Binder jetting additive manufacturing of biodegradable Zn

Biodegradable materials avoid second surgeries and long-term associated risks of conventional inert implants. Zn arose as a potential candidate for bioresorbable implants due to its proper degradation behaviour and biocompatibility [1]. However, its low melting point induces uncontrolled porosity in LPBF, promoting the future cracking of the implant. Therefore, new fabrication techniques need to be explored. In this work, binder jetting 3d printing (BJ3P) was studied for Zn powders. The samples were printed and sintered under different conditions. It is concluded that, the increase the temperature almost up to melting point leads to higher densification, at the same time, the rise of temperature provokes the formation and growth of oxidized layer on the surface of the powders

Biodegradable metallic zinc alloys for biomedical applications

Biodegradable metals, such as zinc (Zn) appear to overcome some of the drawbacks of permanent metallic implants. However, the uncontrolled biodegradation of Zn-alloyed materials is still a concern for biomedical applications compromising biocompatibility and mechanical properties. In this work, two strategies based on severe plastic deformation or polymeric coatings are evaluated to overcome degradation drawbacks. Cold-rolled Zn-0.5Mg and Zn-2Ag bars (Goodfellow, UK) were modified as follows: (1) ECAP was performed to the bars, supplying an equivalent strain of 0.76 each pass; (2) PCL was dissolved in chloroform and spin-coated onto the surfaces. The microstructure was observed by SEM/EDS and EBSD. Tensile and nanoindentation tests were performed. The corrosion was studied by PDP and EIS. Fig. 1 shows the microstructure of the as-received alloys. Ultra-fine grain structure was achieved after ECAP (Fig. 2), providing superplastic behavior to the Zn-2Ag alloy (elongation over 200 %). Nanoindentation maps showed similar hardness distribution after ECAP. PCL-coated samples presented a noteworthy decrease in current density (from 15 A/cm2 down to 0.5 A/cm2), and EIS confirmed the effect of the PCL layer with a higher impedance modulus. The influence of the secondary phases on the mechanical reinforcement of Zn was previously studied [1]. However, their presence also forms galvanic pairs and favors localized corrosion, which could provoke the future cracking of the implant. Regarding this, our study showed that PCL coating delays early degradation, while the refined microstructure obtained after ECAP homogenizes further corrosion. Both approaches can be used to control corrosion at different degradation timepoints, fundamental for the proper biointegration of the Zn-based implants

Zn-Mg and Zn-Cu alloys for stenting applications: From nanoscale mechanical characterization to in vitro degradation and biocompatibility

Reproducció del document publicat a: https://doi.org/10.1016/j.bioactmat.2021.04.015In the recent decades, zinc (Zn) and its alloys have been drawing attention as promising candidates for bioresorbable cardiovascular stents due to its degradation rate more suitable than magnesium (Mg) and iron (Fe) alloys. However, its mechanical properties need to be improved in order to meet the criteria for vascular stents. This work investigates the mechanical properties, biodegradability and biocompatibility of Zn-Mg and Zn-Cu alloys in order to determine a proper alloy composition for optimal stent performance. Nanoindentation measurements are performed to characterize the mechanical properties at the nanoscale as a function of the Zn microstructure variations induced by alloying. The biodegradation mechanisms are discussed and correlated to microstructure, mechanical performance and bacterial/cell response. Addition of Mg or Cu alloying elements refined the microstructure of Zn and enhanced yield strength (YS) and ultimate tensile strength (UTS) proportional to the volume fraction of secondary phases. Zn-1Mg showed the higher YS and UTS and better performance in terms of degradation stability in Hanks’ solution. Zn-Cu alloys presented an antibacterial effect for S. aureus controlled by diffusion mechanisms and by contact. Biocompatibility was dependent on the degradation rate and the nature of the corrosion products.Financial support was received from Spanish Government, MINECO/FEDER, (RTI2018-098075-B-C21) and the Agency for Administration of University and Research Grants of the Government of Catalonia (2017SGR-1165). L.C.C. thanks COFUND scheme (GA 712754) and SEV-2014-0425 (2015–2019) for the financial support. Support for the research of M-P.G. was received through the prize “ICREA Academia” for excellence in research, funded by the Generalitat de Catalunya. Authors acknowledge Dr. Daniel Rodríguez-Rius for helping in the corrosion studies and measurement setup

Influence of ECAP process on mechanical, corrosion and bacterial properties of Zn-2Ag alloy for wound closure devices

Actual polymeric wound closure devices are not optimal for load-bearing applications due to the low mechanical properties and the risk of inflammation and bacterial infection mainly produced by multifilament and braided configurations. Biodegradable metallic Zn alloys are promising materials candidates; however, mechanical performance, corrosion behaviour, and biological response should be controlled in order to inhibit the risk of inflammation and bacterial infection. To this end, a Zn-2Ag (2 wt% Ag) alloy was processed by ECAP to evaluate the concurrent combined effect of grain refinement and Ag alloying on biodegradation and antibacterial activity. Two ECAP cycles were successfully applied to a Zn-2Ag alloy obtaining a homogeneous ultra-fine-grained structure in which nanoindentation maps suggested isotropic mechanical properties. Lower UTS and YS with higher elongation was reported after ECAP with similar corrosion rates as before processing. ECAP processed samples showed a homogeneous Ag+ release below the minimum inhibitory concentration for S. Aureus and no antibacterial effect was observed by diffusion. As expected, the presence of Ag in Zn-Ag alloys reduced bacterial attachment. Nevertheless, ECAP processed Zn-2Ag provided an excellent antibacterial activity after 3 h probably caused by the uniformly degraded and thus, non– stable, surface observed after bacterial adhesion.Peer ReviewedPostprint (published version

Bioresorbable Zn-based alloys for biomedical applications

Tesi amb menció internacional(English) Biodegradable metals emerged as promising materials for bioresorbable devices avoiding the potential side effects of permanent implants. Among them, zinc (Zn) arose dueto its suitable degradation rate for biomedical application, but it needs to be alloyed for mechanical reinforcement via sol id precipitation hardening. However, the secondary phases lead to galvanic corrosion and poor biocompatibility. So far, the compromise among mechanical strength, corrosion rate, and biological response of Zn alloys remains unknown. This PhD Thesis aims to gain an increased understanding of Zn-based alloys for biomedical applications, establishing correlations between Zn matrix and secondary phases and controlling corrosion behaviour and in vitro biological response. Chapter I characterized Zn-xMg (x = 0.5, 1 wt. %) and Zn-xCu (x = 3, 5 wt.%) alloys for bioresorbable cardiovascular stents. Tensilé tests confirmed that alloying with Mg or Cu significantly increased the yield strength (YS), ultimate tensile strength (UTS), and elongation at fracture. Nanoindentation tests confirmed mechanical reinforcement dueto the precipitation of Zn+Mg2Zn11 and E-CuZn5 phases for Zn-Mg and Zn-Cu, respectively. Degradation tests in Hanks' solution indicated the formation of galvanic pairs between secondary phases and Zn matrix. Zn-Cu alloys presented antibacterial activity against S. aureus and P. aeruginosa, but cytotoxicityto endothelial cells (ECs). AII the alloys reported poor biocompatibility, attributed to local ions release into solution and degrading surfaces. Among all the samples, Zn-Mg alloys presented the best compromise among mechanical, corrosion, and biological properties. Chapter II characterized Zn-xAg (x= 2, 4 wt. %) alloys for bioresorbable ureteral stents. Tensile tests evidenced the mechanical reinforcement of Zn-Ag alloys compared with pure Zn, where the higher AgZn3 volume fraction of Zn-4Ag led to reduced UTS and YS than Zn-2Ag alloy. Moreover, the galvanic couple between AgZn3 and Zn of Zn-4Ag alloy resulted in severe localizad corrosion, where bacteria could infiltrate the corrosion pits hampering the antibacterial effect. In summary, Zn-2Ag presented a better degradation performance and optimal antibacterial effect. Chapter III proposed a dual-action coating for Zn-0.5Mg and Zn-2Ag alloys to control corrosion and enhance endothelialisation in cardiovascular stents. First, a pol}Caprolactone (PCL) coatir.ig was implemented on the alloys bycold plasma polymerization of E-caprolactone and PCL spin-coating. Secondly, the PCL-coated alloys were functionalized with RGD (Arg-Gly-Asp), REDV (Arg-Glu-Asp-Val), and RGD-REDV peptides synthesized via solid solution and covalently immobilized via EDC/NHS chemistry. A homogeneous PCL coating of 800 nm with good adhesion strength provided adequate corros ion resistance to both alloys. ECs successfullyadhered to the functionalized surfaces, where the RGD­ REDVplatform presented a significant increase in cell number, deinonstrating the synergistic effect of RGD and REDV peptides. Chapter IV proposed equal channel angular pressing (ECAP) (two C}Cles, route Be; R.T.) to homogenise Zn-2.Ag corrosion. Ultrafine-grained structure and randomlydistributed textura was obtained after ECAP, with no evident AgZn3 breaking or distribution. Nanoindentation mapping indicated mechanical isotropy, and corrosion studies suggested more uniform degradation after ECAP. Moreover, the exceptional antibacterial activity against S. aureus was attributed to the reduction of corrosion pits and distribution of Ag through the matrix. Overall, the ECAP process acted as a potential technique for homogenising the mechanical and corrosion properties of Zn-Ag alloys with excellent antibacterial properties. In summary, PhD Thesis provided relevant clues into the proper Zn·based formulation and coating and deformation strategies to overcome the instrinsic galvanic corrosion of Zn alloys for different biomedical applications.(Español) Los metales biodegradables son investigados como potenciales materiales para implantes reabsorbibles. Entre ellos, el zinc (Zn) destaca por su adecuada velocidad de degradación para-aplicaciones biomédicas. No obstante, requiere ser aleado para su endurecimiento por precipitación, donde la formación de pares galvánicos entre la matriz y las fases secundarias empeoran la degradación y la biocompatibilidad del Zn. Actualmente no se ha descubierto el balance adecuado entre resistencia del material, degradación, y respuesta biológica. Esta Tesis Doctoral tiene como objetivo lograr una mayor comprensión de las aleaciones de Zn para aplicaciones biomédicas, estableciendo relaciones entre la matriz de Zn y las fases secundarias, así como controlando la corrosión y la respuesta biológica in vitro. El Capítulo I estudia las aleaciones Zn-xMg (x = 0.5, 1 %) and Zn-xCu (x = 3, 5 %) para stents cardiovasculares reabsorbibles. Los ensayos de tracción confirmaran el aumento en el limite elástico (oe), la resistencia máxima a la tracción (om) y alargamiento de rotura (AR) al alear el Zn con Mg o Cu. Las medidas de nanoindentación demuestran que el endurecimiento es consecuencia de la precipitación de Zn+Mg2Zn11 en Zn-Mg y E-CuZn5 en Zn-Cu. Se observan además pares galvánicos entre las fases secundarias y la matriz de Zn en los ensayos de degradación. Las aleaciones con Cu presentan efecto antibacteriano contra S. aureus y P. aeruginosa, ycitotoxicidad sobre las células endoteliales (ECs). En resumen, las aleaciones de Zn-Mg presentan el mejor.balance entre propiedades mecánicas, corrosión y biocompatibilidad. El Capítulo II valora las aleaciones Zn- (x = 2, 4 %) para stents ureterales reabsorbibles. Las pruebas de tracción evidencian el endurecimiento de las aleaciones respecto al Zn puro, donde el mayor porcentaje en volumen de .A(¡Zn3 en Zn-4.A(J causa una reducción en oe yom respecto a Zn-2.A(J. Asimismo, los huecos originados en la corrosión por el par galvánico Zn-.A(¡Zn3 en Zn-4.A(J pueden ser penetrados por S. aureus y E. coli, disminuyendo su actividad antibacteriana. En conclusión, Zn-2.A(J presenta un adecuado comportamiento frente a _la corrosión yun óptimo efecto antibacteriano. El Capítulo III propone un recubrimiento en las aleaciones de Zn-0,5Mg yZn-2.A(J para controlar la corrosión y mejorar la endotelialización en stents cardiovasculares. Primero, se recubren las muestras con policaprolactona (PCL) mediante polimerización con plasma frío de E-caprolactona yspin coating de PCL. En segundo lugar, las aleaciones recubiertas se funcionalizan con los péptidos RGD (Arg-Gly-Asp),REDV(Arg-Glu-Asp-Val) yRGD-REDVsintetizados mediante solución sólida e inmovilizados covalentemente por química EDC/NHS. Se obtiene una capa homogénea de PCL de 800 nm de grosor, con buena adherencia y resistencia a la corrosión en ambas aleaciones. Las ECs se adhieren con éxito a las superficies funcionalizadas, donde la plataforma RGD-REDVpresenta un aumento significativo en el número de células, demostrando así el efecto sinérgico de los péptidos lineales RGD y REDV. En el Capitulo IV se presenta la extrusión en canal angular constante (ECAP) (dos pases, ruta Be; temperatura ambiente) de Zn-2.A(J. Después del ECAP, se obtiene una microestructura de grano ultrafino y una distribución aleatoria de la orientación de grano, sin dispersión evidente de .A(¡Zn3. La técnica de nanoindentación muestra isotropía mecánica, y los estudios de corrosión confirman una degradación más uniforme después de ECAP. Además, la reducción de la corrosión localizada y la distribución de .A(¡ en la matriz de Zn confieren a la muestra de un excepcional efecto antibacteriano contra S. aureus. En resumen, la presente Tesis Doctoral proporciona información relevante para el diseño de aleaciones de Zn, así comp diferentes estrategias de recubrimiento y deformación para mejorar su comportamiento frente a la corrosión y mejorar su respuesta biológica en diversas aplicaciones biomédicas.DOCTORAT EN CIÈNCIA I ENGINYERIA DELS MATERIALS (Pla 2012

Influence of ECAP process on mechanical, corrosion and bacterial properties of Zn-2Ag alloy for wound closure devices

Actual polymeric wound closure devices are not optimal for load-bearing applications due to the low mechanical properties and the risk of inflammation and bacterial infection mainly produced by multifilament and braided configurations. Biodegradable metallic Zn alloys are promising materials candidates; however, mechanical performance, corrosion behaviour, and biological response should be controlled in order to inhibit the risk of inflammation and bacterial infection. To this end, a Zn-2Ag (2 wt% Ag) alloy was processed by ECAP to evaluate the concurrent combined effect of grain refinement and Ag alloying on biodegradation and antibacterial activity. Two ECAP cycles were successfully applied to a Zn-2Ag alloy obtaining a homogeneous ultra-fine-grained structure in which nanoindentation maps suggested isotropic mechanical properties. Lower UTS and YS with higher elongation was reported after ECAP with similar corrosion rates as before processing. ECAP processed samples showed a homogeneous Ag+ release below the minimum inhibitory concentration for S. Aureus and no antibacterial effect was observed by diffusion. As expected, the presence of Ag in Zn-Ag alloys reduced bacterial attachment. Nevertheless, ECAP processed Zn-2Ag provided an excellent antibacterial activity after 3 h probably caused by the uniformly degraded and thus, non– stable, surface observed after bacterial adhesion

Evolution over Time of Ventilatory Management and Outcome of Patients with Neurologic Disease∗

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease