Diego Mantovani

Biodegradable Metals for Cardiovascular Stent Application: Interests and New Opportunities

During the last decade, biodegradable metallic stents have been developed and investigated as alternatives for the currently-used permanent cardiovascular stents. Degradable metallic materials could potentially replace corrosion-resistant metals currently used for stent application as it has been shown that the role of stenting is temporary and limited to a period of 6–12 months after implantation during which arterial remodeling and healing occur. Although corrosion is generally considered as a failure in metallurgy, the corrodibility of certain metals can be an advantage for their application as degradable implants. The candidate materials for such application should have mechanical properties ideally close to those of 316L stainless steel which is the gold standard material for stent application in order to provide mechanical support to diseased arteries. Non-toxicity of the metal itself and its degradation products is another requirement as the material is absorbed by blood and cells. Based on the mentioned requirements, iron-based and magnesium-based alloys have been the investigated candidates for biodegradable stents. This article reviews the recent developments in the design and evaluation of metallic materials for biodegradable stents. It also introduces the new metallurgical processes which could be applied for the production of metallic biodegradable stents and their effect on the properties of the produced metals.

Iron–manganese: new class of metallic degradable biomaterials prepared by powder metallurgy

Abstract An Fe–35 wt-%Mn alloy, aimed to be used as a metallic degradable biomaterial for stent applications, was prepared via a powder metallurgy route. The effects of processing conditions on the microstructure, mechanical properties, magnetic susceptibility and corrosion behaviour were investigated and the results were compared to those of the SS316L alloy, a gold standard for stent applications. The Fe35Mn alloy was found to be essentially austenitic with fine MnO particles aligned along the rolling direction. The alloy is ductile with a strength approaching that of wrought SS316L. It exhibits antiferromagnetic behaviour and its magnetic susceptibility is not altered by plastic deformation, providing an excellent MRI compatibility. Its corrosion rate was evaluated in a modified Hanks solution, and found superior to that of pure iron (slow in vivo degradation rate). In conclusion, the mechanical, magnetic and corrosion characteristics of the Fe35Mn alloy are considered suitable for further development of a new class of degradable metallic biomaterials.

Chemical stability of polyether urethanes versus polycarbonate urethanes

The relative chemical stability of two commercially available polyurethanes-Pellethane, currently used in biomedical devices, and Corethane, considered as a potential biomaterial-was investigated following aging protocols in hydrolytic and oxidative conditions (HOC, water, hydrogen peroxide, and nitric acid) and in physiological media (PHM, phosphate buffer, lipid dispersion, and bile from human donors). The chemical modifications induced on these polymers were characterized using differential scanning calorimetry (DSC), gel permeation chromatography (GPC), and Fourier transform infrared spectroscopy (FTIR). With the exception of nitric acid, all of the aging media promoted a mild hydrolytic reaction leading to a slight molecular weight loss in both polymers. When aged in water and hydrogen peroxide, Pellethane experienced structural modifications through microdomain phase separation along with an increase of the order within the soft-hard segment domains. The incubation of Pellethane in nitric acid also resulted in an important decrease of the melting temperature of its hard segments with chain scission mechanisms. Moreover, incubation in PHM led to an increase of the order within shorter hard-segment domains. FTIR data revealed the presence of aliphatic amide molecules used as additives on the Pellethanes surface. The incubation of Corethane under the same conditions promoted an almost uniform molecular reorganization through a phase separation between the hard and soft segments as well as an increase of the short-range order within the hard-segment domains. Incubation of this polymer in nitric acid also resulted in a chain scission process that was less pronounced than that measured for the Pellethane samples. Finally, lipid adsorption occurred on the Corethane sample incubated in bile for 120 days. Overall data indicate that polycarbonate urethane presents a greater chemical stability than does polyetherurethane.

Compliant electrospun silk fibroin tubes for small vessel bypass grafting.

Processing silk fibroin (SF) by electrospinning offers a very attractive opportunity for producing three-dimensional nanofibrillar matrices in tubular form, which may be useful for a biomimetic approach to small calibre vessel regeneration. Bypass grafting of small calibre vessels, with a diameter less than 6mm, is performed mainly using autografts, like the saphenous vein or internal mammary artery. At present no polymeric grafts made of SF are commercially available, mainly due to inadequate properties (low compliance and lack of endothelium cells). The aim of this work was to electrospin SF into tubular structures (Ø=6mm) for small calibre vessel grafting, characterize the morphological, chemico-physical and mechanical properties of the electrospun SF structures and to validate their potential to interact with cells. The morphological properties of electrospun SF nanofibres were investigated by scanning electron microscopy. Chemico-physical analyses revealed an increase in the crystallinity of the structure of SF nanofibres on methanol treatment. Mechanical tests, i.e. compliance and burst pressure measurements, of the electrospun SF tubes showed that the inner pressure to radial deformation ratio was linear for elongation up to 15% and pressure up to 400 mm Hg. The mean compliance value between 80 and 120 mm Hg was higher than the values reported for both Goretex(R) and Dacron(R) grafts and for bovine heterografts, but still slightly lower than those of saphenous and umbilical vein, which nowadays represent the gold standard for the replacement of small calibre arteries. The electrospun tubes resisted up to 575+/-17 mmHg, which is more than four times the upper physiological pressure of 120 mmHg and more than twice the pathological upper pressures (range 180-220 mmHg). The in vitro tests showed a good cytocompatibility of the electrospun SF tubes. Therefore, the electrospun SF tubes developed within this work represent a suitable candidate for small calibre blood vessel replacement.

Electroformed pure iron as a new biomaterial for degradable stents: In vitro degradation and preliminary cell viability studies ☆

In the search for a metallic material showing moderate and uniform degradation for application as degradable cardiovascular stents, electroformed iron (E-Fe) was evaluated by in vitro degradation and cell viability tests. Static immersion and dynamic degradation were used to evaluate degradation rate and mechanism, while cell viability assay was used to assess cytotoxicity. The results were compared with those of iron fabricated by casting and thermomechanical treatment previously investigated as a stent material. Electroformed iron showed faster degradation than iron fabricated by casting (0.25 vs. 0.14 mm year(-1)), with a uniform degradation mechanism. Cell viability results showed that E-Fe did not result in a decrease in metabolic activity when exposed to primary rat smooth muscle cells. However, it caused a decrease in cell proliferation activity which could be beneficial for the inhibition of in-stent restenosis.

Mutant Huntingtin Is Present in Neuronal Grafts in Huntington Disease Patients

Huntington disease (HD) is caused by a genetically encoded pathological protein (mutant huntingtin [mHtt]), which is thought to exert its effects in a cell‐autonomous manner. Here, we tested the hypothesis that mHtt is capable of spreading within cerebral tissue by examining genetically unrelated fetal neural allografts within the brains of patients with advancing HD.

Degradation Behaviour of Metallic Biomaterials for Degradable Stents

The short-term need of scaffolding function of stent and the prevention of potential longterm complication of permanently implanted stent have directed to the original idea of biodegradable stent. Selecting and developing materials showing appropriate mechanical and degradation properties are key steps for the development of this new class of medical devices. Therefore, the study of their in vitro degradation behaviour is mandatory for the selection of potential candidate materials suited in vivo. In this work, the degradation behaviour of current studied biodegradable metals including three magnesium alloys (Mg, AM60B and AZ91D), pure iron and Fe-35Mn was investigated. The tests were performed in a simulated blood plasma solution at 37±0.1 oC, using three different methods; potentiodynamic polarization, static immersion, and dynamic test in a test-bench which mimics the flow condition in human coronary artery. Degradation rate was determined as ion release rate measured by using atomic adsorption spectroscopy (AAS) and also estimated from weight loss and corrosion current. Surface morphology and chemical composition of corroded specimens were analyzed by using SEM/EDS. The three degradation methods provide consistent results in corrosion tendency, where Mg showed the highest corrosion rate followed by AZ91D, AM60B, Fe-35Mn and iron. Potentiodynamic polarization gives a rapid estimation of corrosion behaviour and rate. Static immersion test shows the effect of time on the degradation rate and behaviour. Dynamic test provides the closest approach to the environment after stent implantation and its results show the effect of the flow on the materials degradation. In conclusion, the three investigated methods can be applied for screening, selecting and validating materials for degradable stent application before going further to in vivo assessments.

Collagen‐Reinforced Electrospun Silk Fibroin Tubular Construct as Small Calibre Vascular Graft

None of the replacements proposed in the literature for small-calibre blood vessels (SCBV) fully satisfies the stringent requirements that these grafts have to fulfil. Here, an electrospun silk fibroin tubular construct is hybridized with type I collagen gel to produce a biomimetic SCBV graft with physiologically relevant compliance and burst pressure and optimal cytocompatibility. The hybridization of the two polymers results in the formation of a nanofibrillar hydrated matrix, where the collagen gel enhances the mechanical properties of the SF tubular construct and improves the early response of the material to in vitro cell adhesion and proliferation.

Development of degradable Fe-35Mn alloy for biomedical application

As some biomedical problems require only temporary intervention, there is a clinical need for degradable biomaterials with excellent mechanical properties and controllable degradation behaviour. Although several works were carried out on both polymeric and metallic materials, no proposed degradable biomaterial fully satisfied these requirements. Therefore a new Fe-35Mn alloy has been developed as a valid and well suited alternative. The alloy was fabricated through powder metallurgy route followed by successive cold rolling and sintering cycles. This austenitic alloy exhibits a high strength and ductility, comparable to that of type 316L stainless steel. Its antiferromagnetic behaviour is not changed by cold deformation process. The alloy shows suitable degradation behaviour with a uniform corrosion mechanism and a slow release of ions that make it particularly well suited for the development of a new class of biodegradable stents.

Study of the adhesion of thin plasma fluorocarbon coatings resisting plastic deformation for stent applications

Metallic intravascular stents are medical devices (316L stainless steel) used to support the narrowed lumen of atherosclerotic stenosed arteries. Despite the success of bare metal stents, restenosis remains the main complication after 3–6 months of implantation. To reduce the restenosis rate of bare metal stents, stent coating is an interesting alternative. Firstly, it allows the modification of the surface properties, which is in contact with the biological environment. Secondly, the coating could eventually act as a carrier for drug immobilization and release. Moreover, the in vivo stent implantation requires in situ stent expansion. This mandatory step generates local plastic deformation of up to 25% and may cause coating failures such as cracking and delamination. Fluorocarbon films were selected in this study as a potential stent coating, mainly due to their chemical inertness, high hydrophobicity, protein retention capabilities and thromboresistance properties. The aim of this study was to investigate the adhesion properties of fluorocarbon films of three different thicknesses deposited by plasma polymerization in C2F6/H2 on 316L stainless steel substrates. A previously developed small punch test was used to deform the coated samples. According to atomic force microscopy, field emission scanning electron microscopy and x-ray photoelectron spectroscopy characterizations, among the coatings with different thicknesses studied, only those with a thickness of 36 nm exhibited the required cohesion and interfacial adhesion to resist the stent expansion without cracking or delaminating. Otherwise, cracks were detected in the coatings having thicknesses equal or superior to 100 nm, indicating a lack of cohesion.