Metallic stents are commonly 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. Unfortunately, iron produces a voluminous, retained oxide product in the arterial wall, whereas magnesium and its alloys corrode too rapidly. A third class of metallic bioabsorbable materials that are based on zinc has been introduced in the last few years. As summarized in this contribution, 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. They appear to be free of flaws that limit the application of iron- and magnesium-based alloys, and polymers. This review compares bioabsorbable materials and summarizes progress towards bioabsorbable stents. It emphasizes on 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.

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 6.5 months. 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 6.5 months 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.

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 MgZn 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.

Zinc shows great promise as a bioabsorbable metal. Our early in vivo investigations implanting pure zinc wires into the abdominal aorta of Sprague-Dawley rats revealed that metallic zinc does not promote restenotic responses and may suppress the activities of inflammatory and smooth muscle cells. However, the low tensile strength of zinc remains a major concern. A cast billet of the Zn-Li alloy was produced in a vacuum induction caster under argon atmosphere, followed by a wire drawing process. Two phases of the binary alloy identified by x-ray diffraction include the zinc phase and intermetallic LiZn4 phase. Mechanical testing proved that incorporating 3 at.% of Li into Zn increased its ultimate tensile strength from 116 ± 13 MPa (pure Zn) to 274 ± 61 MPa while the ductility was held at 17 ± 7%. Implantation of 10 mm Zn-3Li wire segments into abdominal aorta of rats revealed an excellent biocompatibility of this material in the arterial environment. The biodegradation rate for Zn-3Li was found to be about 0.008 mm/yr and 0.045 mm/yr at 2 and 12 months, respectively.

Metallic zinc implanted into the abdominal aorta of rats out to 6 months has been demonstrated to degrade while avoiding responses commonly associated with the restenosis of vascular implants. However, major questions remain regarding whether a zinc implant would ultimately passivate through the production of stable corrosion products or via a cell mediated fibrous encapsulation process that prevents the diffusion of critical reactants and products at the metal surface. Here, we have conducted clinically relevant long term in vivo studies in order to characterize late stage zinc implant biocorrosion behavior and products to address these critical questions. We found that zinc wires implanted in the murine artery exhibit steady corrosion without local toxicity for up to at least 20 months post-implantation, despite a steady buildup of passivating corrosion products and intense fibrous encapsulation of the wire. Although fibrous encapsulation was not able to prevent continued implant corrosion, it may be related to the reduced chronic inflammation observed between 10 and 20 months post-implantation. X-ray elemental and infrared spectroscopy analyses confirmed zinc oxide, zinc carbonate, and zinc phosphate as the main components of corrosion products surrounding the Zn implant. These products coincide with stable phases concluded from Pourbaix diagrams of a physiological solution and in vitro electrochemical impedance tests. The results support earlier predictions that zinc stents could become successfully bio-integrated into the arterial environment and safely degrade within a time frame of approximately 1 – 2 years.

Special high grade zinc and wrought zincaluminum (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 nonand 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.

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.

Nitric oxide (NO), identified over the last several decades in many physiological processes and pathways as both a beneficial and detrimental signaling molecule, has been the subject of extensive research. Physiologically, NO is transported by a class of donors known as S-nitrosothiols. Both endogenous and synthetic S-nitrosothiols have been reported to release NO during interactions with certain transition metals, primarily Cu(2+) and Fe(2+). Ag(+) and Hg(2+) have also been identified, although these metals are not abundantly present in physiological systems. Here, we evaluate Pt(2+), Fe(2+), Fe(3+), Mg(2+), Zn(2+), Mn(2+), Co(2+), Ni(2+), and Cu(2+) for their ability to generate NO from S-nitroso-N-acetyl-d-penicillamine (SNAP) under physiological pH conditions. Specifically, we report NO generation from RSNOs initiated by three transition metal ions; Co(2+), Ni(2+), and Zn(2+), which have not been previously reported to generate NO. Additionally, preliminary in vivo evidence of zinc wires implanted in the rat arterial wall and circulating blood is presented which demonstrated inhibited thrombus formation after 6 months. One potentially useful application of these metal ions capable of generating NO from RSNOs is their use in the fabrication of biodegradable metallic stents capable of generating NO at the stent-blood interface, thereby reducing stent-related thrombosis and restenosis.