Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study.

PURPOSE: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). PATIENTS AND METHODS: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety. RESULTS: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups. CONCLUSION: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

A facile template-assisted electrodeposition approach to porous Cu/Cu2O nanowires.

Although nanoporous materials have been fabricated by electrodeposition using micelles of P-123 as structure-directing entities, the possible geometry obtained has been limited to nanoporous films. Herein, a novel dual-template assisted electrodeposition method to fabricate Cu/Cu2O porous nanowires (PNs) using polymeric micelles as a soft template and polycarbonate membranes as a hard template is reported. These nanowires consist of a porous skeleton with nanosized pores of 20 nm on average and crystallized ligaments. Morphology, composition, and crystal structure are systematically investigated and the formation mechanism is discussed. The as-deposited Cu/Cu2O PNs are found to exhibit high electrocatalytic activity toward electroreduction of nitrate. At an applied cathodic potential of 0.53 V vs. the reference reversible hydrogen electrode, the selectivity for NH3 conversion is 37.3%. Our approach is anticipated to work for the synthesis of PNs of other materials that could be obtained via electrochemical means.

The Heat Treatment Influence on the Microstructure and Hardness of TC4 Titanium Alloy Manufactured via Selective Laser Melting.

In this research, the effect of several heat treatments on the microstructure and microhardness of TC4 (Ti6Al4V) titanium alloy processed by selective laser melting (SLM) is studied. The results showed that the original acicular martensite α'-phase in the TC4 alloy formed by SLM is converted into a lamellar mixture of α + ß for heat treatment temperatures below the critical temperature (T0 at approximately 893 °C). With the increase of heat treatment temperature, the size of the lamellar mixture structure inside of the TC4 part gradually grows. When the heat treatment temperature is above T0, because the cooling rate is relatively steep, the ß-phase recrystallization transforms into a compact secondary α-phase, and a basketweave structure can be found because the primary α-phase develop and connect or cross each other with different orientations. The residence time for TC4 SLM parts when the treatment temperature is below the critical temperature has little influence: both the α-phase and the ß-phase will tend to coarsen but hinder each other, thereby limiting grain growth. The microhardness gradually decreases with increasing temperature when the TC4 SLM part is treated below the critical temperature. Conversely, the microhardness increases significantly with increasing temperature when the TC4 SLM part is treated above the critical temperature.

Degradation of Bioresorbable Mg-4Zn-1Sr Intramedullary Pins and Associated Biological Responses in Vitro and in Vivo.

This article reports the degradation and biological properties of as-drawn Mg-4Zn-1Sr (designated as ZSr41) and pure Mg (P-Mg) wires as bioresorbable intramedullary pins for bone repair. Specifically, their cytocompatibility with bone marrow derived mesenchymal stem cells (BMSCs) and degradation in vitro, and their biological effects on peri-implant tissues and in vivo degradation in rat tibiae were studied. The as-drawn ZSr41 pins showed a significantly faster degradation than P-Mg in vitro and in vivo. The in vivo average daily degradation rates of both ZSr41 and P-Mg intramedullary pins were significantly greater than their respective in vitro degradation rates, likely because the intramedullary site of implantation is highly vascularized for removal of degradation products. Importantly, the concentrations of Mg2+, Zn2+, and Sr2+ ions in the BMSC culture in vitro and their concentrations in rat blood in vivo were all lower than their respective therapeutic dosages, i.e., in a safe range. Despite of rapid degradation with a complete resorption time of 8 weeks in vivo, the ZSr41 intramedullary pins showed a significant net bone growth because of stimulatory effects of the metallic ions released. However, proportionally released OH- ions and hydrogen gas caused adverse effects on bone marrow cells and resulted in cavities in surrounding bone. Thus, properly engineering the degradation properties of Mg-based implants is critical for harvesting the bioactivities of beneficial metallic ions, while controlling adverse reactions associated with the release of OH- ions and hydrogen gas. It is necessary to further optimize the alloy processing conditions and/or modify the surfaces, for example, applying coatings onto the surface, to reduce the degradation rate of ZSr41 wires for skeletal implant applications.

A Comparison Study on the Degradation and Cytocompatibility of Mg-4Zn-xSr Alloys in Direct Culture.

This article reports the behaviors of bone-marrow-derived mesenchymal stem cells (BMSCs) in the direct culture with four Mg-4Zn-xSr alloys (x = 0.15, 0.5, 1.0, 1.5 wt %), designated as ZSr41A, B, C, and D, respectively; and a systematic comparison on the degradation of the ZSr41 alloys and their biological impact in the direct culture with different cell types in their respective media. The direct culture method, in which cells are seeded directly onto the surface of the sample, was used to investigate cellular responses at the cell-biomaterial interface in vitro. The results showed that BMSCs adhered and remained viable on the surfaces of all ZSr41 alloys, but the faster degrading ZSr41A and ZSr41B alloys showed a significantly lower amount of viable BMSCs adhered to their surfaces. Moreover, BMSCs adhered to the culture plate surrounding the samples were unaffected by the solubilized degradation products from the ZSr41 alloys. The results from the comparison study showed that the in vitro degradation rates of Mg-based biomaterials in different culture systems might be mostly affected by media buffer capacity (i.e., HCO3- concentration), and to a lesser extent, d-glucose concentration. The comparison study also indicated that BMSCs were more robust than H9 human embryonic stem cells and human umbilical vein endothelial cells for screening the cytocompatibility of Mg-based biomaterials. In general, the adhesion and viability of BMSCs at the cell-material interface were inversely proportional to the alloy degradation rates. This study presented a clinically relevant in vitro culture system for screening bioresorbable alloys in direct culture, and provided valuable guidelines for determining the degradation rates of Mg-based biomaterials.

Cytocompatibility and early inflammatory response of human endothelial cells in direct culture with Mg-Zn-Sr alloys.

Crystalline Mg-Zinc (Zn)-Strontium (Sr) ternary alloys consist of elements naturally present in the human body and provide attractive mechanical and biodegradable properties for a variety of biomedical applications. The first objective of this study was to investigate the degradation and cytocompatibility of four Mg-4Zn-xSr alloys (x=0.15, 0.5, 1.0, 1.5wt%; designated as ZSr41A, B, C, and D respectively) in the direct culture with human umbilical vein endothelial cells (HUVEC) in vitro. The second objective was to investigate, for the first time, the early-stage inflammatory response in cultured HUVECs as indicated by the induction of vascular cellular adhesion molecule-1 (VCAM-1). The results showed that the 24-h in vitro degradation of the ZSr41 alloys containing a ß-phase with a Zn/Sr at% ratio ∼1.5 was significantly faster than the ZSr41 alloys with Zn/Sr at% ∼1. Additionally, the adhesion density of HUVECs in the direct culture but not in direct contact with the ZSr41 alloys for up to 24h was not adversely affected by the degradation of the alloys. Importantly, neither culture media supplemented with up to 27.6mM Mg2+ ions nor media intentionally adjusted up to alkaline pH 9 induced any detectable adverse effects on HUVEC responses. In contrast, the significantly higher, yet non-cytotoxic, Zn2+ ion concentration from the degradation of ZSr41D alloy was likely the cause for the initially higher VCAM-1 expression on cultured HUVECs. Lastly, analysis of the HUVEC-ZSr41 interface showed near-complete absence of cell adhesion directly on the sample surface, most likely caused by either a high local alkalinity, change in surface topography, and/or surface composition. The direct culture method used in this study was proposed as a valuable tool for studying the design aspects of Zn-containing Mg-based biomaterials in vitro, in order to engineer solutions to address current shortcomings of Mg alloys for vascular device applications. STATEMENT OF SIGNIFICANCE: Magnesium (Mg) alloys specifically designed for biodegradable implant applications have been the focus of biomedical research since the early 2000s. Physicochemical properties of Mg alloys make these metallic biomaterials excellent candidates for temporary biodegradable implants in orthopedic and cardiovascular applications. As Mg alloys continue to be investigated for biomedical applications, it is necessary to understand whether Mg-based materials or the alloying elements have the intrinsic ability to direct an immune response to improve implant integration while avoiding cell-biomaterial interactions leading to chronic inflammation and/or foreign body reactions. The present study utilized the direct culture method to investigate for the first time the in vitro transient inflammatory activation of endothelial cells induced by the degradation products of Zn-containing Mg alloys.

In vitro interactions of blood, platelet, and fibroblast with biodegradable magnesium-zinc-strontium alloys.

Magnesium (Mg) alloy is an attractive class of metallic biomaterial for cardiovascular applications due to its biodegradability and mechanical properties. In this study, we investigated the degradation in blood, thrombogenicity, and cytocompatibility of Magnesium-Zinc-Strontium (Mg-Zn-Sr) alloys, specifically four Mg-4 wt % Zn-xSr (x = 0.15, 0.5, 1, and 1.5 wt %) alloys, together with pure Mg control and relevant reference materials for cardiovascular applications. Human whole blood and platelet rich plasma (PRP) were used as the incubation media to investigate the degradation behavior of the Mg-Zn-Sr alloys. The results showed that the PRP had a greater pH increase and greater concentration of Mg(2+) ions when compared with whole blood after 2 h of incubation with the same respective Mg alloys, suggesting that the Mg alloys degraded faster in PRP than in whole blood. The Mg alloy with 4 wt % Zn and 0.15 wt % Sr (named as ZSr41A) was identified as the most promising alloy for cardiovascular stent applications, because it showed slower degradation and less thrombogenicity, as indicated by the lower concentrations of Mg(2+) ions released and less deposition of platelets. Additionally, ZSr41 alloys were cytocompatible with fibroblasts in direct exposure culture in which the cells adhered and proliferated around the samples, with no statistical difference in cell adhesion density compared with the blank reference. Future studies on the ZSr41 alloys are necessary to investigate their direct interactions with other important cells in cardiovascular system, such as vascular endothelial cells and smooth muscle cells.

Investigation of magnesium-zinc-calcium alloys and bone marrow derived mesenchymal stem cell response in direct culture.

Crystalline Mg-Zn-Ca ternary alloys have recently attracted significant interest for biomedical implant applications due to their promising biocompatibility, bioactivity, biodegradability and mechanical properties. The objective of this study was to characterize as-cast Mg-xZn-0.5Ca (x=0.5, 1.0, 2.0, 4.0wt.%) alloys, and determine the adhesion and morphology of bone marrow derived mesenchymal stem cells (BMSCs) at the interface with the Mg-xZn-0.5Ca alloys. The direct culture method (i.e. seeding cells directly onto the surface of the sample) was established in this study to probe the highly dynamic cell-substrate interface and thus to elucidate the mechanisms of BMSC responses to dynamic alloy degradation. The results showed that the BMSC adhesion density on these alloys was similar to the cell-only positive control and the BMSC morphology appeared more anisotropic on the rapidly degrading alloy surfaces in comparison with the cell-only positive control. Importantly, neither culture media supplemented with up to 27.6mM Mg(2+) ions nor media intentionally adjusted up to alkaline pH 9 induced any detectable adverse effects on BMSC responses. We speculated that degradation-induced dynamic surface topography played an important role in modulating cell morphology at the interface. This study presents a clinically relevant in vitro model for screening bioresorbable alloys, and provides useful design guidelines for determining the degradation rate of implants made of Mg-Zn-Ca alloys.

Development and evaluation of a magnesium-zinc-strontium alloy for biomedical applications--alloy processing, microstructure, mechanical properties, and biodegradation.

A new biodegradable magnesium-zinc-strontium (Mg-Zn-Sr) alloy was developed and studied for medical implant applications. This first study investigated the alloy processing (casting, rolling, and heat treatment), microstructures, mechanical properties, and degradation properties in simulated body fluid (SBF). Aging treatment of the ZSr41 alloy at 175 °C for 8h improved the mechanical properties when compared to those of the as-cast alloy. Specifically, the aged ZSr41 alloy had an ultimate tensile strength of 270 MPa, Vickers hardness of 71.5 HV, and elongation at failure of 12.8%. The mechanical properties of the ZSr41 alloy were superior as compared with those of pure magnesium and met the requirements for load-bearing medical implants. Furthermore, the immersion of the ZSr41 alloy in SBF showed a degradation mode that progressed cyclically, alternating between pitting and localized corrosion. The steady-state average degradation rate of the aged ZSr41 alloy in SBF was 0.96 g/(m(2)·hr), while the pH of SBF immersion solution increased. The corrosion current density of the ZSr41 alloy in SBF solution was 0.41 mA/mm(2), which was much lower than 1.67 mA/mm(2) for pure Mg under the same conditions. In summary, compared to pure Mg, the mechanical properties of the new ZSr41 alloy improved while the degradation rate decreased due to the addition of Zn and Sr alloying elements and specific processing conditions. The superior mechanical properties and corrosion resistance of the new ZSr41 alloy make it a promising alloy for next-generation implant applications.

In vitro degradation of four magnesium-zinc-strontium alloys and their cytocompatibility with human embryonic stem cells.

Magnesium alloys have attracted great interest for medical applications due to their unique biodegradable capability and desirable mechanical properties. When designed for medical applications, these alloys must have suitable degradation properties, i.e., their degradation rate should not exceed the rate at which the degradation products can be excreted from the body. Cellular responses and tissue integration around the Mg-based implants are critical for clinical success. Four magnesium-zinc-strontium (ZSr41) alloys were developed in this study. The degradation properties of the ZSr41 alloys and their cytocompatibility were studied using an in vitro human embryonic stem cell (hESC) model due to the greater sensitivity of hESCs to known toxicants which allows to potentially detect toxicological effects of new biomaterials at an early stage. Four distinct ZSr41 alloys with 4 wt% zinc and a series of strontium compositions (0.15, 0.5, 1, and 1.5 wt% Sr) were produced through metallurgical processing. Their degradation was characterized by measuring total mass loss of samples and pH change in the cell culture media. The concentration of Mg ions released from ZSr41 alloy into the cell culture media was analyzed using inductively coupled plasma atomic emission spectroscopy. Surface microstructure and composition before and after culturing with hESCs were characterized using field emission scanning electron microscopy and energy dispersive X-ray spectroscopy. Pure Mg was used as a control during cell culture studies. Results indicated that the Mg-Zn-Sr alloy with 0.15 wt% Sr provided slower degradation and improved cytocompatibility as compared with pure Mg control.

Electrodeposition of hydroxyapatite coating on Mg-4.0Zn-1.0Ca-0.6Zr alloy and in vitro evaluation of degradation, hemolysis, and cytotoxicity.

A novel biodegradable Mg-4.0Zn-1.0Ca-0.6Zr (wt %) alloy was successfully produced using a series of metallurgical processes; including melting, casting, rolling, and heat treatment. The hardness and ultimate tensile strength of the alloy sheets increased to 71.2HV and 320 MPa after rolling and then aging for 12 h at 175°C. These mechanical properties were sufficient for load-bearing orthopedic implants. A hydroxyapatite (HA) coating was deposited on the Mg-4.0Zn-1.0Ca-0.6Zr (wt %) alloy using a novel coating process combining alkali heat pretreatment, electrodeposition, and alkali heat posttreatment. The microstructure, composition, and phases of the Mg-4.0Zn-1.0Ca-0.6Zr (wt %) alloy and HA coating were characterized using scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), and X-ray diffraction (XRD). The degradation, hemolysis, and cytocompatibility of the HA-coated and uncoated Mg-4.0Zn-1.0Ca-0.6Zr (wt %) alloy were studied in vitro. The corrosion potential (E(corr)) of Mg-4.0Zn-1.0Ca-0.6Zr alloy (-1.72 V) was higher than Mg (-1.95 V), Mg-0.6Ca alloy (-1.91 V) and Mg-1.0Ca alloy (-1.97 V), indicating the Mg-Zn-Ca-Zr alloy would be more corrosion resistant. The initial corrosion potential of the HA-coated Mg alloy sample (-1.51 V) was higher than the uncoated sample (-1.72 V). The hemolysis rates of the HA-coated and uncoated Mg-4.0Zn-1.0Ca-0.6Zr (wt %) alloy samples were both <5%, which met the requirements for implant materials. The HA-coated and uncoated Mg-4.0Zn-1.0Ca-0.6Zr (wt %) alloy samples demonstrated the same cytotoxicity score as the negative control. The HA-coated samples showed a slightly greater relative growth rate (RGR%) of fibroblasts than the uncoated samples. Both the HA-coated and uncoated Mg-4.0Zn-1.0Ca-0.6Zr (wt %) alloy provided evidence of acceptable cytocompatibility for medical applications.

In vitro degradation and cytocompatibility of magnesium-zinc-strontium alloys with human embryonic stem cells.

Magnesium-based alloys have attracted great interest for medical applications due to their unique biodegradable capability and desirable mechanical properties. When considered for medical applications, the degradation rate of these alloys must be tailored so that: (i) it does not exceed the rate at which the degradation products can be excreted from the body, and (ii) it is slow enough so that the load bearing properties of the implant are not jeopardized and do not conflict prior to and during synthesis of new tissue. Implant integration with surrounding cells and tissues and mechanical stability are critical aspects for clinical success. This study investigated Magnesium-Zinc-Strontium (ZSr41) alloy degradation rates and the interaction of the degradation products with human embryonic stem cells (hESC) over a 72 hour period. An in vitro hESC model was chosen due to the higher sensitivity of ESCs to known toxicants which allows to potentially detect toxicological effects of new biomaterials at an early stage. Four distinct ZSr41 compositions (0.15 wt.%, 0.5 wt.%, 1 wt.%, and 1.5 wt.% Sr) were designed and produced through metallurgical processing. ZSr41 alloy mechanical properties, degradation, and cytocompatibility were investigated and compared to pure polished Magnesium (Mg). Mechanical properties evaluated included hardness, ultimate tensile strength, and elongation to failure. Degradation was characterized by measuring total weight loss of samples and pH change in the cell culture media. Cytocompatibility was studied by comparing fluorescence and phase contrast images of hESCs after co-culture with Mg alloys. Results indicated that the Mg-Zn-Sr alloy with 0.15 wt.% Sr improved cytocompatibility and provided slower degradation as compared with pure Mg.