Development of bioabsorbable zinc-magnesium alloy wire and validation of its application to urinary tract surgeries.

PURPOSE: Metallic medical devices are typically constructed from non-bioabsorbable metals that remains in the body and causes considerable complications. Particularly in the urinary tract, calculus, intractable infection, and misdiagnosis as calculus are often caused by non-bioabsorbable metals. Here, we developed a zinc-magnesium alloy as a new bioabsorbable metal and sought to evaluate the bioabsorbable behavior of zinc and zinc-magnesium alloy in a rat bladder implantation model. METHODS: We prepared zinc-magnesium alloy wires with various proportions of magnesium and investigated the strength, shape retention, formability, and absorbability of these novel materials. Then, we implanted zinc and zinc-magnesium alloy rings formed by the wires into rat bladder. Rats were euthanized at the end of the observation period, and the rings were removed for volume evaluation. Extracted bladder tissues were subjected to histological analysis. RESULTS: The strength of the zinc wire was enhanced by more than fourfold upon the addition of magnesium, without loss of ductility. Linear reduction of ring volume in urine was observed based on the concentration of magnesium within the ring. Nearly all rings were covered with a thin layer of calculus. Histological findings of the transected urinary bladder tissues did not differ among groups. CONCLUSIONS: Zinc-magnesium alloy is a promising candidate for use as a bioabsorbable medical device in the urinary tract.

Novel biodegradable magnesium alloy clips compared with titanium clips for hepatectomy in a rat model.

BACKGROUND: The use of surgical metal clips is crucial for ligating vessels in various operations. The currently available metal clips have several drawbacks; they are permanent and interfere with imaging techniques such as computed tomography (CT) or magnetic resonance (MR) imaging and carry the potential risk of endo-clip migration. We recently developed a novel magnesium (Mg) alloy for biodegradable clips that reduces artifacts on CT imaging. This study aimed to examine the tolerance, biodegradability, and biocompatibility of the Mg alloy clips compared with those of standard titanium (Ti) clips in hepatectomy. METHODS: Thirty Wistar rats were divided into two groups based on the clip used (groups A and B). The vascular pedicle, including hepatic artery, portal vein, bile duct, and hepatic vein of the left lateral lobe, was ligated with the Ti clip in group A or the Mg alloy clip in group B, and then the left lateral lobe was removed. The rats were sacrificed at 1, 4, 12, 24, and 36 weeks after surgery. Clinical and histological evaluations were performed. Absorption rate was calculated by measuring the clip volume. RESULTS: Although the Mg alloy clips showed biodegradability over time, there were no significant differences in the serum concentration of Mg between the two groups. The remaining volume ratio of Mg alloy clips was 95.5, 94.3, 80.0, 36.2, and 16.7% at 1, 4, 12, 24, and 36 weeks, respectively. No side effects occurred. Most of the microscopic changes were similar in both groups. CONCLUSIONS: The new biodegradable Mg alloy clips are safe and feasible in vessel ligation for hepatectomy in a rat model and reduce artifacts in CT imaging compared with the standard Ti clips.

Biodegradation behaviors of magnesium(Mg)-based alloy nails in autologous bone grafts: In vivo study in rabbit skulls.

OBJECTIVE: In this study, autologous bone grafts using bone-fixing nails made of magnesium-zinc-calcium ternary alloys were performed using rabbit skulls. MATERIAL AND METHODS: Two types of nails for bone fixation were prepared: 2.5 mm width, 3 mm length and 2.5 mm width, 2 mm length. A disk-shaped bone with a diameter of 5 mm was resected from the parietal bone and fixed with a 3 mm long nail. As a control group, a 2 mm long nail was driven into the existing bone. The rabbits were sacrificed at 1, 4, 12, and 24 weeks after surgery. The resected samples were observed with micro X-ray CT, and embedded in methyl methacrylate to prepare non-decalcified specimens. The in vivo localization of elements was examined using energy-dispersive X-ray spectroscopy (EDS). RESULTS: Micro X-ray CT images of samples showed volume reduction due to degradation in both the bone graft and control groups. No significant difference in the amount of degradation between the two groups was observed, however characteristic degradation processes were observed in each group. The samples stained with alizarin red S showed amorphous areas around the nails, which were considered as corrosion products and contacted directly with the newly formed bones. EDS analysis showed that corrosion products were mainly composed of magnesium and oxygen at an early stage, while calcium and phosphorus were detected on the surface layer during the long-term observation. CONCLUSIONS: The degradation speed of the magnesium alloy nails varied depending on the shapes of the nails and surrounding tissue conditions. A calcium phosphate layer was formed on the surface of magnesium alloy nails, suggesting that the degradation rate of the nail was slow.

Novel artifact-robust and highly visible zinc solid fiducial marker for kilovoltage x-ray image-guided radiation therapy.

PURPOSE: To develop a novel biocompatible solid fiducial marker that prevents radiopaque imaging artifacts and also maintains high imaging contrast for kilovoltage x-ray image-guided radiation therapy. METHODS: The fiducial marker was made of pure zinc. An in-house water-equivalent phantom was designed to evaluate artifacts and visibility under various simulated treatment scenarios. Image artifacts were quantitatively assessed in terms of the metal artifact index (MAI) on kilovoltage computed tomography (CT) and cone-beam CT (CBCT) scans. Marker visibility was evaluated on two types of kilovoltage planar x-ray images in terms of the contrast-to-background ratio (CBR). Comparisons with a conventional gold fiducial marker were conducted. RESULTS: The use of zinc rather than a gold marker mitigates imaging artifacts. The MAI near the zinc marker decreased by 76, 79, and 77 % in CT, and by 77 (81), 74 (80), and 79 (85) % in CBCT full-fan (half-fan) scans, when using one-, two-, and three-marker phantom settings, respectively. The high-contrast part of the zinc marker exhibited CBRs above 2.00 for 28/32 exposures under four (lung, tissue, low-density bone, and high-density bone) different simulation scenarios, making its visibility comparable to that of the gold marker (30/32 exposures with CBRs > 2.00). CONCLUSIONS: We developed a biocompatible, artifact-robust, and highly visible solid zinc fiducial marker. Although further evaluation is needed in clinical settings, our findings suggest its feasibility and benefits for kilovoltage x-ray image-guided radiation therapy.

In vitro and in vivo analysis of the biodegradable behavior of a magnesium alloy for biomedical applications.

The present study was designed to investigate the biodegradation behavior of Mg alloy plates in the maxillofacial region. For in vitro analysis, the plates were immersed in saline solution and simulated body fluid. For in vivo, the plates were implanted into the tibia, head, back, abdominal cavity, and femur and assessed at 1, 2, and 4 weeks after implantation. After implantation, the plate volumes and the formed insoluble salt were measured via micro-computed tomography. SEM/EDX analysis of the insoluble salt and histological analysis of the surrounding tissues were performed. The volume loss of plates in the in vitro groups was higher than that in the in vivo groups. The volume loss was fastest in the abdomen, followed by the head, back, tibia, and femur. There were no statistically significant differences in the insoluble salt volume of the all implanted sites. The corrosion of the Mg alloy will be affected to the surrounding tissue responses. The material for the plate should be selected based on the characteristic that Mg alloys are decomposed relatively easily in the maxillofacial region.

Initial organ distribution and biological safety of Mg2+ released from a Mg alloy implant.

Magnesium (Mg) alloys are considered promising materials for biodegradable medical devices; however, the initial effects and distribution of released Mg2+ ions following implantation are unclear. This is addressed in the present study, using two types of Mg alloys implanted into rats. An in vitro immersion test was first carried out to quantify Mg2+ ions released from the alloys at early stages. Based on these data, we performed an in vivo experiment in which large amounts of alloys were subcutaneously implanted into the backs of rats for 1, 5, 10, and 25 h. Mg2+ accumulation in organs was measured by inductively coupled plasma mass spectrometry. In vivo, blood and urine Mg2+ concentrations were higher in rats receiving the implants than in controls after 1 h; however, the levels were within clinically accepted guidelines. The Mg2+ concentration in bone was significantly higher in the 25 h implanted group than in the other groups. Our results suggest that homeostasis is maintained by urinary excretion and bone accumulation of released Mg2+ ions in response to sudden changes in Mg2+ ion concentration in the body fluid in a large number of Mg alloy implants at the early stages.

Development of a new biodegradable operative clip made of a magnesium alloy: Evaluation of its safety and tolerability for canine cholecystectomy.

BACKGROUND: Operative clips used to ligate vessels in abdominal operation usually are made of titanium. They remain in the body permanently and form metallic artifacts in computed tomography images, which impair accurate diagnosis. Although biodegradable magnesium instruments have been developed in other fields, the physical properties necessary for operative clips differ from those of other instruments. We developed a biodegradable magnesium-zinc-calcium alloy clip with good biologic compatibility and enough clamping capability as an operative clip. In this study, we verified the safety and tolerability of this clip for use in canine cholecystectomy. METHODS: Nine female beagles were used. We performed cholecystectomy and ligated the cystic duct by magnesium alloy or titanium clips. The chronologic change of clips and artifact formation were compared at 1, 4, 12, 18, and 24 weeks postoperative by computed tomography. The animals were killed at the end of the observation period, and the clips were removed to evaluate their biodegradability. We also evaluated their effect on the living body by blood biochemistry data. RESULTS: The magnesium alloy clip formed much fewer artifacts than the titanium clip, and it was almost absorbed at 6 months postoperative. There were no postoperative complications and no elevation of constituent elements such as magnesium, calcium, and zinc during the observation period in both groups. CONCLUSION: The novel magnesium alloy clip demonstrated sufficient sealing capability for the cystic duct and proper biodegradability in canine models. The magnesium alloy clip revealed much fewer metallic artifacts in CT than the conventional titanium clip.

In vivo corrosion behaviour of magnesium alloy in association with surrounding tissue response in rats.

Biodegradable magnesium (Mg) alloys are the most promising candidates for osteosynthesis devices. However, their in vivo corrosion behaviour has not been fully elucidated. The aim of this study was to clarify the influence of the physiological environment surrounding Mg alloys on their corrosion behaviour. A Mg-1.0Al alloy with a fine-grained structure was formed into plates using titanium (Ti) as a control. These plates were implanted into the subperiosteum in the head, subcutaneous tissue of the back, and in the muscle of the femur of rats for 1, 2 and 4 weeks. The volumes of the remaining Mg alloy and of the insoluble salt deposition and gas cavities around the Mg alloy were determined by microtomography, and the volume losses were calculated. Then, the tissue response around the plates in each implantation site was examined histopathologically, and its relation to the respective volume loss was analyzed. These analyses determined that the Mg alloy was corroded fastest in the head, at an intermediate level in the back, and slowest in the femur. The insoluble salt deposition at the Mg alloy surface had no influence on the volume loss. Gas cavities formed around the Mg alloy at all implantation sites and decreased after 4 weeks. Histopathological examination revealed that the Mg alloy exhibited good biocompatibility, as was seen with Ti. In addition, vascularized fibrous capsules formed around the plates and became mature with time. Notably, the volume loss in the different anatomical locations correlated with capsule thickness. Together, our results suggest that, to facilitate the successful clinical application of Mg alloys, it will be necessary to further comprehend their interactions with specific in vivo environments.

Fabrication of a magnesium alloy with excellent ductility for biodegradable clips.

To develop a biodegradable clip, the equivalent plastic strain distribution during occlusion was evaluated by the finite element analysis (FEA) using the material data of pure Mg. Since the FEA suggested that a maximum plastic strain of 0.40 is required to allow the Mg clips, the alloying of magnesium with essential elements and the control of microstructure by hot extrusion and annealing were conducted. Mechanical characterization revealed that the Mg-Zn-Ca alloy obtained by double extrusion followed by annealing at 673K for 2h possessed a fracture strain over 0.40. The biocompatibility of the alloy was confirmed here by investigating its degradation behavior and the response of extraperitoneal tissue around the Mg-Zn-Ca alloy. Small gas cavity due to degradation was observed following implantation of the developed Mg-Zn-Ca clip by in vivo micro-CT. Histological analysis, minimal observed inflammation, and an only small decrease in the volume of the implanted Mg-Zn-Ca clip confirmed its excellent biocompatibility. FEA using the material data for ductile Mg-Zn-Ca also showed that the clip could occlude the simulated vessel without fracture. In addition, the Mg-Zn-Ca alloy clip successfully occluded the renal vein. Microstructural observations using electron backscattering diffraction confirmed that dynamic recovery occurred during the later stage of plastic deformation of the ductile Mg-Zn-Ca alloy. These results suggest that the developed Mg-Zn-Ca alloy is a suitable material for biodegradable clips. STATEMENT OF SIGNIFICANCE: Since conventional magnesium alloys have not exhibited significant ductility for applying the occlusion of vessels, the alloying of magnesium with essential elements and the control of microstructure by hot extrusion and annealing were conducted. Mechanical characterization revealed that the Mg-Zn-Ca alloy obtained by double extrusion followed by annealing at 673K for 2h possessed a fracture strain over 0.40. The biocompatibility of the alloy was confirmed by investigating its degradation behavior and the response of extraperitoneal tissue around the Mg-Zn-Ca alloy. Finite element analysis using the material data for the ductile Mg-Zn-Ca alloy also showed that the clip could occlude the simulated vessel without fracture. In addition, the Mg-Zn-Ca alloy clip successfully occluded the renal vein. Microstructural observations using electron backscattering diffraction confirmed that dynamic recovery occurred during the later stage of plastic deformation of the ductile Mg-Zn-Ca alloy.