DEGRADABLE ZINC MATERIAL CHARACTERISTICS AND ITS INFLUENCE ON BIOCOMPATIBILITY IN AN IN-VIVO MURINE MODEL

Biodegradable stents based on zinc have been under development since their introduction in 2013. While metallic zinc is highly ductile, it unfortunately lacks the mechanical strength required for arterial stents. This has led to the development of an abundance of novel zinc-based materials, with the aim of improving the mechanical strength without sacrificing too much ductility. Although these materials are intended to function and slowly degrade within an artery, most zinc-based materials have been developed without deep consideration for their biological effects. The present work explores the biological effects elicited by zinc-based materials implanted within the arterial system. The biological effects of degradable arterial implants were characterized in terms of quantifiable metrics, including neointimal area, implant to lumen thickness, and base neointimal length. These metrics were used to clarify relationships between material characteristics, including surface oxide film stability, elemental composition, and microstructure, with biological responses. The metrics were also used to compare materials in terms of their biocompatibility. In addition to evaluating biocompatibility, beneficial elements identified by these approaches can be further investigated for their therapeutic value, since all the elements in the implant will be released due to implant degradation. The combined work makes it possible to screen materials in terms of their biocompatibility and provides fundamental insights that impact the metallurgical design of materials

Hepatic cell mobilization for protection against ischemic myocardial injury

The heart is capable of activating protective mechanisms in response to ischemic injury to support myocardial survival and performance. These mechanisms have been recognized primarily in the ischemic heart, involving paracrine signaling processes. Here, we report a distant cardioprotective mechanism involving hepatic cell mobilization to the ischemic myocardium in response to experimental myocardial ischemia–reperfusion (MI-R) injury. A parabiotic mouse model was generated by surgical skin-union of two mice and used to induce bilateral MI-R injury with unilateral hepatectomy, establishing concurrent gain- and loss-of-hepatic cell mobilization conditions. Hepatic cells, identified based on the cell-specific expression of enhanced YFP, were found in the ischemic myocardium of parabiotic mice with intact liver (0.2 ± 0.1%, 1.1 ± 0.3%, 2.7 ± 0.6, and 0.7 ± 0.4% at 1, 3, 5, and 10 days, respectively, in reference to the total cell nuclei), but not significantly in the ischemic myocardium of parabiotic mice with hepatectomy (0 ± 0%, 0.1 ± 0.1%, 0.3 ± 0.2%, and 0.08 ± 0.08% at the same time points). The mobilized hepatic cells were able to express and release trefoil factor 3 (TFF3), a protein mitigating MI-R injury as demonstrated in TFF3−/− mice (myocardium infarcts 17.6 ± 2.3%, 20.7 ± 2.6%, and 15.3 ± 3.8% at 1, 5, and 10 days, respectively) in reference to wildtype mice (11.7 ± 1.9%, 13.8 ± 2.3%, and 11.0 ± 1.8% at the same time points). These observations suggest that MI-R injury can induce hepatic cell mobilization to support myocardial survival by releasing TFF3

Patient-specific cardiovascular superelastic NiTi stents produced by laser powder bed fusion

To date, there is a general lack of customizability within the selection of endovascular devices for catheter-based vascular interventions. Laser powder bed fusion (LPBF) has been flexibly exploited to produce customized implants using conventional biomedical alloys for orthopedic and dental applications. Applying LPBF for cardiovascular applications, patient-specific stents can be produced with small struts (approximately 100-300 µm), variable geometries, and clinically used metals capable of superelastic behaviour at body temperature (eg. equiatomic nickel-titanium alloys, NiTi). Additionally, the growing availability and use of patient-specific 3D models provides a unique opportunity to outline the necessary manufacturing process that would be required for customizable NiTi devices based on patient geometry. In order to fulfil the potential of the patient-specific superelastic stents, process and design know-how should be expanded to the novel material and fine details at the limits of conventional LPBF machines. In this work, a framework for developing a patient-specific superelastic NiTi stent produced by LPBF is demonstrated. At a proof-of-concept stage, the design procedures are shown in a geometry similar to the artery. The stents with 100 µm nominal strut diameter are later produced with a Ni50.8Ti49.2 powder and heat treated. The results confirm the possibility of producing stents with a design suitable for highly complex patient-specific anatomies and having superelastic behavior at body temperature

An Assessment of Blood Vessel Remodeling of Nanofibrous Poly(ε-Caprolactone) Vascular Grafts in a Rat Animal Model

The development of an ideal vascular prosthesis represents an important challenge in terms of the treatment of cardiovascular diseases with respect to which new materials are being considered that have produced promising results following testing in animal models. This study focuses on nanofibrous polycaprolactone-based grafts assessed by means of histological techniques 10 days and 6 months following suturing as a replacement for the rat aorta. A novel stereological approach for the assessment of cellular distribution within the graft thickness was developed. The cellularization of the thickness of the graft was found to be homogeneous after 10 days and to have changed after 6 months, at which time the majority of cells was discovered in the inner layer where the regeneration of the vessel wall was found to have occurred. Six months following implantation, the endothelialization of the graft lumen was complete, and no vasa vasorum were found to be present. Newly formed tissue resembling native elastic arteries with concentric layers composed of smooth muscle cells, collagen, and elastin was found in the implanted polycaprolactone-based grafts. Moreover, the inner layer of the graft was seen to have developed structural similarities to the regular aortic wall. The grafts appeared to be well tolerated, and no severe adverse reaction was recorded with the exception of one case of cartilaginous metaplasia close to the junctional suture

Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo

Meeting Abstracts: Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo Clearwater Beach, FL, USA. 9-11 June 201

Transition-Metal-Mediated Release of Nitric Oxide (NO) from S-Nitroso-N-acetyl-D-penicillamine (SNAP): Potential Applications for Endogenous Release of NO at the Surface of Stents Via Corrosion Products

© 2016 American Chemical Society. 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 Cu2+ and Fe2+. Ag+ and Hg2+ have also been identified, although these metals are not abundantly present in physiological systems. Here, we evaluate Pt2+, Fe2+, Fe3+, Mg2+, Zn2+, Mn2+, Co2+, Ni2+, and Cu2+ 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; Co2+, Ni2+, and Zn2+, 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

Long-term surveillance of zinc implant in murine artery: Surprisingly steady biocorrosion rate

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

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

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

Effect of PLLA coating on corrosion and biocompatibility of zinc in vascular environment

Zinc (Zn) has recently been introduced as a promising new metal candidate for biodegradable vascular stent applications with a favorable degradation rate and biocompatibility. Corrosion-resistant metal stents are often coated with drug-eluting polymer layers to inhibit harmful biological responses. Here, the authors aimed to investigate the interaction between biodegradable zinc metal and a conventional biodegradable polymer coating. Zinc wires with a diameter of 0·25 mm were surface-modified using 3-(trimethoxysilyl)propyl methacrylate (MPS) and then coated with a 1–12 μm film of poly(l-lactic acid) (PLLA). The corrosion behavior of PLLA/MPS-coated zinc wires was studied in simulated body fluid using electrochemical impedance spectroscopy. An increase in the impedance from \u3c1000 to \u3e15 000 Ω cm2 was recorded for the zinc wires after being coated with PLLA. The PLLA/MPS-coated zinc specimens were implanted into the abdominal rat aorta to assess their biodegradation and biocompatibility compared to uncoated zinc wires. PLLA/MPS-coated wires corroded at approximately half the rate of unmodified zinc during the first 4·5 months. A histological analysis of the biological tissue surrounding the zinc implants revealed a reduction in the biocompatibility of the polymer-coated samples, as indicated by increasing cell toxicity and neointimal hyperplasia