Cyclic Voltammetry Study of Noble Metals and Their Alloys for Use in Implantable Electrodes.

Innovation in the application and miniaturization of implantable electrodes has caused a spike in new electrode material research; however, few robust studies are available that compare different metal electrodes in biologically relevant media. Herein, cyclic voltammetry has been employed to compare platinum, palladium, and gold-based electrodes' potentiometric scans and their corresponding charge storage capacities (CSCs). Ten different noble metals and alloys in these families were tested under pseudophysiological conditions in phosphate-buffered saline (pH 7.4) at 37 °C. Charge storage capacity values (mC/cm2) were calculated for the oxide reduction, hydrogen adsorption, hydrogen desorption, and oxide formation peaks. Five scan rates spanning 2 orders of magnitude (10, 50, 100, 500, and 1000 mV/s) in both sparged and aerated environments were evaluated. Materials have been ranked by their charge storage capacities, reversibility, and trends discussed. Palladium-based alloys outperformed platinum-based alloys in the sparged condition and were ranked equally as high in the aerated condition. The Paliney 1100 (Pd-Re) alloy gave the highest observed calculated CSC value of 0.64 ± 0.02 mC/cm2 in the aerated condition, demonstrating 73 ± 5% reversibility. Trends between metal electrode families elicited in this study can afford valuable insight into future engineering of high performing implantable electrode materials.

Novel high-strength, low-alloys Zn-Mg (<0.1wt% Mg) and their arterial biodegradation.

It is still an open challenge to find a biodegradable metallic material exhibiting sufficient mechanical properties and degradation behavior to serve as an arterial stent. In this study, Zn-Mg alloys of 0.002 (Zn-002Mg), 0.005 (Zn-005Mg) and 0.08wt% Mg (Zn-08Mg) content were cast, extruded and drawn to 0.25mm diameter, and evaluated as potential biodegradable stent materials. Structural analysis confirmed formation of Mg2Zn11 intermetallic in all three alloys with the average grain size decreasing with increasing Mg content. Tensile testing, fractography analysis and micro hardness measurements showed the best integration of strength, ductility and hardness for the Zn-08Mg alloy. Yield strength, tensile strength, and elongation to failure values of >200-300MPa, >300-400MPa, and >30% respectively, were recorded for Zn-08Mg. This metal appears to be the first formulated biodegradable material that satisfies benchmark values desirable for endovascular stenting. Unfortunately, the alloy reveals signs of age hardening and strain rate sensitivity, which need to be addressed before using this metal for stenting. The explants of Zn-08Mg alloy residing in the abdominal aorta of adult male Sprague-Dawley rats for 1.5, 3, 4.5, 6 and 11months demonstrated similar, yet slightly elevated inflammation and neointimal activation for the alloy relative to what was recently reported for pure zinc.

Evaluation of wrought Zn-Al alloys (1, 3, and 5 wt % Al) through mechanical and in vivo testing for stent applications.

Special high grade zinc and wrought zinc-aluminum (Zn-Al) alloys containing up to 5.5 wt % Al were processed, characterized, and implanted in rats in search of a new family of alloys with possible applications as bioabsorbable endovascular stents. These materials retained roll-induced texture with an anisotropic distribution of the second-phase Al precipitates following hot-rolling, and changes in lattice parameters were observed with respect to Al content. Mechanical properties for the alloys fell roughly in line with strength (190-240 MPa yield strength; 220-300 MPa ultimate tensile strength) and elongation (15-30%) benchmarks, and favorable elastic ranges (0.19-0.27%) were observed. Intergranular corrosion was observed during residence of Zn-Al alloys in the murine aorta, suggesting a different corrosion mechanism than that of pure zinc. This mode of failure needs to be avoided for stent applications because the intergranular corrosion caused cracking and fragmentation of the implants, although the composition of corrosion products was roughly identical between non- and Al-containing materials. In spite of differences in corrosion mechanisms, the cross-sectional reduction of metals in murine aorta was nearly identical at 30-40% and 40-50% after 4.5 and 6 months, respectively, for pure Zn and Zn-Al alloys. Histopathological analysis and evaluation of arterial tissue compatibility around Zn-Al alloys failed to identify areas of necrosis, though both chronic and acute inflammatory indications were present. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 245-258, 2018.

Biocompatible curcumin loaded PMMA-PEG/ZnO nanocomposite induce apoptosis and cytotoxicity in human gastric cancer cells.

Although curcumin is efficient in killing cancer cells, its poor water solubility and assocaited inadequate bioavailability remain major limitations to its therapeutic application. The formulation of curcumin micellar nanoparticles (NPs) encapsulated with a biodegradable polymer promises to significantly improve curcumin's solubility, stability, and bioavailability. The past decade has witnessed the development of nanoscale curcumin delivery systems: curcumin-loaded liposomes or nanoparticles, self-microemulsifying drug delivery systems (SMEDDS), cyclodextrin inclusions, solid dispersions, nanodisks, and nanotubes. The intention of the present investigation was to enhance the bioavailability and ultimately the efficacy of curcumin by developing a curcumin loaded PMMA-PEG/ZnO bionanocomposite utilizing insoluble curcumin and poorly soluble ZnO nanoparticles. Here, the drug (curcumin) may be carry and deliver the biomolecule(s) by polymer-encapsulated ZnO NPs. Physical characteristics of these novel nanomaterials have been studied with transmission electron microscopy (TEM) and powder X-ray diffraction (XRD) in conjunction with spectral techniques. Aqueous solubility of curcumin was augmented upon conjugation with the polymer-stabilized ZnO NPs. A narrow nanocomposite particle size distribution with an average value of 40 to 90nm was found via TEM. Most importantly, the pH-responsive release of curcumin from the nano-vehicle ensures safer, more controlled delivery of the drug at physiological pH. Cytotoxic potential and cellular uptake of curcumin loaded ZnO NPs were assessed by) cell viability assay, cell cycle assays along with the cell imaging studies have been done in addition to MTT using AGS cancer cells. Hence, these studies demonstrate that the clinical potential of the Curcumin Loaded PMMA-PEG/ZnO can induce the apoptosis of cancer cells through a cell cycle mediated apoptosis corridor, which raises its probability to cure gastric cancer cells.

In Vitro Cytotoxicity, Adhesion, and Proliferation of Human Vascular Cells Exposed to Zinc.

Zinc (Zn) and its alloys have recently been introduced as a new class of biodegradable metals with potential application in biodegradable vascular stents. Although an in vivo feasibility study pointed to outstanding biocompatibility of Zn-based implants in vascular environments, a thorough understanding of how Zn and Zn2+ affect surrounding cells is lacking. In this comparative study, three vascular cell types-human endothelial cells (HAEC), human aortic smooth muscle cells (AoSMC), and human dermal fibroblasts (hDF)-were studied to advance the understanding of Zn/Zn2+-cell interactions. Aqueous cytotoxicity using a Zn2+ insult assay resulted in LD50 values of 50 µM for hDF, 70 µM for AoSMC, and 265 µM for HAEC. Direct cell contact with the metallic Zn surface resulted initially in cell attachment, but was quickly followed by cell death. After modification of the Zn surface using a layer of gelatin-intended to mimic a protein layer seen in vivo-the cells were able to attach and proliferate on the Zn surface. Further experiments demonstrated a Zn dose-dependent effect on cell spreading and migration, suggesting that both adhesion and cell mobility may be hindered by free Zn2+.

Biodegradable Metals for Cardiovascular Stents: from Clinical Concerns to Recent Zn-Alloys.

Metallic stents are used to promote revascularization and maintain patency of plaqued or damaged arteries following balloon angioplasty. To mitigate the long-term side effects associated with corrosion-resistant stents (i.e., chronic inflammation and late stage thrombosis), a new generation of so-called "bioabsorbable" stents is currently being developed. The bioabsorbable coronary stents will corrode and be absorbed by the artery after completing their task as vascular scaffolding. Research spanning the last two decades has focused on biodegradable polymeric, iron-based, and magnesium-based stent materials. The inherent mechanical and surface properties of metals make them more attractive stent material candidates than their polymeric counterparts. A third class of metallic bioabsorbable materials that are based on zinc has been introduced in the last few years. This new zinc-based class of materials demonstrates the potential for an absorbable metallic stent with the mechanical and biodegradation characteristics required for optimal stent performance. This review compares bioabsorbable materials and summarizes progress towards bioabsorbable stents. It emphasizes the current understanding of physiological and biological benefits of zinc and its biocompatibility. Finally, the review provides an outlook on challenges in designing zinc-based stents of optimal mechanical properties and biodegradation rate.

Corrosion Characteristics Dictate the Long-Term Inflammatory Profile of Degradable Zinc Arterial Implants.

There has been considerable recent interest to develop a feasible bioresorbable stent (BRS) metal. Although zinc and its alloys have many potential advantages, the inflammatory response has not been carefully examined. Using a modified wire implantation model, we characterize the inflammatory response elicited by zinc at high purity (4N) [99.99%], special high grade (SHG)[∼99.7%], and alloyed with 1 wt % (Zn-1Al), 3% (Zn-3Al), and 5.5% (Zn-5Al) aluminum. We found that inflammatory cells were able to penetrate the thick and porous corrosion layer that quickly formed around SHG, Zn-1Al, Zn-3Al, and Zn-5Al implants. In contrast, a delayed entrance of inflammatory cells into the corrosion layer around 4N zinc due to a significantly lower corrosion rate was associated with greater fibrous encapsulation, appearance of necrotic regions, and increased macrophage labeling. Interestingly, cell viability at the interface decreased from SHG, to Zn-1Al, and then Zn-3Al, a trend associated with an increased CD68 and CD11b labeling and capsule thickness. Potentially, the shift to intergranular corrosion due to the aluminum addition increased the activity of macrophages. We conclude that the ability of macrophages to penetrate and remain viable within the corrosion layer may be of fundamental importance for eliciting biocompatible inflammatory responses around corrodible metals.

Influence of Oxygen Concentration on the Performance of Ultra-Thin RF Magnetron Sputter Deposited Indium Tin Oxide Films as a Top Electrode for Photovoltaic Devices.

The opportunity for substantial efficiency enhancements of thin film hydrogenated amorphous silicon (a-Si:H) solar photovoltaic (PV) cells using plasmonic absorbers requires ultra-thin transparent conducting oxide top electrodes with low resistivity and high transmittances in the visible range of the electromagnetic spectrum. Fabricating ultra-thin indium tin oxide (ITO) films (sub-50 nm) using conventional methods has presented a number of challenges; however, a novel method involving chemical shaving of thicker (greater than 80 nm) RF sputter deposited high-quality ITO films has been demonstrated. This study investigates the effect of oxygen concentration on the etch rates of RF sputter deposited ITO films to provide a detailed understanding of the interaction of all critical experimental parameters to help create even thinner layers to allow for more finely tune plasmonic resonances. ITO films were deposited on silicon substrates with a 98-nm, thermally grown oxide using RF magnetron sputtering with oxygen concentrations of 0, 0.4 and 1.0 sccm and annealed at 300 °C air ambient. Then the films were etched using a combination of water and hydrochloric and nitric acids for 1, 3, 5 and 8 min at room temperature. In-between each etching process cycle, the films were characterized by X-ray diffraction, atomic force microscopy, Raman Spectroscopy, 4-point probe (electrical conductivity), and variable angle spectroscopic ellipsometry. All the films were polycrystalline in nature and highly oriented along the (222) reflection. Ultra-thin ITO films with record low resistivity values (as low as 5.83 × 10-4 Ω·cm) were obtained and high optical transparency is exhibited in the 300-1000 nm wavelength region for all the ITO films. The etch rate, preferred crystal lattice growth plane, d-spacing and lattice distortion were also observed to be highly dependent on the nature of growth environment for RF sputter deposited ITO films. The structural, electrical, and optical properties of the ITO films are discussed with respect to the oxygen ambient nature and etching time in detail to provide guidance for plasmonic enhanced a-Si:H solar PV cell fabrication.

Metallic zinc exhibits optimal biocompatibility for bioabsorbable endovascular stents.

Although corrosion resistant bare metal stents are considered generally effective, their permanent presence in a diseased artery is an increasingly recognized limitation due to the potential for long-term complications. We previously reported that metallic zinc exhibited an ideal biocorrosion rate within murine aortas, thus raising the possibility of zinc as a candidate base material for endovascular stenting applications. This study was undertaken to further assess the arterial biocompatibility of metallic zinc. Metallic zinc wires were punctured and advanced into the rat abdominal aorta lumen for up to 6.5months. This study demonstrated that metallic zinc did not provoke responses that often contribute to restenosis. Low cell densities and neointimal tissue thickness, along with tissue regeneration within the corroding implant, point to optimal biocompatibility of corroding zinc. Furthermore, the lack of progression in neointimal tissue thickness over 6.5months or the presence of smooth muscle cells near the zinc implant suggest that the products of zinc corrosion may suppress the activities of inflammatory and smooth muscle cells.

Fabrication and Short-Term in Vivo Performance of a Natural Elastic Lamina-Polymeric Hybrid Vascular Graft.

Although significant advances have been made in the development of artificial vascular grafts, small-diameter grafts still suffer from excessive platelet activation, thrombus formation, smooth muscle cell intimal hyperplasia, and high occurrences of restenosis. Recent discoveries demonstrating the excellent blood-contacting properties of the natural elastic lamina have raised the possibility that an acellular elastic lamina could effectively serve as a patent blood-contacting surface in engineered vascular grafts. However, the elastic lamina alone lacks the requisite mechanical properties to function as a viable vascular graft. Here, we have screened a wide range of biodegradable and biostable medical-grade polymers for their ability to adhere to the outer surface of the elastic lamina and allow cellular repopulation following engraftment in the rat abdominal aorta. We demonstrate a novel method for the fabrication of elastic lamina-polymeric hybrid small-diameter vascular grafts and identify poly(ether urethane) (PEU 1074A) as ideal for this purpose. In vivo results demonstrate graft patency over 21 days, with low thrombus formation, mild inflammation, and the general absence of smooth muscle cell hyperplasia on the graft's luminal surface. The results provide a new direction for developing small-diameter vascular grafts that are mass-producible, shelf-stable, and universally compatible due to a lack of immune response and inhibit the in-graft restenosis response that is common to nonautologous materials.

Rates of in vivo (arterial) and in vitro biocorrosion for pure magnesium.

The development of magnesium-based materials for bioabsorbable stents relies heavily on corrosion testing by immersion in pseudophysiological solutions, where magnesium degrades faster than it does in vivo. The quantitative difference in corrosion kinetics in vitro and in vivo is largely unknown, but, if determined, would help reduce dependence on animal models. In order to create a quantitative in vitro-in vivo correlation based on an accepted measure of corrosion (penetration rate), commercially pure magnesium wires were corroded in vivo in the abdominal aortas of rats for 5-32 days, and in vitro for up to 14 days using Dulbecco's modified eagle medium. Cross-sectioning, scanning electron microscopy, image analysis, a modified penetration rate tailored to degraded wires, and empirical modeling were used to analyze the corroded specimens. In vitro penetration rates were consistently higher than comparable in vivo rates by a factor of 1.2-1.9× (±0.2×). For a sample <20% corroded, an approximate in vitro-in vivo multiplier of 1.3 ± 0.2× was applied, whereas a multiplier of 1.8 ± 0.2× became appropriate when the magnesium specimen was 25-35% degraded.

FIB-TEM Study of Magnesium Corrosion Products after 14 Days in the Murine Artery.

After a decade of intensive research on magnesium biodegradation, the composition and structure of corrosion products formed during in vivo corrosion are still not precisely known. Focused ion beam (FIB) micromilling and transmission electron microscopy (TEM) were used to elucidate the nanostructure and crystallography of the corrosion products that form at or near the interface between the corrosion products and metallic magnesium. This study built upon previously reported scanning electron microscopy, infrared spectroscopy, and energy dispersive X-ray spectroscopy data. These prior results revealed a duplex corrosion layer comprising a calcium- and phosphorus-containing outer product (near the tissue interface) and a magnesium- and oxygen-containing inner product (near the metallic interface). A specimen that had resided in the murine arterial wall for 14 days was selected for FIB-TEM analysis. Highly oriented, nanocrystalline magnesium oxide was identified near the metallic magnesium, apparently without the co-occurrence of magnesium hydroxide or carbonates. The calcium- and phosphorus-containing surface layer was also examined, and shown to be nearly amorphous.

Magnesium in the murine artery: probing the products of corrosion.

Many publications are available on the physiological and pseudophysiological corrosion of magnesium and its alloys for bioabsorbable implant application, yet few focus on the characterization of explanted materials. In this work, commercially pure magnesium wires were corroded in the arteries of rats for up to 1 month, removed, and both bulk and surface products characterized. Surface characterization using infrared spectroscopy revealed a duplex structure comprising heavily magnesium-substituted hydroxyapatite that later transformed into an A-type (carbonate-substituted) hydroxyapatite. To explain this transformation, an ion-exchange mechanism is suggested. Elemental mapping of the bulk products of biocorrosion revealed the elemental distribution of Ca, P, Mg and O in the outer and Mg, O and P in the inner layers. Carbon was not observed in any significant quantity from the inner corrosion layer, suggesting that carbonates are not a prevalent product of corrosion. Backscatter electron imaging of cross-sections showed that thinning or absence of the hydroxyapatite in the later stages of degradation is related to local thickening of the inner corrosion layer. Based on these experimental observations, mechanisms describing corrosion in the quasi-steady state and during terminal breakdown of the magnesium specimens are proposed.

A new in vitro-in vivo correlation for bioabsorbable magnesium stents from mechanical behavior.

Correlating the in vitro and in vivo degradation of candidate materials for bioabsorbable implants is a subject of interest in the development of next-generation metallic stents. In this study, pure magnesium wire samples were corroded both in the murine artery (in vivo) and in static cell culture media (in vitro), after which they were subjected to mechanical analysis by tensile testing. Wires corroded in vivo showed reductions in strength, elongation, and the work of fracture, with additional qualitative changes between tensile profiles. The in vivo degradation was 2.2±0.5, 3.1±0.8, and 2.3±0.3 times slower than corrosion in vitro in terms of effective tensile strength, strain to failure, and sample lifetime, respectively. Also, a combined metric, defined as strength multiplied by elongation, was 3.1±0.7 times faster in vitro than in vivo. Consideration of the utility and restrictions of each metric indicates that the lifetime-based multiplier is the best suited to general use for magnesium, though other metrics could be used to deduce the mechanical properties of degradable implants in service.

Zinc exhibits ideal physiological corrosion behavior for bioabsorbable stents.

Zinc is proposed as an exciting new biomaterial for use in bioabsorbable cardiac stents. Not only is zinc a physiologically relevant metal with behavior that promotes healthy vessels, but it combines the best behaviors of both current bioabsorbable stent materials: iron and magnesium. Shown here is a composite image of zinc degradation in a murine (rat) artery.

Tensile testing as a novel method for quantitatively evaluating bioabsorbable material degradation.

Bioabsorbable metallic materials have become a topic of interest in the field of interventional cardiology because of their potential application in stents. A well-defined, quantitative method for evaluating the degradation rate of candidate materials is currently needed in this area. In this study, biodegradation of 0.25-mm iron and magnesium wires was simulated in vitro through immersion in cell-culture medium with and without a fibrin coating (meant to imitate the neointima). The immersed samples were corroded under physiological conditions (37°C, 5% CO(2)). Iron degraded in a highly localized manner, producing voluminous corrosion product while magnesium degraded more uniformly. To estimate the degradation rate in a quantitative manner, both raw and corroded samples underwent tensile testing using a protocol similar to that used on polymeric nanofibers. The effective ultimate tensile stress (tensile stress holding constant cross-sectional area) was determined to be the mechanical metric that exhibited the smallest amount of variability. When the effective tensile stress data were aggregated, a statistically significant downward, linear trend in strength was observed in both materials (Fe and Mg) with and without the fibrin coating. It was also demonstrated that tensile testing is able to distinguish between the higher degradation rate of the bare wires and the lower degradation rate of the fibrin-coated wires with confidence.