Radiopaque FeMnN-Mo composite drawn filled tubing wires for braided absorbable neurovascular devices.

Flow diverter devices are small stents used to divert blood flow away from aneurysms in the brain, stagnating flow and inducing intra-aneurysmal thrombosis which in time will prevent aneurysm rupture. Current devices are formed from thin (∼25 µm) wires which will remain in place long after the aneurysm has been mitigated. As their continued presence could lead to secondary complications, an absorbable flow diverter which dissolves into the body after aneurysm occlusion is desirable. The absorbable metals investigated to date struggle to achieve the necessary combination of strength, elasticity, corrosion rate, fragmentation resistance, radiopacity, and biocompatibility. This work proposes and investigates a new composite wire concept combining absorbable iron alloy (FeMnN) shells with one or more pure molybdenum (Mo) cores. Various wire configurations are produced and drawn to 25-250 µm wires. Tensile testing revealed high and tunable mechanical properties on par with existing flow diverter materials. In vitro degradation testing of 100 µm wire in DMEM to 7 days indicated progressive corrosion and cracking of the FeMnN shell but not of the Mo, confirming the cathodic protection of the Mo by the FeMnN and thus mitigation of premature fragmentation risk. In vivo implantation and subsequent µCT of the same wires in mouse aortas to 6 months showed meaningful corrosion had begun in the FeMnN shell but not yet in the Mo filament cores. In total, these results indicate that these composites may offer an ideal combination of properties for absorbable flow diverters.

Intraluminal Flow Diverter Design Primer for Neurointerventionalists.

The clinical use of flow diverters for the treatment of intracranial aneurysms has rapidly grown. Consequently, the market and technology for these devices has also grown. Clinical performance characteristics of the flow diverter are well-known to the clinician. However, the engineering design principles behind how these devices achieve ideal clinical performance are less understood. This primer will summarize flow diverter design parameters for neurointerventionalists with the aim of promoting collaboration between clinicians and engineers.

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.

Innate glycosidic activity in metallic implants for localized synthesis of antibacterial drugs.

Iron-containing metallic implants are shown herein to mediate hydrolysis of glycosidic linkages. Using glucuronide prodrugs for broad-spectrum fluoroquinolone antibacterial agents, we capitalize on this behaviour and perform localized synthesis of antimicrobials which affords a significant zone of inhibition of bacterial growth around the metallic material.

Enzyme Prodrug Therapy Achieves Site-Specific, Personalized Physiological Responses to the Locally Produced Nitric Oxide.

Nitric oxide (NO) is a highly potent but short-lived endogenous radical with a wide spectrum of physiological activities. In this work, we developed an enzymatic approach to the site-specific synthesis of NO mediated by biocatalytic surface coatings. Multilayered polyelectrolyte films were optimized as host compartments for the immobilized ß-galactosidase (ß-Gal) enzyme through a screen of eight polycations and eight polyanions. The lead composition was used to achieve localized production of NO through the addition of ß-Gal-NONOate, a prodrug that releases NO following enzymatic bioconversion. The resulting coatings afforded physiologically relevant flux of NO matching that of the healthy human endothelium. The antiproliferative effect due to the synthesized NO in cell culture was site-specific: within a multiwell dish with freely shared media and nutrients, a 10-fold inhibition of cell growth was achieved on top of the biocatalytic coatings compared to the immediately adjacent enzyme-free microwells. The physiological effect of NO produced via the enzyme prodrug therapy was validated ex vivo in isolated arteries through the measurement of vasodilation. Biocatalytic coatings were deposited on wires produced using alloys used in clinical practice and successfully mediated a NONOate concentration-dependent vasodilation in the small arteries of rats. The results of this study present an exciting opportunity to manufacture implantable biomaterials with physiological responses controlled to the desired level for personalized treatment.

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.

An in vitro and in vivo characterization of fine WE43B magnesium wire with varied thermomechanical processing conditions.

Absorbable implants made of magnesium alloys may revolutionize surgical intervention, and fine magnesium wire will be critical to many applications. Functionally, the wires must have sufficient mechanical properties to withstand implantation and in-service loading, have excellent tissue tolerance, and exhibit an appropriate degradation rate for the application. Alloy chemistry and thermomechanical processing conditions will significantly impact the material's functional performance, but the exact translation of these parameters to implant performance is unclear. With this in mind, fine (127 µm) WE43B magnesium alloy wires in five thermomechanical process (TMP) conditions (90% cold work [CW], and 250, 375, 400, and 450°C heat treatments) were investigated for their effect on mechanical and corrosion behavior. The TMP conditions gave clear metallurgical differences: transverse grain dimensions ranged from 200 nm (CW) to 3 µm (450°C), UTS varied from 324 MPa (450°C) to 608 MPa (250°C), and surgical knotting showed some were suitable (CW, 400°C, 450°C) while others were not (250°C, 350°C). In vitro and in vivo corrosion testing yielded interesting and in some cases conflicting results. After 1 month immersion in cell culture medium, wire corrosion was extensive, and TMP conditions altered the macrocorrosion morphology but not the rate or total release of magnesium ions. After 1 month subdermal implantation in mice, all wires were well tolerated and showed very little corrosion (per µCT and histology), but differences in localized corrosion were detected between conditions. This study indicates that WE43B wires treated at 450°C may be most suitable for surgical knotting procedures. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1987-1997, 2018.

Continuously Grooved Stent Struts for Enhanced Endothelial Cell Seeding.

PURPOSE: Implantation of pre-endothelialized stents could enhance cellular recovery of a damaged vessel wall provided attached cells remain viable, functional and are present in sufficient numbers after deployment. The purpose of this study was to evaluate the feasibility of grooved stainless steel (SS) stents as a primary endothelial cell (EC) carrier with potentially enhanced EC protection upon stent deployment. MATERIALS AND METHODS: Attachment and behavior of enzymatically harvested human adult venous ECs seeded onto gelatin-coated vascular stents were evaluated in an in vitro setting. Smooth and grooved SS stents and smooth nitinol stents were studied. RESULTS: All cells expressed EC markers vWF and CD31. Using rotational seeding for a period of 16-24 h, ECs attached firmly to the stents with sufficient coverage to form a confluent EC monolayer. The grooved SS wire design was found to enable attachment of three times the number of cells compared to smooth wires. This also resulted in an increased number of cells remaining on the stent after deployment and after pulsatile flow of 180 ml/min for 24 h, which did not result in additional EC detachment. CONCLUSIONS: The grooved stent provides a potential percutaneous means to deliver sufficient numbers of viable and functional cells to a vessel segment during vascular intervention. The grooves were found to offer a favorable surface for EC attachment and protection during stent deployment in an in vitro setting.

Magnetically Inserted Neural Electrodes: Tissue Response and Functional Lifetime.

Neural recording and stimulation have great clinical potential. Long-term neural recording remains a challenge, however, as implantable electrodes eventually fail due to the adverse effects of the host tissue response to the indwelling implant. Astrocytes and microglia attempt to engulf the electrode, increasing the electrical impedance between the electrode and neurons, and possibly pushing neurons away from the recording site. Faster insertion speed, finer tip geometry, smaller size, and lower material stiffness all seem to decrease damage caused by insertion and reduce the intensity of the tissue response. However, electrodes that are too small result in buckling, making insertion impossible. In this paper, we assess the viability of high-speed (27.8 m/s) deployment of 25 µm, ferromagnetic microelectrodes into rat brain. To characterize functionality of magnetically inserted electrodes, 4 Long-Evans rats were implanted for 31 days with impedance measurements and neural recordings taken daily. Performance was compared to 150 µm diameter PlasticsOne electrodes since 25 µm electrodes buckled during "slow speed" insertion. Platinum-iron magnetically inserted electrodes resolved single unit activity throughout the duration of the study in one rat, and saw no significant change (p=0.970) in impedance (4.54% increase) from day 0 (Z0 ≈ 144 kΩ,Z31 ≈ 150 kΩ). These findings provide a proof-of-concept for magnetic insertion as a viable insertion method that enables nonbuckling implantation of small (25 µm) microelectrodes, with potential for neural recording applications.

Cold drawn bioabsorbable ferrous and ferrous composite wires: an evaluation of in vitro vascular cytocompatibility.

A systematic approach is applied to quantify the impact of bioabsorbable metals on human vascular endothelial cells (EC) and aortic smooth muscle cells (SMC) with the aim of optimizing bioabsorbable endovascular stent development. Composite wires comprising novel combinations of Fe, Mn, Mg, and Zn were produced and fabricated into tubular mesh stents. The stents were incubated with primary EC in order to assess attachment and cell proliferation. Migration of SMCs from the vessel medial wall to the target lesion site following recanalization of an atherosclerotic artery is important in the process of neointimal hyperplasia. Metal ion species were assayed for their impact on cell migration and survival at concentrations ranging from 0.037 to 10 mM. An MTT-based assay was used to assess cytotoxicity after insult with various metal ion concentrations. Fe(2+) and Fe(3+) ion species were found to repress the migration of SMCs across a porous polycarbonate track etch membrane at concentrations of 1 mM. Mn(2+) promoted SMC migration at a concentration of 1 mM, however, this effect was quenched when Fe(2+) was included. Mg(2+) was found to significantly increase SMC migration at concentrations above 1 mM. Cell survival was not reduced after 24 h insult with concentrations of Mg(2+) up to 10 mM. LD50 concentrations of greater than 1 mM were found for Mg(2+), Fe(2+), Fe(3+), and Fe(2+) with 35 wt.% Mn(2+). Significantly greater numbers of EC attached to bioabsorbable metal species compared with 316L stainless steel. Good EC coverage and proliferation were observed for all tested materials up to 120 h.

Nanocrystalline material with gigacycle fatigue life.

A processing technology has been developed that can be applied to many different fine wire medical alloys to improve their fatigue properties. This technology has been used to process a low inclusion alloy, 35 cobalt-35 nitinol-20 chromium-10 Molybdenum (ASTM F562 chemistry), hereinafter referred to as System A. After processing, this ultra fine microstructure exhibited relatively high yield strength, good axial ductility and a fatigue limit of 1 GPa at a fatigue lifetime that exceeded 100 million cycles, as reported here.