Rational design, synthesis and prospect of biodegradable magnesium alloy vascular stents

Biodegradable magnesium(Mg) alloys are expected to be promising materials for cardiovascular stents(CVS), which can avoid the longterm clinical problems of current CVS, such as in-stent restenosis, late stent thrombosis, etc. Mg alloy stents exhibit superior biocompatibility and tunable biodegradability, compared with conventional permanent metallic stents. However, the poor formability and non-uniform corrosion of Mg alloy stents hinder their clinical application of CVS. This review focuses on the development of Mg alloys for CVS in recent years.According to the results of bibliometric analysis, we analyzed different biodegradable Mg alloy systems. Moreover, the structural design strategies for Mg alloy stents that can reduce the stress concentration, as well as the surface modification methods to control the corrosion behavior and biological performance of Mg alloy stents are also highlighted. At last, this review systematically discussed the potential directions and challenges of biodegradable magnesium stents(BMgS) in cardiovascular fields.

Understanding the corrosion of Mg alloys in in vitro urinary tract conditions: A step forward towards a biodegradable metallic ureteral stent

Ureteral stents play a fundamental role in modern time urology. However, following the deployment, stent-related symptoms are frequent and affect patient health and quality of life. Using biodegradable metals as ureteral stent materials have emerged as a promising strategy, mainly due to the improved radial force and slower degradation rate expected. Therefore, this study aimed to characterize different biodegradable metals in urinary tract environment to understand their propensity for future utilization as base materials for ureteral stents. The corrosion of 5 Mg alloys - AZ31, Mg-1Zn, Mg-1Y, pure Mg, and Mg-4Ag - under simulated urinary tract conditions was accessed. The corrosion layer of the different alloys presented common elements, such as Mg(OH)_(2), MgO, and phosphate-containing products, but slight variations in their chemical compositions were detected. The corrosion rate of the different metals varied, which was expected given the differences in the corrosion layers. On top of this, the findings of this study highlighted the significant differences in the samples' corrosion and corrosion layers when in stagnant and flowing conditions. With the results of this study, we concluded that Mg-1Zn and Mg-4Ag presented a higher propensity for localized corrosion, probably due to a less protective corrosion layer;Mg-4Ag corroded faster than all the other four alloys,and Mg-1Y stood out due to its distinct corrosion pattern, that showed to be more homogeneous than all the other four samples, making this one more attractive for the future studies on biodegradable metals.

Long-term effects of biodegradable versus durable polymercoated sirolimus-eluting stents on arterial wall morphology as assessed by virtual histology intravascular ultrasound

Objectives To assess long-term coronary arterial response to biodegradable polymer-coated sirolimus-eluting stent(BSES) in vivo by using virtual histology intravascular ultrasound(VH-IVUS).Methods 41 patients were enrolled in this study and VH-IVUS was performed to assess the native artery vascular responses to BSES compared with durable polymer-coated SES(DSES) during long-term follow-up(median =8 months).The presence of necrotic core abutting to the lumen was evaluated at follow-up.Results With similar in-stent late luminal loss(0.15[0.06,0.30]vs 0.19[0.03, 0.30]mm,P=0.772),the overall incidence of necrotic core abutting to the lumen was significantly less in BSES than DSES group(44%vs.63%,P=0.019)(proximal 18%,stented site 14%and distal 12%in BSES group,proximal 19%, stented site 28%and distal 16%in DSES group).Compared with stented segments each other,the DSES -treated segments had a significant higher incidence of necrotic core abutting to the lumen through the stent struts(73%vs.36%, P=0.005).In addition,more multiple necrotic core abutting to the lumen was observed in DSES group(overall:63%vs. 36%,P=0.015).Furthermore,among the total number of stented segments with necrotic core abutting to the lumen, DSES -treated lesions had more multiple necrotic core abutting to the lumen through the stent struts than BSES -treated lesions in evidence(74%vs.33%,P=0.027).Conclusions By VH-IVUS analysis at follow-up,a greater frequency of stable lesion morphometry was shown in lesions treated with BSESs compared with lesions treated with DSESs.The major reason was BSES produced less toxicity to the arterial wall and facilitated neointimal healing as a result of polymer coating on drug-eluting stent(DES) surface biodegraded as time went by.

Five-year outcomes of biodegradable versus second-generation durable polymer drug-eluting stents used in complex percutaneous coronary intervention

Background:There are few data comparing clinical outcomes of complex percutaneous coronary intervention(CPCI)when using biodegradable polymer drug-eluting stents(BP-DES)or second-generation durable polymer drug-eluting stents(DP-DES).The purpose of this study was to investigate the safety and efficacy of BP-DES and compare that with DP-DES in patients with and without CPCI during a 5-year follow-up.Methods:Patients who exclusively underwent BP-DES or DP-DES implantation in 2013 at Fuwai Hospital were consecutively enrolled and stratified into two categories based on CPCI presence or absence.CPCI included at least one of the following features:unprotected left main lesion,≥2 lesions treated,≥2 stents implanted,total stent length>40 mm,moderate-to-severe calcified lesion,chronic total occlusion,or bifurcated target lesion.The primary endpoint was major adverse cardiac events(MACE)including all-cause death,recurrent myocardial infarction,and total coronary revascularization(target lesion revascularization,target vessel revascularization[TVR],and non-TVR)during the 5-year follow-up.The secondary endpoint was total coronary revascularization.Results:Among the 7712 patients included,4882(63.3%)underwent CPCI.Compared with non-CPCI patients,CPCI patients had higher 2-and 5-year incidences of MACE and total coronary revascularization.Following multivariable adjustment including stent type,CPCI was an independent predictor of MACE(adjusted hazard ratio[aHR]:1.151;95%confidence interval[CI]:1.017–1.303,P=0.026)and total coronary revascularization(aHR:1.199;95%CI:1.037–1.388,P=0.014)at 5 years.The results were consistent at the 2-year endpoints.In patients with CPCI,BP-DES use was associated with significantly higher MACE rates at 5 years(aHR:1.256;95%CI:1.078–1.462,P=0.003)and total coronary revascularization(aHR:1.257;95%CI:1.052–1.502,P=0.012)compared with that of DP-DES,but there was a similar risk at 2 years.However,BP-DES had comparable safety and efficacy profiles including MACE and total coronary revascularization compared with DP-DES in patients with non-CPCI at 2 and 5 years.Conclusions:Patients underwent CPCI remained at a higher risk of mid-to long-term adverse events regardless of the stent type.The effect of BP-DES compared with DP-DES on outcomes was similar in CPCI and non-CPCI patients at 2 years but had inconsistent effects at the 5-year clinical endpoints.

Processing of a Novel Zn Alloy Micro-Tube for Biodegradable Vascular Stent Application

In recent years, zinc based alloys as a new biodegradable metal material aroused intensive interests. However, the processing of Zn alloys micro-tubes （named slender-diameter and thin-walled tubes） is very difficult due to their HCP crystal structure and unfavorable mechanical properties. This study aimed to develop a novel technique to produce micro-tube of Zn alloy with good performance for biodegrad- able vascular stent application. In the present work, a processing method that combined drilling, cold rolling and optimized drawing was proposed to produce the novel Zn-5Mg-1Fe （wt%） alloy micro- tubes. The micro-tube with outer diameter of 2.5 mm and thickness of 130 μm was fabricated by this method and its dimension errors are within 10 μm. The micro-tube exhibits a fine and homogeneous microstructure, and the ultimate tensile strength and ductility are more than 220 MPa and 20% respectively. In addition, the micro-tube and stents of Zn alloy exhibit superior in vitro corrosion and expansion performance. It could be concluded that the novel Zn alloy micro-tube fabricated by above method might be a promising candidate material for biodegradable stent.

Short-term safety and efficacy of the biodegradable iron stent in mini-swine coronary arteries

Background To overcome the drawbacks of permanent years. The bioabsorbable polymer vascular scaffold （BVS） stents, biodegradable stents have been studied in recent was the first bioabsorbable stent to undergo clinical trials, demonstrating safety and feasibility in the ABSORB studies. Iron can potentially serve as the biomatedal for biodegradable stents. This study aimed to assess the short4erm safety and efficacy of a biodegradable iron stent in mini-swine coronary arteries. Methods Eight iron stents and eight cobalt chromium alloy （VISION） control stents were randomly implanted into the LAD and RCA of eight healthy mini-swine, respectively. Two stents of the same metal base were implanted into one animal. At 28 days the animals were sacrificed after coronary angiography, and histopathological examinations were performed. Results Histomorphometric measurements showed that mean neointimal thickness （（0.46±0.17） mm vs. （0.45±0.18） mm, P=0.878）, neointimal area （（2.55±0.91） mm2 vs. （3.04±1.15） mm2, P=0.360） and percentage of area stenosis （（44.50±11.40）% vs. （46.00±17.95）%, P=0.845） were not significantly different between the iron stents and VISION stents. There was no inflammation, thrombosis or necrosis in either group. The scanning electron microscopy （SEM） intimal injury scores （0.75±1.04 vs. 0.88±0.99, P=0.809） and number of proliferating cell nuclear antigen （PCNA） positive staining cells were not significantly different between the two groups. The percentage of neointimal coverage by SEM examination was numerically higher in iron stents than in VISION stents （（84.38±14.50）% vs. （65.00±22.04）%, P=0.057）, but the difference was not statistically significant. Iron staining in the tissue surrounding the iron stents at 28 days was positive and the vascular wall adjacent to the iron stent had a brownish tinge, consistent with iron degradation. No abnormal histopathological changes were detected in coronary arteries or major organs. Conclusions The biodegradable iron stent has good biocompatibility and short-term safety and efficacy in the mini- swine coronary artery. Corrosion of iron stents is observed at four weeks and no signs of organ toxicity related to iron degradation were noted.

A review on biodegradable biliary stents: materials and future trends

Biliary stricture is defined as the reduction and narrowing of the bile duct lumen, which can be caused by many factors such as cancer and inflammation. Biliary stent placement can effectively alleviate benign and malignant biliary strictures. However, the commonly used plastic or metallic biliary stents are far from ideal and do not satisfy all clinical requirements,although several types of biodegradable biliary stents have been developed and used clinically. In this review, we summarized current development status of biodegradable stents with the emphasis on the stent materials. We also presented the future development trends based on the published literature.

Research and development strategy for biodegradable magnesium-based vascular stents:a review

Magnesium alloys are an ideal material for biodegradable vascular stents,which can be completely absorbed in the human body,and have good biosafety and mechanical properties.However,the rapid corrosion rate and excessive localized corrosion,as well as challenges in the preparation and processing of microtubes for stents,are restricting the clinical application of magnesium-based vascular stents.In the present work we will give an overview of the recent progresses on biodegradable magnesium based vascular stents including magnesium alloy design,high-precision microtubes processing,stent shape optimisation and functional coating preparation.In particular,the Triune Principle in biodegradable magnesium alloy design is proposed based on our research experience,which requires three key aspects to be considered when designing new biodegradable magnesium alloys for vascular stents application,i.e.biocompatibility and biosafety,mechanical properties,and biodegradation.This review hopes to inspire the future studies on the design and development of biodegradable magnesium alloy-based vascular stents.

3D Printing of Biodegradable Polymer Vascular Stents:A Review

Biodegradable polymer vascular stents(BPVSs)have been widely used in percutaneous coronary interventions for the treatment of coronary artery diseases.The development of BPVSs is an integrated process that combines material design/selection,manufacturing,and performance characterization.Three-dimensional(3D)printing technology is a powerful tool for polymer stent fabrication.Current review studies have focused primarily on the material and structural design of polymer stents but have failed to comprehensively discuss different 3D printing approaches and stent characterization techniques.In this paper,we address these shortcomings by discussing 3D printing methods and their application in BPVSs.First,some commonly used 3D printing methods(including material extrusion,vat polymerization,and powder bed fusion)and potential 3D printing strategies(including material jetting and binder jetting)for fabricating BPVSs are discussed;furthermore,the main post-treatments are summarized.Then,techniques to characterize the morphology,mechanical properties,and biological prop-erties of the printed BPVSs are introduced.Subsequently,representative commercial BPVSs and lab-grade BPVSs are compared.Finally,based on the limitations of stent printing and characterization processes,future perspec-tives are proposed,which may help develop new techniques to fabricate more customized stents and accurately evaluate their performance.

miR-22 eluting cardiovascular stent based on a self-healable spongy coating inhibits in-stent restenosis

The in-stent restenosis(IRS)after the percutaneous coronary intervention contributes to the major treatment failure of stent implantation.MicroRNAs have been revealed as powerful gene medicine to regulate endothelial cells(EC)and smooth muscle cells(SMC)in response to vascular injury,providing a promising therapeutic candidate to inhibit IRS.However,the controllable loading and eluting of hydrophilic bioactive microRNAs pose a challenge to current lipophilic stent coatings.Here,we developed a microRNA eluting cardiovascular stent via the self-healing encapsulation process based on an amphipathic poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone)(PCL-PEG-PCL,PCEC)triblock copolymer spongy network.The miR-22 was used as a model microRNA to regulate SMC.The dynamic porous coating realized the uniform and controllable loading of miR-22,reaching the highest dosage of 133 pmol cm^(-2).We demonstrated that the sustained release of miR-22 dramatically enhanced the contractile phenotype of SMC without interfering with the proliferation of EC,thus leading to the EC dominating growth at an EC/SMC ratio of 5.4.More importantly,the PCEC@miR-22 coated stents showed reduced inflammation,low switching of SMC phenotype,and low secretion of extracellular matrix,which significantly inhibited IRS.This work provides a simple and robust coating platform for the delivery of microRNAs on cardiovascular stent,which may extend to other combination medical devices,and facilitate practical application of bioactive agents in clinics.

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.

Vascular restoration therapy and bioresorbable vascular scaffold

This article describes the evolution of minimally invasive intervention technologies for vascular restoration therapy from early-stage balloon angioplasty in 1970s,metallic bare metal stent and metallic drug-eluting stent technologies in 1990s and 2000s,to bioresorbable vascular scaffold(BVS)technology in large-scale development in recent years.The history,the current stage,the challenges and the future of BVS development are discussed in detail as the best available approach for vascular restoration therapy.The criteria of materials selection,design and processing principles of BVS,and the corresponding clinical trial results are also summarized in this article.