In-vivo evaluation of molybdenum as bioabsorbable stent candidate.

Biodegradable stents have tremendous theoretical potential as an alternative to bare metal stents and drug-eluting stents for the treatment of obstructive coronary artery disease. Any bioresorbable or biodegradable scaffold material needs to possess optimal mechanical properties and uniform degradation behavior that avoids local and systemic toxicity. Recently, molybdenum (Mo) has been investigated as a potential novel biodegradable material for this purpose. With its proven moderate degradation rate and excellent mechanical properties, Mo may represent an ideal source material for clinical cardiac and vascular applications. The present study was performed to evaluate the mechanical performance of metallic Mo in vitro and the biodegradation properties in vivo. The results demonstrated favorable mechanical behavior and a uniform degradation profile as desired for a new generation ultra-thin degradable endovascular stent material. Moreover, Mo implants in mouse arteries avoided the typical cellular response that contributes to restenosis. There was minimal neointimal hyperplasia over 6 months, an absence of excessive smooth muscle cell (SMC) proliferation or inflammation near the implant, and avoidance of significant harm to regenerating endothelial cells (EC). Qualitative inspection of kidney sections showed a potentially pathological remodeling of kidney Bowman's capsule and glomeruli, indicative of impaired filtering function and development of kidney disease, although quantifications of these morphological changes were not statistically significant. Together, the results suggest that the products of Mo corrosion may exert beneficial or inert effects on the activities of inflammatory and arterial cells, while exerting potentially toxic effects in the kidneys that warrant further investigation.

Recent advances and directions in the development of bioresorbable metallic cardiovascular stents: Insights from recent human and in vivo studies.

Over the past two decades, significant advancements have been made regarding the material formulation, iterative design, and clinical translation of metallic bioresorbable stents. Currently, magnesium-based (Mg) stent devices have remained at the forefront of bioresorbable stent material development and use. Despite substantial advances, the process of developing novel absorbable stents and their clinical translation is time-consuming, expensive, and challenging. These challenges, coupled with the continuous refinement of alternative bioresorbable metallic bulk materials such as iron (Fe) and zinc (Zn), have intensified the search for an ideal absorbable metallic stent material. Here, we discuss the most recent pre-clinical and clinical evidence for the efficacy of bioresorbable metallic stents and material candidates. From this perspective, strategies to improve the clinical performance of bioresorbable metallic stents are considered and critically discussed, spanning material alloy development, surface manipulations, material processing techniques, and preclinical/biological testing considerations. STATEMENT OF SIGNIFICANCE: Recent efforts in using Mg, Fe, and Zn based materials for bioresorbable stents include elemental profile changes as well as surface modifications to improve each of the three classes of materials.  Although a variety of alloys for absorbable metallic stents have been developed, the ideal absorbable stent material has not yet been discovered. This review focuses on the state of the art for bioresorbable metallic stent development. It covers the three bulk materials used for degradable stents (Mg, Fe, and Zn), and discusses their advances from a translational perspective. Strategies to improve the clinical performance of bioresorbable metallic stents are considered and critically discussed, spanning material alloy development, surface manipulations, material processing techniques, and preclinical/biological testing considerations.

The effects of alloying with Cu and Mn and thermal treatments on the mechanical instability of Zn-0.05Mg alloy.

The detrimental effect of natural aging on mechanical properties of zinc alloys restricts their application as bioresorbable medical implants. In this study, aging of Zn-0.05Mg alloy and the effect of 0.5 Cu and 0.1 Mn (in weight percent) addition on the microstructure and tensile properties were studied. The alloys were cold rolled, aged and annealed; aiming to investigate the effects of precipitates and grain size on the mechanical properties and their stability. TEM analysis revealed that in ultrafine-grained binary Zn-0.05Mg alloy, the natural aging occurred due to the formation of nano-sized Mg2Zn11 precipitates. After 90 days of natural aging, the yield strength and ultimate tensile strength of Zn-0.05Mg alloy increased from 197±4 MPa and 227±5 MPa to 233±8 MPa and 305±7 MPa, respectively, while the elongation was drastically reduced from 34±3% to 3±1%. This natural aging was retarded by adding the third element at either 0.1Mn or 0.5Cu quantities, which interacted with Mg in Zn solid solution and impeded the formation of Mg2Zn11 precipitates. The addition of Cu and Mn elements increased alloy's strength, ductility, and its mechanical stability at a room temperature. The measured tensile strength and elongation were 274±5 MPa and 41±1% for Zn-0.1Mn-0.05Mg and 312±2 MPa and 44±2% for Zn-0.5Cu-0.05Mg, respectively. Annealing the alloys at elevated temperatures caused increase in both grain size and dissolution of secondary phases, and both affected alloy deformation mechanisms.

Towards revealing key factors in mechanical instability of bioabsorbable Zn-based alloys for intended vascular stenting.

Zn-based alloys are recognized as promising bioabsorbable materials for cardiovascular stents, due to their biocompatibility and favorable degradability as compared to Mg. However, both low strength and intrinsic mechanical instability arising from a strong strain rate sensitivity and strain softening behavior make development of Zn alloys challenging for stent applications. In this study, we developed binary Zn-4.0Ag and ternary Zn-4.0Ag-xMn (where x = 0.2-0.6wt%) alloys. An experimental methodology was designed by cold working followed by a thermal treatment on extruded alloys, through which the effects of the grain size and precipitates could be thoroughly investigated. Microstructural observations revealed a significant grain refinement during wire drawing, leading to an ultrafine-grained (UFG) structure with a size of 700 nm and 200 nm for the Zn-4.0Ag and Zn-4.0Ag-0.6Mn, respectively. Mn showed a powerful grain refining effect, as it promoted the dynamic recrystallization. Furthermore, cold working resulted in dynamic precipitation of AgZn3 particles, distributing throughout the Zn matrix. Such precipitates triggered mechanical degradation through an activation of Zn/AgZn3 boundary sliding, reducing the tensile strength by 74% and 57% for Zn-4.0Ag and Zn-4.0Ag-0.6Mn, respectively. The observed precipitation softening caused a strong strain rate sensitivity in cold drawn alloys. Short-time annealing significantly mitigated the mechanical instability by reducing the AgZn3 fraction. The ternary alloy wire showed superior microstructural stability relative to its Mn-free counterpart due to the pinning effect of Mn-rich particles on the grain boundaries. Eventually, a shift of the corrosion regime from localized to more uniform was observed after the heat treatment, mainly due to the dissolution of AgZn3 precipitates. STATEMENT OF SIGNIFICANCE: Owing to its promising biodegradability, zinc has been recognized as a potential biodegradable material for stenting applications. However, Zn's poor strength alongside intrinsic mechanical instability have propelled researchers to search for Zn alloys with improved mechanical properties. Although extensive researches have been conducted to satisfy the mentioned concerns, no Zn-based alloys with stabilized mechanical properties have yet been reported. In this work, the mechanical properties and stability of the Zn-Ag-based alloys were systematically evaluated as a function of microstructural features. We found that the microstructure design in Zn alloys can be used to find an effective strategy to not only improve the strength and suppress the mechanical instability but also to minimize any damage by augmenting the corrosion uniformity.

Analysis of vascular inflammation against bioresorbable Zn-Ag based alloys.

Zinc (Zn) has emerged as a promising bioresorbable stent material due to its satisfactory corrosion behavior and excellent biocompatibility. However, for load bearing implant applications, alloying is required to boost its mechanical properties as pure Zn exhibits poor strength. Unfortunately, an increase in inflammation relative to pure Zn is a commonly observed side-effect of Zn alloys. Consequently, the development of a Zn-based alloy that can simultaneously feature improved mechanical properties and suppress inflammatory responses is a big challenge. Here, a bioresorbable, biocompatible Zn-Ag-based quinary alloy was comprehensively evaluated in vivo, in comparison to reference materials. The inflammatory and smooth muscle cellular response was characterized and correlated to metrics of neointimal growth. We found that implantation of the quinary alloy was associated with significantly improved inflammatory activities relative to the reference materials. Additionally, we found that inflammation, but not smooth muscle cell hyperplasia, significantly correlates to neointimal growth for Zn alloys. The results suggest that inflammation is the main driver of neointimal growth for Zn-based alloys and that the quinary Zn-Ag-Mn-Zr-Cu alloy may impart inflammation-resistance properties to arterial implants.

Precipitation induced room temperature superplasticity in Zn-Cu alloys.

In this study, the effect of grain size and precipitates on tensile properties of Zn-1.0Cu alloy were investigated. The alloy was cold rolled and annealed to manipulate the grain size and precipitation of CuZn4 particles at grain boundaries. Cold rolling resulted in an almost ultrafinegrained structure alongside precipitation of nano-sized CuZn4 particles. Strain induced precipitates triggered room temperature superplasticity through activation of Zn/CuZn4 boundary sliding, exhibiting maximum elongation of 470% at the strain rate of 1.0 × 10-4 s-1. Short-time annealing led to significantly reduced strain rate sensitivity due to the reduction of CuZn4 fraction, while the grain size remained nearly intact. This suggests that precipitates rather than grain size mainly influence the mechanical properties of Zn alloys.

In Vitro Corrosion and in Vivo Response to Zinc Implants with Electropolished and Anodized Surfaces.

Zinc (Zn)-based biodegradable metals have been widely investigated for cardiovascular stent and orthopedic applications. However, the effect of Zn surface features on adverse biological responses has not been well established. Here, we hypothesized that a metallic zinc implant's surface oxide film character may critically influence early neointimal growth and development. Electropolishing of surfaces has become the industry standard for metallic stents, while anodization of surfaces, although not practiced on stents at present, could increase the thickness of the stable oxide film and delay early-stage implant degradation. In this study, pure zinc samples were electropolished (EP) and anodized (AD) to engineer oxide films with distinctive physical and degradation characteristics, as determined by potentiodynamic polarization, electrochemical impedance spectroscopy, and static immersion tests. The samples were then implanted within the aortic lumen of adult Sprague-Dawley rats to determine the influence of surface engineering on biocompatibility responses to Zn implants. It was found that in vitro corrosion produced a porous corrosion layer for the EP samples and a densified layer on the AD samples. The AD material was more resistant to corrosion, while localized corrosion and pitting was seen on the EP surface. Interestingly, the increased variability from localized corrosion due to the surface film character translated directly to the in vivo performance, where 100% of the AD implants but only 44% of the EP implants met the biocompatibility benchmarks. Overall, the results suggest that oxide films on degradable zinc critically affect early neointimal progression and overall success of degradable Zn materials.

Zinc-based alloys for degradable vascular stent applications.

The search for biodegradable metals with mechanical properties equal or higher to those of currently used permanent biomaterials, such as stainless steels, cobalt chromium and titanium alloys, desirable in vivo degradation rate and uniform corrosion is still an open challenge. Magnesium (Mg), iron (Fe) and zinc (Zn)-based alloys have been proposed as biodegradable metals for medical applications. Over the last two decades, extensive research has been done on Mg and Fe. Fe-based alloys show appropriate mechanical properties, but their degradation rate is an order of magnitude below the benchmark value. In comparison, alongside the insufficient mechanical performance of most of its alloys, Mg degradation rate has proven to be too high in a physiological environment and corrosion is rarely uniform. During the last few years, Zn alloys have been explored by the biomedical community as potential materials for bioabsorbable vascular stents due to their tolerable corrosion rates and tunable mechanical properties. This review summarizes recent progress made in developing Zn alloys for vascular stenting application. Novel Zn alloys are discussed regarding their microstructural characteristics, mechanical properties, corrosion behavior and in vivo performance. STATEMENT OF SIGNIFICANCE: Numerous studies on magnesium and iron materials have been reported to date, in an effort to formulate bioabsorbable stents with tailorable mechanical characteristics and corrosion behavior. Crucial concerns regarding poor ductility and remarkably rapid corrosion of magnesium, and very slow degradation of iron, seem to be still not desirably fulfilled. Zinc was introduced as a potential implant material in 2013 due to its promising biodegradability and biocompatibility. Since then, extensive investigations have been made toward development of zinc alloys that meet clinical benchmarks for vascular scaffolding. This review critically surveys the zinc alloys developed since 2013 from metallurgical and biodegradation points of view. Microstructural features, mechanical, corrosion and in vivo performances of these new alloys are thoroughly reviewed and evaluated.