Benchtop proof of concept and comparison of iron- and magnesium-based bioresorbable flow diverters.

OBJECTIVE: Bioresorbable flow diverters (BRFDs) could significantly improve the performance of next-generation flow diverter technology. In the current work, magnesium and iron alloy BRFDs were prototyped and compared in terms of porosity/pore density, radial strength, flow diversion functionality, and resorption kinetics to offer insights into selecting the best available bioresorbable metal candidate for the BRFD application. METHODS: BRFDs were constructed with braided wires made from alloys of magnesium (MgBRFD) or iron (FeBRFD). Pore density and crush resistance force were measured using established methods. BRFDs were deployed in silicone aneurysm models attached to flow loops to investigate flow diversion functionality and resorption kinetics in a simulated physiological environment. RESULTS: The FeBRFD exhibited higher pore density (9.9 vs 4.3 pores/mm2) and crush resistance force (0.69 ± 0.05 vs 0.53 ± 0.05 N/cm, p = 0.0765, n = 3 per group) than the MgBRFD, although both crush resistances were within the range previously reported for FDA-approved flow diverters. The FeBRFD demonstrated greater flow diversion functionality than the MgBRFD, with significantly higher values of established flow diversion metrics (mean transit time 159.6 ± 11.9 vs 110.9 ± 1.6, p = 0.015; inverse washout slope 192.5 ± 9.0 vs 116.5 ± 1.5, p = 0.001; n = 3 per group; both metrics expressed as a percentage of the control condition). Last, the FeBRFD was able to maintain its braided structure for > 12 weeks, whereas the MgBRFD was almost completely resorbed after 5 weeks. CONCLUSIONS: The results of this study demonstrated the ability to manufacture BRFDs with magnesium and iron alloys. The data suggest that the iron alloy is the superior material candidate for the BRFD application due to its higher mechanical strength and lower resorption rate relative to the magnesium alloy.

Biodegradable magnesium materials regulate ROS-RNS balance in pro-inflammatory macrophage environment.

The relationship between reactive oxygen and nitrogen species (ROS-RNS) secretion and the concomitant biocorrosion of degradable magnesium (Mg) materials is poorly understood. We found that Mg foils implanted short term in vivo (24 h) displayed large amounts of proinflammatory F4/80+/iNOS + macrophages at the interface. We sought to investigate the interplay between biodegrading Mg materials (98.6% Mg, AZ31 & AZ61) and macrophages (RAW 264.7) stimulated with lipopolysaccharide (RAW 264.7LPS) to induce ROS-RNS secretion. To test how these proinflammatory ROS-RNS secreting cells interact with Mg corrosion in vitro, Mg and AZ61 discs were suspended approximately 2 mm above a monolayer of RAW 264.7 cells, either with or without LPS. The surfaces of both materials showed acute (24 h) changes when incubated in the proinflammatory RAW 264.7LPS environment. Mg discs incubated with RAW 264.7LPS macrophages showed greater corrosion pitting, while AZ61 showed morphological and elemental bulk product changes via scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX). X-ray photoelectron spectroscopy (XPS) analysis showed a reduction in the Ca/P ratio of the surface products for AZ61 disc incubated with RAW 264.7LPS, but not the Mg discs. Moreover, RAW 264.7LPS macrophages were found to be more viable in the acute biodegradative environment generated by Mg materials, as demonstrated by calcein-AM and cleaved (active) caspase-3 staining (CC3). LPS stimulation caused an increase in ROS-RNS, and a decrease in antioxidant peroxidase activity. Mg and AZ61 were found to change this ROS-RNS balance, independently of physiological antioxidant mechanisms. The findings highlight the complexity of the cellular driven acute inflammatory responses to different biodegradable Mg, and how it can potentially affect performance of these materials.

Bioresorbable flow diverters for the treatment of intracranial aneurysms: review of current literature and future directions.

The use of flow diverters is a rapidly growing endovascular approach for the treatment of intracranial aneurysms. All FDA-approved flow diverters are composed of nitinol or cobalt-chromium, which will remain in the patient for the duration of their life. Bioresorbable flow diverters have been proposed by several independent investigators as the next generation of flow diverting devices. These devices aim to serve their transient function of occluding and healing the aneurysm prior to being safely resorbed by the body, eliminating complications associated with the permanent presence of conventional flow diverters. Theoretical advantages of bioresorbable flow diverters include (1) reduction in device-induced thrombosis; (2) reduction in chronic inflammation and device-induced stenosis; (3) reduction in side branch occlusion; (4) restoration of physiological vasomotor function; (5) reduction in imaging artifacts; and (6) use in pediatric applications. Advances made in the similar bioresorbable coronary stenting field highlight some of these advantages and demonstrate the feasibility and safety of bioresorbable endovascular devices in the clinic. The current work aims to review the progress of bioresorbable flow diverters, identify opportunities for further investigation, and ultimately stimulate the advancement of this technology.

Improved biocompatibility of Zn-Ag-based stent materials by microstructure refinement.

The metallurgical engineering of bioresorbable zinc (Zn)-based medical alloys would greatly benefit from clarification of the relationships between material properties and biological responses. Here we investigate the biocompatibility of three Zn-based silver (Ag)-containing alloys, ranging from binary to quinary alloy systems. Selected binary and quinary Zn-Ag-based alloys underwent solution treatment (ST) to increase the solubility of Ag-rich phases within the Zn bulk matrix, yielding two different microstructures (one without ST and a different one with ST) with the same elemental composition. This experimental design was intended to clarify the relationship between elemental profile/microstructure and biocompatibility for the Zn-Ag system. We found that the quinary alloy system (Zn-4Ag-0.8Cu-0.6Mn-0.15Zr) performed significantly better, in terms of histomorphometry, than any alloy system we have evaluated to date. Furthermore, when solution treated to increase strength and ductility and reduce the fraction of Ag-rich phases, the quinary alloy's biocompatibility further improved. In vitro corrosion testing and metallographic analysis of in vivo implants demonstrated a more uniform mode of corrosion for the solution treated alloy. We conclude that Zn-Ag alloys can be engineered through alloying to substantially reduce neointimal growth. The positive effect on neointimal growth can be further enhanced by dissolving the AgZn3 precipitates in the Zn matrix to improve the corrosion uniformity. These findings demonstrate that neointimal-forming cells can be regulated by elemental additions and microstructural changes in degradable Zn-based implant materials. STATEMENT OF SIGNIFICANCE: The metallurgical engineering of bioresorbable zinc (Zn)-based medical alloys would greatly benefit from clarification of the relationships between material properties and biological responses. Here, selected binary and quinary Zn-Ag-based alloys underwent solution treatment (ST) to increase the solubility of Ag-rich phases within the Zn bulk matrix, yielding two different microstructures (one without ST and a different one with ST) with the same elemental composition. We found that applying a thermal treatment restores mechanical strength and mitigates the strain rate sensitivity of Zn-Ag alloys by dissolving AgZn3 precipitates. Ag-rich nano-precipitates in Zn decrease biocompatibility, a phenomenon that can be counteracted by dissolving the AgZn3 precipitates in the bulk Zn matrix.

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.

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.

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.

Zn2+-dependent suppression of vascular smooth muscle intimal hyperplasia from biodegradable zinc implants.

Biodegradable arterial implants based on zinc have been found to suppress neointimal hyperplasia, suggesting that biodegradable materials containing zinc may be used to construct vascular implants with a reduced rate of restenosis. However, the molecular mechanism has remained unclear. In this report, we show that zinc-containing materials can be used to prevent neointimal formation when implanted into the rat aorta. Indeed, neointimal cells were significantly more TUNEL positive and alpha-actin negative at the interface of biodegradable zinc vs. biostable platinum implants, in association with greater caspase-3 activity. Although zinc stimulated extensive neointimal smooth muscle cell (SMC) death, macrophage and proinflammatory markers CD68 and iNOS were not increased in neointimal tissue relative to biostable platinum control implants. Using arterial explants, ionic zinc was confirmed to promote SMC apoptosis by activating the caspase apoptotic signaling pathway. These observations suggest that zinc-containing materials can be used to construct vascular implants such as stents with reduced neointimal hyperplasia.

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.

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.

Preclinical In-Vivo Evaluation and Screening of Zinc Based Degradable Metals for Endovascular Stents.

Zinc alloy development and characterization for vascular stent application has been facilitated by many standardized and inexpensive methods. In contrast, overly simplistic in vitro approaches dominate the preliminary biological testing of materials. In 2012, our group introduced a metal wire implantation model in rats as a cost effective and realistic approach for the biocompatibility evaluation of degradable materials in the vascular environment. Here, we have adapted metrics routinely used for evaluating stents to quantitatively characterize the long-term progression of the neointima that forms around zinc based wire implants. Histological cross-sections were used to measure the length of neointimal protrusion from the wire into the lumen (denoted wire to lumen thickness), the base neointimal length (describing the breadth of neointimal activation), and the neointimal area. These metrics were used to provide in depth characterization details for neointimal responses to Zn-Mg and Zn-Li alloys and may be used to compare different materials.

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.

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

Metallic zinc implanted into the abdominal aorta of rats out to 6months 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 20months 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 20months 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 1-2years. STAEMENT OF SIGNIFICANCE: Previous studies have shown zinc to be a promising candidate material for bioresorbable endovascular stenting applications. An outstanding question, however, is whether a zinc implant would ultimately passivate through the production of stable corrosion products or via a cell mediated tissue encapsulation process that prevented the diffusion of critical reactants and products at the metal surface. We found that zinc wires implanted in the murine artery exhibit steady corrosion for up to at least 20months post-implantation. The results confirm earlier predictions that zinc stents could safely degrade within a time frame of approximately 1-2years.

Zn-Li alloy after extrusion and drawing: Structural, mechanical characterization, and biodegradation in abdominal aorta of rat.

Zinc shows great promise as a bio-degradable 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 0.1wt% of Li into Zn increased its ultimate tensile strength from 116±13MPa (pure Zn) to 274±61MPa while the ductility was held at 17±7%. Implantation of 10mm Zn-Li wire segments into abdominal aorta of rats revealed an excellent biocompatibility of this material in the arterial environment. The biodegradation rate for Zn-Li was found to be about 0.008mm/yr and 0.045mm/yr at 2 and 12months, respectively.

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.

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.

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.

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.

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.

Fibrosis worsens chronic lymphedema in rodent tissues.

Secondary lymphedema in humans is a common consequence of lymph node dissection (LND) to treat breast cancer. A peculiar characteristic of the disease is that lifelong swelling often precipitously appears several years after the surgical treatment, often due to an inflammatory stimulus. Although the incidence of secondary lymphedema dramatically increases after radiation therapy, the relationship between fibrotic scarring and the eventual appearance of lymphedema remains unclear. To clarify the role of fibrosis in secondary lymphedema initiation, we chemically increased fibrosis in rodent tissues with bleomycin and assessed the ability of the local lymphatic system to prevent lymphedema, either acutely or in a chronic state induced by inflammation. We found that bleomycin injections exacerbated fibrotic matrix deposition in an acute mouse tail lymphedema model (P < 0.005), reduced wound closure (P < 0.005), and impaired the ability of tail lymphatics to regenerate (P < 0.005) and reduce the swelling (P < 0.05). When fibrosis was worsened with bleomycin after axillary LND in the rat foreleg, the ability of the foreleg lymphatic system to reduce the chronic state swelling induced by stimulated inflammation was severely impaired (P < 0.005). Indocyanine green lymphography in axillary LND-recovered rat forelegs revealed a worsened lymphatic drainage due to inflammation and bleomycin pretreatment. Although inflammation reduced the drainage of dextran fluid tracer from control forelegs (P < 0.05), the reduction in fluid drainage was more severe after axillary LND when fibrosis was first increased (P < 0.005). These findings demonstrate that fibrosis reduces the lymphatic capacity to functionally regenerate and prevent the chronic appearance of lymphedema.