Thrombogenicity of biodegradable metals

Biodegradable metals offer a promising means to ameliorate many of the long-term risks associated with vascular devices made of conventional biostable stent metals.While numerous biodegradable metal alloys have been developed and characterized in animal models,knowledge of their blood reactivity and thrombogenicity remains unknown.Metal hemocompatibility is particularly valuable because current generation drug-eluting stents pose a significant long-term thrombosis risk.In this study,four pure metals,widely used as degradable base materials(Fe,Zn,Mg,and Mo),and three alloys commonly used in cardiovascular devices[NiTi,CoCr,and stainless steel(SS)]were evaluated.This work examined how each of these metals activate platelets,coagulation factors,and inflammation using in vitro hemocompatibility assays and a clinically relevant ex vivo non-human primate arteriovenous shunt model.Testing found that while all metals promoted a downstream activation of platelets and coagulation in flowing whole blood,platelet and fibrin attachment to Mg was markedly reduced.Additionally,Fe and Mo trended toward higher platelet attachment and contact pathway activation.Overall,the results suggest that Mg may delay clot initiation,but not eliminate clot formation,indicating the importance of understanding thrombosis in Mg alloys that are currently being developed for clinical use as biodegradable stents.

Effects of serum proteins on corrosion rates and product bioabsorbability of biodegradable metals

Corrodible metals are the newest kind of biodegradable materials and raise a new problem of the corrosion products.However,the removal of the precipitated products has been unclear and even largely ignored in publications.Herein,we find that albumin,an abundant macromolecule in serum,enhances the solubility of corrosion products of iron in blood mimetic Hank’s solution significantly.This is universal for other main biodegradable metals such as magnesium,zinc and polyester-coated iron.Albumin also influences corrosion rates in diverse trends in Hank’s solution and normal saline.Based on quantitative study theoretically and experimentally,both the effects on corrosion rates and soluble fractions are interpreted by a unified mechanism,and the key factor leading to different corrosion behaviors in corrosion media is the interference of albumin to the Ca/P passivation layer on the metal surface.This work has illustrated that the interactions between metals and media macromolecules should be taken into consideration in the design of the next-generation metal-based biodegradable medical devices in the formulism of precision medicine.The improved Hank’s solution in the presence of albumin and with a higher content of initial calcium salt is suggested to access biodegradable metals potentially for cardiovascular medical devices,where the content of calcium salt is calculated after consideration of chelating of calcium ions by albumin,resulting in the physiological concentration of free calcium ions.

Fabrication and performance of Zinc-based biodegradable metals: From conventional processes to laser powder bed fusion

Zinc (Zn)-based biodegradable metals (BMs) fabricated through conventional manufacturing methods exhibit adequate mechanical strength, moderate degradation behavior, acceptable biocompatibility, and bioactive functions. Consequently, they are recognized as a new generation of bioactive metals and show promise in several applications. However, conventional manufacturing processes face formidable limitations for the fabrication of customized implants, such as porous scaffolds for tissue engineering, which are future direction towards precise medicine. As a metal additive manufacturing technology, laser powder bed fusion (L-PBF) has the advantages of design freedom and formation precision by using fine powder particles to reliably fabricate metallic implants with customized structures according to patient-specific needs. The combination of Zn-based BMs and L-PBF has become a prominent research focus in the fields of biomaterials as well as biofabrication. Substantial progresses have been made in this interdisciplinary field recently. This work reviewed the current research status of Zn-based BMs manufactured by L-PBF, covering critical issues including powder particles, structure design, processing optimization, chemical compositions, surface modification, microstructure, mechanical properties, degradation behaviors, biocompatibility, and bioactive functions, and meanwhile clarified the influence mechanism of powder particle composition, structure design, and surface modification on the biodegradable performance of L-PBF Zn-based BM implants. Eventually, it was closed with the future perspectives of L-PBF of Zn-based BMs, putting forward based on state-of-the-art development and practical clinical needs.

Comparative in vitro Study on Pure Metals(Fe,Mn,Mg,Zn and W) as Biodegradable Metals

Five pure metals including Fe, Mn, Mg, Zn and W have been investigated on their corrosion behavior and in vitro biocompatibility by electrochemical measurement, static immersion test, contact angle measurement, cytotoxicity and hemocompatibility tests. It is found that the sequence of corrosion rate of five metals in Hank＇s solution from high to low is： Mg 〉 Fe 〉 Zn 〉 Mn 〉 W. Fe, Mg and W show no cytotoxicity to L929 and ECV304 cells, Mn induces significant cytotoxicity to both L929 and ECV304 cells, and Zn has almost no inhibition effect on the metabolic activities of ECV304 while largely reduces the cell viability of L929 cells. The hemolysis percentage of five pure metals is lower than 5% except for Mg and platelets adhered on Zn has been activated and pseudopodia-like structures can be observed while platelets on the other four metals keep normal.

Research status of biodegradable metals designed for oral and maxillofacial applications:A review

The oral and maxillofacial regions have complex anatomical structures and different tissue types,which have vital health and aesthetic functions.Biodegradable metals(BMs)is a promising bioactive materials to treat oral and maxillofacial diseases.This review summarizes the research status and future research directions of BMs for oral and maxillofacial applications.Mg-based BMs and Zn-based BMs for bone fracture fixation systems,and guided bone regeneration(GBR)membranes,are discussed in detail.Zn-based BMs with a moderate degradation rate and superior mechanical properties for GBR membranes show great potential for clinical translation.Fe-based BMs have a relatively low degradation rate and insoluble degradation products,which greatly limit their application and clinical translation.Furthermore,we proposed potential future research directions for BMs in the oral and maxillofacial regions,including 3D printed BM bone scaffolds,surface modification for BMs GBR membranes,and BMs containing hydrogels for cartilage regeneration,soft tissue regeneration,and nerve regeneration.Taken together,the progress made in the development of BMs in oral and maxillofacial regions has laid a foundation for further clinical translation.

In vitro degradation and biocompatibility evaluation of typical biodegradable metals (Mg/Zn/Fe) for the application of tracheobronchial stenosis

Tracheobronchial obstruction in children due to benign stenosis or tracheobronchomalacia still remains a challenging matter of concern.Currently,there is 10%–20%complication rate in clinical treatment.The nonbiodegradable property of silicone stents and nickel-titanium memory alloy stents take the primary responsibility for drawbacks including stimulating local granulation tissue proliferation,displacement,and stent-related infections.Permanent tracheobronchial stent will be a persistent foreign object for a long time,causing excessive secretion of tracheal mucosa,ulceration and even perforation,which is particularly unsuitable for young children with persistent tracheal growth.In this study,the degradation and biocompatibility performance of three typical biodegradable metals were investigated as potential tracheobronchial stent materials.The results exhibited that these materials showed different degradation behaviors in the simulating respiratory fluid environment compared with SBF.Except for pure iron group,high purity magnesium and zinc showed favorable cell adhesion and proliferation in three culture methodologies(direct culture,indirect culture and extraction culture).The proper corrosion rate and good biocompatibility indicated that high purity magnesium and zinc may be good candidates as tracheobronchial stent materials.

A review on current research status of the surface modification of Zn-based biodegradable metals

Recently,zinc and its alloys have been proposed as promising candidates for biodegradable metals(BMs),owning to their preferable corrosion behavior and acceptable biocompatibility in cardiovascular,bone and gastrointestinal environments,together with Mg-based and Fe-based BMs.However,there is the desire for surface treatment for Zn-based BMs to better control their biodegradation behavior.Firstly,the implantation of some Zn-based BMs in cardiovascular environment exhibited intimal activation with mild inflammation.Secondly,for orthopedic applications,the biodegradation rates of Zn-based BMs are relatively slow,resulting in a long-term retention after fulfilling their mission.Meanwhile,excessive Zn2+release during degradation will cause in vitro cytotoxicity and in vivo delayed osseointegration.In this review,we firstly summarized the current surface modification methods of Zn-based alloys for the industrial applications.Then we comprehensively summarized the recent progress of biomedical bulk Zn-based BMs as well as the corresponding surface modification strategies.Last but not least,the future perspectives towards the design of surface bio-functionalized coatings on Zn-based BMs for orthopedic and cardiovascular applications were also briefly proposed.

Biodegradable metals for bone defect repair:A systematic review and meta-analysis based on animal studies

Biodegradable metals are promising candidates for bone defect repair.With an evidence-based approach,this study investigated and analyzed the performance and degradation properties of biodegradable metals in animal models for bone defect repair to explore their potential clinical translation.Animal studies on bone defect repair with biodegradable metals in comparison with other traditional biomaterials were reviewed.Data was carefully collected after identification of population,intervention,comparison,outcome,and study design(PICOS),and following the inclusion criteria of biodegradable metals in animal studies.30 publications on pure Mg,Mg alloys,pure Zn and Zn alloys were finally included after extraction from a collected database of 2543 publications.A qualitative systematic review and a quantitative meta-analysis were performed.Given the heterogeneity in animal model,anatomical site and critical size defect(CSD),biodegradable metals exhibited mixed effects on bone defect repair and degradation in animal studies in comparison with traditional non-degradable metals,biodegradable polymers,bioceramics,and autogenous bone grafts.The results indicated that there were limitations in the experimental design of the included studies,and quality of the evidence presented by the studies was very low.To enhance clinical translation of biodegradable metals,evidence-based research with data validity is needed.Future studies should adopt standardized experimental protocols in investigating the effects of biodegradable metals on bone defect repair with animal models.

In Vitro Evaluation of the Feasibility of Commercial Zn Alloys as Biodegradable Metals

In this work, three widely used commercial Zn alloys （ZA4-1, ZA4-3, ZA6-1 ） were purchased and pre- pared by hot extrusion at 200℃. The microstructure, mechanical properties, corrosion behaviors, biocompatibility and hemocompatibility of Zn alloys were studied with pure Zn as control, Commercial Zn alloys demonstrated increased strength and superb elongation compared with pure Zn. Accelerated corrosion rates and uniform corrosion morphologies were observed in terms of commercial Zn alloys due to galvanic effects between Zn matrix and α-Al phases. 100% extracts of ZA4-1 and ZA6-1 alloys showed mild cytotoxicity while 50% extracts of all samples displayed good biocompatibility. Retardant cell cycle and inhibited stress fibers expression were observed induced by high concentration of Zn^2＋ releasing during corrosion. The hemolysis ratios of Zn alloys were lower than 1% while the adhered platelets showed slightly activated morphologies. In general, commercial Zn alloys possess promising mechanical properties, appropriate corrosion rates, significantly improved biocompatibility and good hemocompatibility in comparison to pure Zn. It is feasible to develop biodegradable metals based on commercial Zn alloys.

Current status and outlook of biodegradable metals in neuroscience and their potential applications as cerebral vascular stent materials

Over the past two decades,biodegradable metals(BMs)have emerged as promising materials to fabricate temporary biomedical devices,with the purpose of avoiding potential side effects of permanent implants.In this review,we first surveyed the current status of BMs in neuroscience,and briefly summarized the representative stents for treating vascular stenosis.Then,inspired by the convincing clinical evidence on the in vivo safety of Mg alloys as cardiovascular stents,we analyzed the possibility of producing biodegradable cerebrovascular Mg alloy stents for treating ischemic stroke.For these novel applications,some key factors should also be considered in designing BM brain stents,including the anatomic features of the cerebral vasculature,hemodynamic influences,neuro-cytocompatibility and selection of alloying elements.This work may provide insights into the future design and fabrication of BM neurological devices,especially for brain stents.

Design of Fe–Mn–Ag Alloys as Potential Candidates for Biodegradable Metals

In this work,a series of biodegradable pure iron,Fe–30Mn and Fe–30Mn–Ag alloys were developed by using a rapid solidification technology.A fine a-Fe dendrite was formed in pure iron,resulting in a high compressive yield strength of above 300 MPa.The Fe–30Mn alloy doped with only 1%Ag exhibited a significant increase in the degradation rate in simulated body fluid due to the precipitation of Ag-rich particles in alloy matrix and the induction of the microgalvanic corrosion.In addition,the novel Fe–30Mn–Ag alloy also exhibited a good magnetic compatibility and offered a closely approaching requirement for biodegradable medical applications.

Advances and perspective on the translational medicine of biodegradable metals

Biodegradable metals,designed to be safely degraded and absorbed by the body after fulfil the intended functions,are of particular interest in the 21st century.The marriage of advanced biodegradable metals with clinical needs have yield unprecedented possibility.Magnesium,iron,and zinc-based materials constitute the main components of temporary,implantable metallic medical devices.A burgeoning number of studies on biodegradable metals have driven the clinical translation of biodegradable metallic devices in the fields of cardiology and orthopaedics over the last decade.Their ability to degrade as well as their beneficial biological functions elicited during degradation endow this type of material with the potential to shift the paradigm in the treatment of musculoskeletal and cardiovascular diseases.This review provides an insight into the degradation mechanism of these metallic devices in specific application sites and introduces state-of-the-art translational research in the field of biodegradable metals,as well as highlighting some challenges for materials design strategies in the context of mechanical and biological compatibility.

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.

A review on in vitro corrosion performance test of biodegradable metallic materials

Extensive in vitro corrosion test systems have been carried out to simulate the in vivo corrosion behavior of biodegradable metallic materials. Various methods have their own unique benefits and limitations. The corrosion mechanism of biodegradable alloys and in vitro corrosion test systems on biodegradable metallic materials are reviewed, to build a reasonable simulated in vitro test system for mimicking the in vivo animal test from the aspects of electrolyte solution selection, surface roughness influence, test methods and evaluation methodology of corrosion rate. Buffered simulated body fluid containing similar components to human blood plasma should be applied as electrolyte solution, such as simulated body fluid （SBF） and culture medium with serum. Surface roughness of samples and ratio of solution volume to sample surface area should be adopted based on the real implant situation, and the dynamic corrosion is preferred. As to the evaluation methodology of corrosion rate, different methods may complement one another.

Femtosecond laser-mediated anchoring of polymer layers on the surface of a biodegradable metal

Mg has received much attention as a next-generation implantable material owing to its biocompatibility,bone-like mechanical properties,and biodegradability in physiological environments.The application of various polymer coatings has been conducted in the past to reduce the rapid formation of hydrogen gas and the local change in pH during the initial phase of the chemical reaction with the body fluids.Here,we propose femtosecond(fs)laser-mediated Mg surface patterning for significant enhancement of the binding strength of the coating material,which eventually reduces the corrosion rate.Analyses of the structural,physical,crystallographic,and chemical properties of the Mg surface have been conducted in order to understand the mechanism by which the surface adhesion increases between Mg and the polymer coating layer.Depending on the fs laser conditions,the surface structure becomes rough owing to the presence of several microscaled pits and grooves of nanoporous MgO,resulting in a tightly bonded poly(lactic-co-glycolic acid)(PLGA)layer.The corrosion rate of the PLGA-coated,fs laser-treated Mg is considerably slow compared with the non-treated Mg;the treated Mg is also more biocompatible compared with the non-treated Mg.The fs laser-based surface modification technique offers a simple and quick method for introducing a rough coating on Mg;further,it does not require any chemical treatment,thereby overcoming a potential obstacle for its clinical use.

New insights on the high-corrosion resistance of UHP Mg-Ge alloys tested in a simulated physiological environment

UHP Mg-Ge alloys was recently found to provide excellent corrosion resistance.This paper provides new insights on the mechanism of improved corrosion resistance of UHP Mg-Ge alloys in Hanks’solution.The studied UHP Mg-0.5Ge and UHP Mg-1Ge alloys showed superior corrosion resistance compared to UHP Mg and WE43,with the Mg-1Ge exhibiting the best corrosion performance.The exceptional corrosion resistance of the UHP alloy is attributed to(i)Mg_(2)Ge’s ability to suppress cathodic kinetics,(ii)Ge’s capability to accelerate the formation of a highly passive layer,and the(iii)low amounts of corrosion-accelerating impurities.

Investigation of the degradation rate of electron beam processed and friction stir processed biocompatible ZKX50 magnesium alloy

Together with the mechanical properties,the degradation rate is an important factor for biodegradable implants.The ZKX50 Mg alloy is a suitable candidate to be used as a biodegradable implant due to its favorable biocompatibility and mechanical properties.Current research investigates the degradation rate and corrosion behavior of the ZKX50 as a function of the microstructure constituents and their morphology.Since grain refinement is the main strengthening mechanism for the ZKX50,the effect of the microstructure refinement on the corrosion rate was studied by applying electron beam processing(EBP)and friction stir processing(FSP)on the ZKX50 cast alloy.To study the effect of the microstructure constituents and their morphology a subsequent solution heat treatment(HT)was applied to the processed samples.The results show that the EBP and FSP lead to a uniform and remarkably refined microstructure of the ZKX50 alloy and homogeneous distribution of the intermetallic phases.The results of electrochemical corrosion tests together with the microstructure characterization show that microgalvanic corrosion is the predominant mechanism that occurs between the Ca2Mg6Zn3 intermetallic phase andα-Mg matrix.According to the results attained through the electrochemical tests,the EBPed-HT ZKX50 alloy shows higher corrosion resistance compared to all other conditions immersed in 0.5 wt.%NaCl solution.The dissolution and spheroidizing of Ca2Mg6Zn3 particles during the solution heat treatment provides higher corrosion resistance mainly by decreasing the microgalvanic corrosion.The microstructure of the heat-treated samples does not show a significant grain coarsening which can degrade the enhancement of the mechanical properties achieved by the EBP and FSP.

Degradation behavior of austenite, ferrite, and martensite present in biodegradable Fe-based alloys in three protein-rich pseudo-physiological solutions

This study investigates the degradation behavior of three distinct Fe-based alloys immersed in three pseudo-physiological solutions.These alloys,which have varied Mn and C contents,include a commercially available Fe-0.15C alloy,namely Fe–C,and two newly developed alloys,that is Fe–5Mn-0.2C(namely Fe–5Mn)and Fe–18Mn-0.6C(namely Fe–18Mn).The aim was to understand the effect of alloying elements and the testing solution on the in-vitro degradation behavior of these Fe-based materials.Static immersion degradation and potentiodynamic corrosion tests were carried out using three pseudo-physiological solutions with albumin supply,that is modified Hanks’saline solution(MHSS),phosphate buffered saline solution(PBS),and sodium chloride solution(NaCl).After two weeks of static immersion,the results revealed that Fe–5Mn,characterized by a mixture of ferrite and martensite,showed the highest degradation rate,while Fe–C,composed solely of ferrite,showed the lowest rate of degradation.The predominant degradation products in MHSS and PBS were phosphates and carbonates.In PBS,these products formed a remarkably stable protective layer on the surface,contributing to the lowest degradation rate.In contrast,porous hydroxides appeared as the main degradation products for samples immersed in NaCl solution,leading to the highest degradation rate.These results provided important insights into the customization of Fe–Mn–C alloys for a range of biomedical applications,meeting a variety of clinical requirements,and highlighting the considerable potential of Fe–Mn–C alloys for biomedical applications.

Biodegradable Zn-2Cu-0.5Zr alloy promotes the bone repair of senile osteoporotic fractures via the immune-modulation of macrophages

Delayed bone-healing of senile osteoporotic fractures remains a clinical challenge due to the alterations caused by aging in bone and immune systems.The novel biomaterials that address the deficiencies in both skeletal cells and immune systems are required to effectively treat the bone injuries of older patients.Zinc(Zn)has shown promise as a biodegradable material for use in orthopedic implants.To address the bone-healing deficiencies in elderly patients with bone injuries,we developed a biodegradable Zn-based alloy(Zn-2Cu-0.5Zr)with enhanced mechanical properties,including a yield strength of 198.7 MPa and ultimate tensile strength of 217.6 MPa,surpassing those of pure Zn and Zn-2Cu alloys.Cytotoxicity tests conducted on bone marrow mesenchymal stem cells(BMSCs)and MC3T3-E1 cells demonstrated that the extracts from Zn-2Cu-0.5Zr alloy exhibited no observable cytotoxic effects.Furthermore,the extracts of Zn-2Cu-0.5Zr alloy exhibited significant anti-inflammatory effects through regulation of inflammation-related cytokine production and modulation of macrophage polarization.The improved immune-osteo microenvironment subsequently contributed to osteogenic differentiation of BMSCs.The potential therapeutic application of Zn-2Cu-0.5Zr in senile osteoporotic fracture was tested using a rat model of age-related osteoporosis.The Zn-2Cu-0.5Zr alloy met the requirements for load-bearing applications and accelerated the healing process in a tibial fracture in aged rats.The imaging and histological analyses showed that it could accelerate the bone-repair process and promote the fracture healing in senile osteoporotic rats.These findings suggest that the novel Zn-2Cu-0.5Zr alloy holds potential for influencing the immunomodulatory function of macrophages and facilitating bone repair in elderly individuals with osteoporosis.

A Comparison of Corrosion Behavior in Saline Environment: Rare Earth Metals (Y, Nd, Gd, Dy) for Alloying of Biodegradable Magnesium Alloys

Rare earth （RE） metals are widely used as the alloying implants. However, corrosion behavior of pure RE elements in biodegradable magnesium alloys as medical metals not only in physiological media but also in chlorinated saline environment is not well understood. In the present work, the RE metals Y, Nd, Gd and Dy are selected to investigate their corrosion behavior in 0.1 mol/L NaCI solution with immersion and electrochemistry techniques. As indicated, corrosion of the currently investigated RE metals is promoted in the order of Dy, Y, Gd and Nd. In terms of electrochemical response, such a sequence correlates with the increased impedance and the decreased corrosion rate （CR）. These RE metals manifest weak ability for passivation in the native surface. Then, reaction with aqueous solution easily happens through the anodic dissolution and cathodic hydrogen evolution. The corrosion products, RE（OH）3, adhered on the surface of RE metals, do not have an appreciable power to resist the reaction proceeding with corrosive chloride ions. In contrast to pure Mg, the RE metals, including Y, Nd, Gd and Dy, exhibit significantly fragile corrosion resistance in saline media. Therefore, with the curr correlation of corrosion resistance between RE-contain ent findings, it is impossible to reveal a well-defined ng Mg alloy and RE metal itself