledge gap by fabricating nitinol stents to possess distinct surface properties and evaluating their corrosion susceptibility both in-vitro and after six months of in-vivo exposure. Relationships between stent processing, surface characterization, corrosion bench testing, and outcomes from explanted devices are discussed. These findings highlight the importance of surface characterization in nitinol devices and provide in-vitro pitting corrosion levels that can induce in-vivo corrosion in nitinol stents.

Electrosurgery Induced Damage to Ti-6Al-4V and CoCrMo Alloy Surfaces in Orthopedic Implants In Vivo and In Vitro.

BACKGROUND: Recent observations of specific metal damage patterns on retrieved total joint implants implied a cellular origin and was termed inflammatory cell-induced (ICI) corrosion. Although ICI corrosion continues to present a potential damage source for metallic biomaterials surfaces, an alternate source of some damage patterns may arise from electrosurgery instruments in total joint arthroplasty. METHODS: To characterize electrosurgically-induced damage patterns on metal implants, a model system of highly polished CoCrMo and Ti-6Al-4V disks and commercial electrosurgical generator was evaluated in various modes and power settings using monopolar and bipolar configurations. Surfaces were tested dry, wet with phosphate-buffered saline, or covered with known thicknesses of hydrated 5% agarose hydrogel. RESULTS: In all cases, surface damage was generated on both alloy surfaces, directly resulting from plasma discharge interacting with the metal. Direct surface contact caused pitting and oxide buildup at the contact area. Damage was produced through 3 mm thickness of hydrogel on the surface and across metal-metal junctions representing modular tapers. Damage patterns on wetted surfaces were highly consistent with damage patterns observed on retrieved total joint implants; circular, ruffled areas with centralized pits, occasionally presenting trail- and weld-like features. CONCLUSION: Surgeons using electrosurgical systems in proximity to metallic implants should exercise caution. Discharge of electrical energy through implants can induce localized surface damage and may result in other adverse outcomes. Although these results show some damage reported to be ICI corrosion is indeed the result of electrosurgery, there remains damage observed in retrievals not explained by this process.

Effect of Applied Potential on Fatigue Life of Electropolished Nitinol Wires.

Nitinol is used as a metallic biomaterial in medical devices due to its shape memory and pseudoelastic properties. The clinical performance of nitinol depends on factors which include the surface finish, the local environment, and the mechanical loads to which the device is subjected. Preclinical evaluations of device durability are performed with fatigue tests while electrochemical characterization methods such as ASTM F2129 are employed to evaluate corrosion susceptibility by determining the rest potential and breakdown potential. However, it is well established that the rest potential of a metal surface can vary with the local environment. Very little is known regarding the influence of voltage on fatigue life of nitinol. In this study, we developed a fatigue testing method in which an electrochemical system was integrated with a rotary bend wire fatigue tester. Samples were fatigued at various strain levels at electropotentials anodic and cathodic to the rest potential to determine if it could influence fatigue life. Wires at potentials negative to the rest potential had a significantly higher number of cycles to fracture than wires held at potentials above the breakdown potential. For wires for which no potential was applied, they had fatigue life similar to wires at negative potentials.

Effect of wire fretting on the corrosion resistance of common medical alloys.

Metallic medical devices such as intravascular stents can undergo fretting damage in vivo that might increase their susceptibility to pitting corrosion. As a result, the US Food and Drug Administration has recommended that such devices be evaluated for corrosion resistance after the devices have been fatigue tested in situations where significant micromotion can lead to fretting damage. Three common alloys that cardiovascular implants are made from [MP35N cobalt chromium (MP35N), electropolished nitinol (EP NiTi), and 316LVM stainless steel (316LVM)] were selected for this study. In order to evaluate the effect of wire fretting on the pitting corrosion susceptibility of these medical alloys, small and large fretting scar conditions of each alloy fretting against itself, and the other alloys in phosphate buffered saline (PBS) at 37°C were tested per ASTM F2129 and compared against as received or PBS immersed control specimens. Although the general trend observed was that fretting damage significantly lowered the rest potential (Er ) of these specimens (p < 0.01), fretting damage had no significant effect on the breakdown potential (Eb , p > 0.05) and hence did not affect the susceptibility to pitting corrosion. In summary, our results demonstrate that fretting damage in PBS alone is not sufficient to cause increased susceptibility to pitting corrosion in the three common alloys investigated. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2487-2494, 2017.

Sensitizing Pseudomonas aeruginosa to antibiotics by electrochemical disruption of membrane functions.

Recently, we reported synergistic effects between 70 µA/cm(2) direct current and tobramycin in killing Pseudomonas aeruginosa PAO1 persister cells, a phenomenon we named electrochemical control of persister cells (ECCP; Niepa et al. Biomaterials 33: 7356-7365, 2012). To understand the mechanism of ECCP, the effects of electrochemical treatments mediated via stainless steel 304 and carbon electrodes on P. aeruginosa PAO1 were systematically compared using complementary approaches in this study. Electron microscopic analysis revealed that µA/cm(2) level direct current (DC) caused substantial changes in the structure and membrane integrity of P. aeruginosa PAO1 cells. DC treatments using SS304 electrodes induced cell lysis, while the same level of DC generated using carbon electrodes led to aggregation of intracellular proteins and increased permeabilization of P. aeruginosa PAO1 cells to antibiotics. The profound effects of DC on the physiology of persister cells were corroborated with DNA microarray analysis, which revealed the induction of genes associated with pyocin production and SOS response in DC-treated persister cells. Interestingly, sequential treatment using DC mediated with carbon electrodes followed by tobramycin was found more effective than concurrent treatment; and total eradication of persister cells was achieved.

Direct in vivo inflammatory cell-induced corrosion of CoCrMo alloy orthopedic implant surfaces.

Cobalt-chromium-molybdenum (CoCrMo) alloy, used for over five decades in orthopedic implants, may corrode and release wear debris into the body during use. These degradation products may stimulate immune and inflammatory responses in vivo. We report here on evidence of direct inflammatory cell-induced corrosion of human implanted and retrieved CoCrMo implant surfaces. Corrosion morphology on CoCrMo implant surfaces, in unique and characteristic patterns, and the presence of cellular remnants and biological materials intimately entwined with the corrosion indicates direct cellular attack under the cell membrane region of adhered and/or migrating inflammatory cells. Evidence supports a Fenton-like reaction mechanism driving corrosion in which reactive oxygen species are the major driver of corrosion. Using in vitro tests, large increases in corrosion susceptibility of CoCrMo were seen (40-100 fold) when immersed in phosphate buffered saline solutions modified with hydrogen peroxide and hydrochloric acid to represent the chemistry under inflammatory cells. This discovery raises significant new questions about the clinical consequences of such corrosion interactions, the role of patient inflammatory reactions, and the detailed mechanisms at play.

The effect of cathodic electrochemical potential of Ti-6Al-4V on cell viability: voltage threshold and time dependence.

The biocompatibility of metallic biomaterials is dependent on the redox state of the surface and its effect on cellular redox equilibrium. When metallic biomaterials experience mechanically assisted corrosion such as fretting, there is a drop in the voltage of its surface. Studies have demonstrated that cell viability is significantly degraded by sustained cathodic excursion in voltage of metallic biomaterials below a critical potential between -300 and -600 mV on commercially pure titanium. Cells cultured at above -300 mV showed little loss in viability whereas cells cultured on -600 mV Ti were almost 100% killed at 24 h. The goal of this study is to concisely define the voltage threshold and time-dependence of the cell killing effect seen on titanium surfaces. MC3T3 cells were cultured on electrochemically controlled Ti-6Al-4V surfaces at voltages ranging from -300 to -1000 mV for time periods ranging from 1 to 24 h. Cell viability and morphology was monitored with live-dead assay and scanning electron microscopy. Cell viability decreased from -300 to -400 mV and exhibited time-dependence where the more cathodic the potential, the faster the drop-off of viability. Hundred percent cell killing took as little as 4 h at -1000 mV and required 24 h at -400 mV. Sustained net cathodic currents with densities as low as 0.1 µA/cm(2) are observed during cell killing. This work shows reduction reactions are an important element of cellular viability in a time and potential dependent way and may explain why mechanically assisted corrosion reactions may lead to increased cell killing in metallic implants. Note: All voltages are versus Ag/AgCl.

Does Taper Angle Clearance Influence Fretting and Corrosion Damage at the Head-Stem Interface? A Matched Cohort Retrieval Study.

Previous studies have speculated that modular taper design may have an effect on the corrosion and material loss at the taper surfaces. We present a novel method to measure taper angle for retrieved head taper and stem trunnions using a roundness machine (Talyrond 585, Taylor Hobson, UK). We also investigated the relationship between taper angle clearance and visual fretting-corrosion score at the taper-trunnion junction using a matched cohort study of 50 ceramic and 50 metal head-stem pairs. In this study, no correlation was observed between the taper angle clearance and the visual fretting-corrosion scores in either the ceramic or the metal cohorts.

Titanium is not "the most biocompatible metal" under cathodic potential: The relationship between voltage and MC3T3 preosteoblast behavior on electrically polarized cpTi surfaces.

An electrochemically controlled system has been developed which allows for cell culture directly on electrically polarized metal surfaces with simultaneous control and assessment of the electrochemical current, potential, and impedance of the interface. This system was utilized in this study to assess the interactions between electrochemically polarized commercially pure titanium (cpTi) and MC3T3 preosteoblast cells. Cells were cultured on CpTi for 24 h at static potentials between -1000 mV and +1000 mV vs. Ag/AgCl and cell morphology (SEM and cell area) and viability (MTT and Live-Dead assay) were assessed along with the electrochemical current densities and surface oxide impedance properties. The results indicate that cathodic polarization in the range of -600 mV to -1000 mV markedly reduces the spreading and viability of cells cultured directly on cpTi within 24 h, while anodic polarization (-300 mV to +1000 mV) out to 72 h shows no difference in cell behavior as compared to the OCP condition. Analysis of the relationship between the cell outcomes and the electrochemical current densities and impedance indicated the presence of voltage-dependent electrochemical thresholds (cathodic current density, i(c) > 1.0 microA/cm(2), R(p) < 10(5) Omega cm(2)) which may control the biocompatibility of cpTi. In addition, these outcomes have direct clinical significance for modular orthopedic implants whose potential can shift, via fretting corrosion, down into the range of potentials exhibiting poor cell behavior.