Safety Evaluation for Nickel Release of Nickel–Titanium alloys Cardiovascular stents

Safety Evaluation for Nickel Release of Nickel–Titanium alloys Cardiovascular stents | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Safety Evaluation for Nickel Release of Nickel–Titanium alloys Cardiovascular stents Bin Liu, Yafan Hu, Kai Xu, Bo Zhang, Dong Liu, Changyan Wu, Xiuyun Han, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4057011/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Nickel (Ni) is a major element of several alloys for implantable cardiovascular devices (stents and blockers).Due to the lack of reliable research models, there is no domestic and international evaluation system for Ni release in the medical device field before 2018.Now, there are some standards such as ASTM F3306-19 and ISO 10993 appeared. They should help us to control and analyze the Ni ion release from the implant medical devices. But all these standards are short of a solution that it can take the place of the complex simulated body solutions and blood, serum. Our aim is to discover the easy solution. It should make the evaluation of Ni release easy to do. Nickel-Titanium (NiTi) cardiovascular alloy products with registration certificate in National Medical Product Administration in China were chosen as samples in the investigation. In this study, C, H, N, O was measured by oxygen, nitrogen and hydrogen elements analyzer and mental element content was determined by Electron - coupled plasma atomic emission spectrometry (ICP-AES). While corrosion resistance was evaluated by electrochemistry. Ni release curves were plotted by measuring the amount of Ni released from seven extraction media. All the metallic and non-metallic content of samples were qualified with GB24627-2009. Wilcoxon Test showed that HCl was identified as a possible alternative to blood. The extraction medium was determined to be 10mL 0.005% HCl with a limit 50μg /d while time was 7 consecutive days with the temperature at 37°C.It was proved with a high degree of specificity and reliability. The evaluation guideline provides technical support for the review and regulatory authorities, and is of great significance in improving the quality and safety of such products, providing guidance for the standardized development of the Ni-Ti alloy cardiovascular product industry in China, with significant social benefits. Ni release safety evaluation extraction media Ni-Ti alloys cardiovascular stents in vitro Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Ni-Ti alloys are used in many medical devices in the human body, including cardiovascular blockers and stents, due to their unique strong elasticity and shape memory properties[1]. However, the Ni element in them is a carcinogen[2].According to relevant reports, Ni in jewelry and textile clothing is prone to cause Ni allergic reactions in human skin. Ni is the most common allergenic metal, about 20% of people are allergic to Ni, and the number of female patients is higher than that of male patients. Once sensitization occurs, Ni allergy can persist indefinitely. The Ni released by long-term implantation of NiTi alloy, because of its direct contact with human blood organs and tissues, may bring more serious harm to patients compared to skin and gastrointestinal absorption[3-6], therefore, more attention should be paid to its safety issues. The international jewelry and textile industry has discovered the allergic reaction of Ni and promulgated relevant regulations to avoid its risk. Based on their experiences, it is very necessary to establish a safety evaluation system for Ni in the field of medical devices. The release of Ni from cardiovascular devices made of Ni-Ti alloys that are implanted in the human body for long periods of time has caused widespread concern in recent years[7-9]. The domestic NiTi alloy cardiovascular products have developed rapidly, and the domestic market was almost zero before 2000. With the influx of imported products into Chinese market, domestic manufacturers have obtained some technical factors of this kind of products and began to make the same products themselves. Gradually it breaks the monopoly position of foreign products, and also make lower price of such products, so that the poor can also afford this kind of products. In recent years，release of implanted Ni has received attention from regulatory authorities, including Food and Drug Administration (FDA)[10]. For the quality control of this kind of products, the regulatory authorities only control the quality from the raw materials of NiTi alloy, such as GB24627-2009, the corresponding standard is ASTM F2063-18, and the quality is controlled with by the content of various elements in NiTi alloy. Later, with the gradual maturity and development of products, the requirements for products are becoming more and more stringent. With the implementation of ISO16429:2004 in the world, it is required to evaluate the long-term corrosion behavior of metal implant materials, and the main evaluation indexes are corrosion potential and open-circuit potential. The national standard was introduced into domestic standard YY/T 1552-2017. The relevant standard in the United States is ASTM F2129-06, and the evaluation index is a cyclic polarization curve of the product under certain PH condition, which is difficult to interpret (there are three forms, one is the material that shows the protective potential, one is the material that does not show the protective potential, and the other is the material with oxidation on the surface), which is transformed into the domestic standard YY/T0695-2008.Corrosion resistance indicators[11] are currently used to evaluate the risk of unintended corrosion leading to the release of elements from metallic materials into the human body to produce adverse reactions. However, this method is not specific in terms of physiological environment simulation, such as the blood environment, and does not address qualitative and quantitative of the potential risk. Therefore, this issue is currently of more concern to regulatory authorities, which has also received attention in recent years[12], including the U.S. FDA review department, but due to the lack of reliable research models, there are no relevant evaluation standards or guidelines This study proposes to find an extraction medium that can replace blood for simulated extraction tests to specifically and safely evaluate the performance of Ni release from Ni-Ti products in vitro, and to develop an evaluation system for Ni-Ti alloy cardiovascular devices so as to provide effective evaluation guidelines for government regulation and management to evaluate the safety of such products. The introduction should briefly place the study in a broad context and highlight why it is important. It should define the purpose of the work and its significance. The current state of the research field should be carefully reviewed and key publications cited. Please highlight controversial and diverging hypotheses when necessary. Finally, briefly mention the main aim of the work and highlight the principal conclusions. As far as possible, please keep the introduction comprehensible to scientists outside your particular field of research. References should be numbered in order of appearance and indicated by a numeral or numerals in square brackets—e.g., [1] or [2,3], or [4–6]. See the end of the document for further details on references. 2. Materials and Methods 2.1 Materials HNO 3 was obtained from J.T. Baker, USA; Ni, Ti, Co, Cr, Cu, Fe, Nb standard solutions were purchased from Central Iron & Steel Research Institute，China ; Ni-Ti and Ni-Cr wires were obtained from SHSMA ，China; goat blood was purchased from Yudo Biotech ，China; goat serum was purchased from Yudo Biotech ，China; phosphate buffer solution （PBS ）was purchased from Sigma, USA; Hydrochloric acid(HCl) was purchased from J.T. Baker, USA. Four alloys that cardiovascular implants were selected for this study ：Samples S1: Left Atrial Appendage occluder (LAAO) was obtained from LAFDQ-26, Shsma ,China; S2: LAAO was obtained from YFD Q-27-1, Ydb med, China; S3: Ventricular septal defect occluder (VSDO) was obtained from WXVSDMD-22 ，Visee,china; S4:atrial septal defect occluder （ASDO ）was obtained from Shsma, China; S5:Nickel-Nitium wires were obtained from Shsma ,China ; S6:Nickel-Chromium wires were obtained from market. 2.2 Determination of the C, H, N, O content The carbon(C) content was measured by Carbon-Sulfur elements analyzer (CS800, Eltra, Germany), 6 samples were used for each S1, S2. Oxygen(O), nitrogen(N) and hydrogen(H) were measured by oxygen, nitrogen and hydrogen elements analyzer (Onh600, Eltra, Germany). 8 samples were used for each S1, S2. They were calibrated according to the content of the elements C, O, N and H in “Standard Specification for Wrought Ni-Ti Shape Memory Alloys for Medical Devices and Surgical Implants” GB24627-2009[13]. YSB C11140-2007 was selected as the standard for the determination of C; the AR650 was selected as the standard for the determination of O, N and H elements. 2.3 Determination of metal element content The metal content was determined by electron-cloupled plasma atomic emission spectrometry (ICP-AES) with modifications[14]. Weigh 0.20 g of Ni-Ti alloy S1 and S2, (each S1sample’s weight is 0.56647g, each S2 sample’s weight is 0.46855g, so S1 and S2 must to be divided into small parts) place them in poly tetra fluoroethylene (PTFE) digestion tank, add 10 mL of aqua regia, mix well, soak overnight and place in an ultra-high pressure microwave system (Multiwave Pro, Austria), see Table 1 for digestion parameters. The solution was transferred to a 25 mL measuring flask with 2% HCl and diluted to the scale with shaking. The same method was used to prepare the reagent blank solution as a blank correction. The standard solutions of Ni, Ti, Co, Cr, Cu, Fe and Nb were all pipetted separately at 1,000 mg/L and diluted with 2% HNO 3 to make a mixed standard stock solution containing 10 μg/mL of Ni, Ti, Co, Cr, Cu, Fe and Nb. The mixed standard stock solution was diluted with 2% HNO 3 to make the control solution containing 0.1 μg/mL, 0.2 μg/mL, 0.5 μg/mL, 1.0 μg/mL and 2.0 μg/mL of Ni, Ti, Co, Cr, Cu, Fe and Nb respectively. Prepared and used as needed. The test solution and the control solution were taken in appropriate amounts and analyzed using ICP (Thermo, USA) with a pump speed of 50 rpm; RF frequency of 27.12 MHz; RF power of 1150 w; auxiliary gas of 0.5 L/min; glass concentric atomizer with a cyclonic fog chamber; and wavelengths of Ni 221.647 nm, Cr 283.616 nm, Cu 324.754 nm, Fe 259.940 nm, Nb 309.418 nm, Co 228.616 nm, Cu 324.754nm, Fe 259.940nm, Nb 309.418nm and Co 228.616nm. The net intensity value was used as the integration method and calculated. Table 1. Microwave digestion conditions for Ni-Ti products stage power/W ramp time/ min temperature/℃ holding time/s 1 1600 5 120 3 2 1600 6 150 2 3 1600 6 180 20 2.4 Corrosion resistance The sample to be tested is placed in a suitably De-oxygenated phosphate buffered saline (PBS) solution and the resting potential (Er) is recorded for 1h, followed by a scan in the anodic direction or forward from Er. When the peak potential is reached or the current density reaches two orders of magnitude of the current density corresponding to the breakdown potential (Eb), the scan is reversed. The reverse scan stops when the current density is less than the value in the forward scan or when the potential reaches Er. 2 samples were used for each S1,S3,S4. 2.5 Screening of extraction media Weigh 1.2 g of Ni-Ti wire (S5) and add 12 mL of goat blood and goat serum respectively; weigh 2.0 g of Ni-Ti wire(S5) and add 20 mL of 1% HNO 3 , 1% HCL, PBS, artificial simulated body fluid (MBF ) and water respectively. Shake at 37°C, 180 r/min and remove all the extraction medium at 1, 6, 24, 48, 72, 120 and 168 h. Then extracting medium was replenished with fresh extracting medium and shaking was continued. 2.5.1 Determination of Ni in goat blood The standard stock solution containing 1.0 μg /mL was prepared and diluted three times with water to make a control solution containing 0. 01 μg/mL, 0. 05 μg/mL, 0.15 μg/mL, 0.3 μg/mL and 0. 5 μg/mL of Ni. Prepared and used as needed. 2 ml of goat blood was measured and placed in PTFE digestion tank. Add 5 mL of HNO 3 and 2 mL of H 2 O 2 , mix well, soak overnight, place in a microwave digestion system and digest according to the procedure in Table 2. After digestion, the inner jar was removed and placed on an electric heater, heated at 120°C until the red-brown vapor evaporated and nearly dried, transferred to a 25 mL measuring flask with three times water and diluted to the scale, shaken well and used as the test solution. The same method was used to prepare a reagent blank solution as a blank correction. Table 2. Microwave digestion conditions for goat blood stage power/W ramp time/ min temperature/℃ holding time/s 1 900 5 120 3 2 900 6 150 2 3 900 6 180 90 2.5.2 Determination of Ni in goat serum The ICP working conditions were the same as in method 2.3, and control solutions containing 0. 02 μg /mL, 0. 05 μg /mL, 0. 15 μg /mL, 0. 3 μg /mL and 0. 5 μg /mL of Ni were prepared using the dilution method. Prepared and used as needed. The solution of the test sample was prepared by taking 5 mL of goat serum extract, fixing it with three times of water into a 20 mL measuring flask and shaking well. In the same way, 5 mL of blank goat serum was fixed into a 20 mL flask and used as blank calibration. 2.5.3 Determination of Ni in 1% HNO 3 The ICP working conditions were the same as in method 2.3, and the control solution was the same as in method 2.5.1. 1% HNO 3 was diluted one hundredfold and then directly injected into the sample. 1% HNO 3 was used as a blank calibration. 2.5.4 Determination of Ni in 1% HCl A control solution containing 10 μg /mL, 20 μg /mL, 40 μg /mL, 80 μg /mL and 100 μg /mL was prepared using the same ICP working conditions as in method 2.3. The 1% HCl extract was fed directly into the sample and 1% HCl was used for the blank. 2.5.5 Determination of Ni in PBS The ICP working conditions were the same as method 2.3 and the control solution was the same as method 2.5.1. The PBS extract was injected directly and the blank was used directly with PBS. 2.5.6 Determination of Ni in SBF The ICP working conditions were the same as method 2.3 and the control solution was the same as method 2.5.1. The SBF were injected directly into the sample and the blank was used directly with SBF. 2.5.7 Determination of Ni in water The ICP working conditions were the same as method 2.3 and the control solution was the same as method 2.5.1. The aqueous extract was directly injected and the blank was directly used with water. The Ni content in the extracted medium was calculated by integrating the net intensity value. 2.6 Recovery of Ni from extraction media Precisely measure 2.0mL of goat blood extract and add 1,000 μg/mL of Ni standard stock solution 2.5μL and 25μL to the solution for determination according to the aforementioned preparation method and ICP conditions. Precisely measure 2mL of goat serum extract and add 2.0 μL of 1000 μg/mL of Ni standard stock solution; Precisely measure 1mL of 1% HNO 3 extract and add 50μL of 1,000 μg/mL of Ni standard stock solution; Precisely measure 10mL of 1% HCl extract and add 10μL of 1,000 μg/mL of Ni standard stock solution; Precisely measure 10mL of PBS 10 mL of PBS extract and add exactly 5 μL of 1000 μg/mL of Ni standard stock solution. Precisely measure 10mL of SBF extract and add 5μL of Ni standard stock solution at 1000 μg/mL; precisely measure 10mL of the water extract and add 10μL of Ni standard stock solution at 1000 μg/mL. The Ni content was determined according to the aforementioned method of preparation of the test solution and ICP conditions. 2.7 Confirmation of HCl concentration HCl at 0.01%, 0.05%, 0.1%, 0.2%, 0.005% and 0.007% by mass were prepared and the extracts were removed at 1, 6, 24, 48, 72, 120 and 168 hours and stored in the refrigerator while being replenished with fresh extracts. The amount of Ni in the hydrochloric acid extracts was determined for each concentration according to the procedure in 2.4.3.6 and the total amount of Ni released at each time point was calculated. The samples are Ni-Ti wire(S5). 2.8 Microscopic observation of samples A field emission scanning electron microscope (EM) (model Hitachi SU8010) was used to observe the secondary electron image morphology of the sample at a voltage of 1 kV at a magnification of between 500x and 1000x. 2.9 Specificity verification The 0.005% HCl extraction medium was used to extract a Ni-chromium alloy, Cr15 Ni60(S6), at the same extraction ratios and under the same extraction conditions as a comparison, and its solution was taken at 1, 6, 24, 48, 72, 120 and 168h to determine the concentration of Ni and to find the total release versus time release curve, compared to the release curve of a Ni-Ti alloy under the same conditions. 2.10 Safety evaluation The samples were then incubated in a constant temperature shaker at 37°C,180r/min. 41 days after the investigation period, the extracts were removed and the Ni content of the extracts was measured by ICP to calculate the daily release of Ni from the product. The ICH regulations state that the maximum intravenous dose of Ni is 20μg/day, and this was used as a benchmark to investigate the safety of Ni release from the product. 2 samples were used for each S1, S3, S4. This was used as a benchmark to investigate the safety of Ni release. 2.11 Statistical analysis Statistical analysis was performed using GraphPad Prism（version 8.0.1）. p value < 0.05 was considered statistically significant (Wilcoxon Test). n=3. 3. Results 3.1 Determination of C, H, N, O and metal elements Table 3. the standard curve and correlation coefficient of Ni、Ti、Co、Cr、Cu、Fe、Nb Element Standard curve equation Density scope ug/mL Correlation coefficient Ni-221 Y=1710X+1.609 0~2. 0 1.0000 Ti-334 Y=12050X+8.186 0~2. 0 0.9999 Co-228 Y=1910X-1.348 0~2.0 1.0000 Cr-283 Y=4605X+27.59 0~2.0 1.0000 Cu-324 Y=4956X+13.29 0~2.0 1.0000 Fe-259 Y=2737X+12.23 0~2. 0 1.0000 Nb-309 Y=2803X-21.21 0~2. 0 0.9985 Table 4. the limits of detection and the limits of quantification about Ni、Ti、Co、Cr、Cu、Fe、Nb Table 5. Ni-Ti alloy cardiovascular products with C, H, N, O and metal elements S1:LAAO ( LAFDQ-26, Shsma ， China); S2: LAAO ( YFD Q-27-1, Ydb med, Ch ina). n=3 The table 5 above illustrates the element of Ni-Ti alloys. The results of S1 and S2 were in full compliance with the provisions of GB24627-2009, where the elemental content of metallic Ni was below 57.0%. The standard curves for the samples are shown in Table 3, the limits of detection and the limits of quantification are shown in Table 4. 3.2 Evaluation of corrosion resistance A represents rest potentials; b represents breakdown potentials. Before means the original sample; after means the samples were extracted by PBS. Er means the resting potentials; Eb means breakdown potentials.S1: LAAO, (LAFDQ-26, Shsma, China); S3: VSDO (WXVSDMD-22,Visee, China); S4: ASDO (Shsma, China).1 and 2 means different batches of the same type of sample. Fig.1a shows that there is no significant difference of rest potentials before and after extraction in simulated media in vitro. Fig.1b shows that the breakdown potential increases after extraction, with the exception of sample S3-1. It is suggested that S3 has better corrosion resistance. 3.3 Recovery rate of extraction media Table 6. Recovery of Ni in different media extraction media recovery rate /% goat blood 97.5±1.36 goat serum 89.3±0.80 1% HNO 3 100.76±0.74 1% HCL 91.64±1.80 PBS 110.48±0.78 SBF 85.22±0.13 H 2 O 110.74±0.95 As shown in Table 6, the spiked recoveries of Ni metal ranged from 85.22 % to 110.74%，indicating that the results were accurate and reliable for the seven media measured by the three methods of digestion, dilution and direct injection. 3.4 Nickel release curves from samples From the release time curves of the Ni content in the seven extraction media (Fig.2), it is evident that 1% HNO 3 and 1% HCl, as the extraction media examined in vitro, have a very large release of Ni compared to goat blood and cannot be used as reference extraction media. Goat blood, as the closest physiological environment to the body, is undoubtedly the most ideal extraction medium to examine in vitro, but its non-storability and complex matrix nature promoted us to look for solutions comparable to its Ni release as a reliable extraction medium to examine the safety of Ni release risk. The difference in Ni release between water, PBS and SBF was not significant, however, compared to goat whole blood, the Ni release from goat whole blood was 3-4 times higher than that from water, PBS and SBF, so water, PBS and SBF were not suitable as media for investigating extraction in vitro. Considering the safety and simplicity of preparation, HCl was chosen as the extraction medium, but and further dilution of 1% HCl was required to investigate whether the release of Ni at 168h was compared to that of goat blood at 168h. From Fig.3, it can be seen that the Ni release at a reduced HCl concentration of 0.01% was still more than 6 times the Ni release from goat blood, and continued to dilute the HCl to 0.005% and 0.007% to examine the Ni release. From the above results, it can be seen that the mass percentage concentration of 0.005% HCl, its Ni release at 168h is 2.55 of the release from goat blood. Considering the error, offset and addition of strict, so 0.005% HCl was chosen as the best extraction medium, which can completely and effectively replace goat whole blood, to examine the biosafety evaluation of Ni-Ti metal implanted into human body. 3.5 EM observation of the surface morphology of Ni-Ti alloy wires in seven extraction media (a) Unleached NiTi wire (b) Goat blood (c) Goat serum (d) 1% HNO 3 (e)1% HCl (f)PBS (g)SBF(h)H 2 O (i)0.005% HCl As can be seen in Fig.4, the Ni-Ti wire corroded most severely in the 1% HNO 3 and 1% HCl extraction media, with the surface layer showing severe peeling. In the goat blood Ni-Ti wire surface appears more obvious corrosion spots, in 0.005% HCl also have more serious corrosion surface, other extraction media surface smooth, no obvious corrosion characteristics. It can also be seen from Fig.1 that the Ni-Ti wire precipitated the most Ni in the 1% HNO 3 and 1% HCl extraction media, which is consistent with the EM photographs of its most severe corrosion. There was also a higher release of Ni from goat blood, so there were also more obvious corrosion spots in the electron micrographs, while in the other media there was a small amount of Ni precipitation, but no obvious corrosion in the electron micrographs and the surface was smooth. Fig 5 compares the experimental data on different alloys. Under the same extraction medium of 0.005% HCl and the same extraction conditions of 37°C and 180 r/min, the release of Ni from Ni-Cr and Ni-Ti alloys is very different, with Ni-Ti being more than 10 times the release rate of Ni-Cr. Therefore, the media selected for this method and the associated experimental conditions and evaluation criteria are closely related to the type of alloy tested and are clearly specific. 3.7 Evaluation of safety Table 7. Nickel release in 0.005%HCl S1: LAAO (LAFDQ-26, Shsma, China); S3: VSDO (WXVSDMD-22, Visee, China); S4: ASDO (Shsma, China). Table 8. Sample S3 and S4 nickel release in 0.005%HCl Table 8、Fig.6 and table 6 provides the summary statistics for total and daily Ni release of different samples. According to the permitted daily exposure（PDE）value for Group III elements in ICH-Q3D[15], the PDE value for Ni is 20 μg/day. The total release of Ni from sample S1 for 41 days was less than 2 μg, which is clearly safe. The total Ni release for samples S3 and S4 for forty-one days was over seventy to eighty micrograms respectively, with the average daily release not exceeding the maximum limit of 20 μg/day, but it is to be further confirmed whether the exact daily release exceeds 20 μg/day. In order to further evaluate whether the daily release of Ni from samples S3 and S4 exceeded the limit value of 20 μg/day, samples S3 and S4 were taken for daily Ni release extraction experiments and the results are shown in table 6the graph. Release exceeded the maximum limit of 20μg/day for each of the first 4 days about sample S3. The amount we got should be sufficient to cause concern. And the average daily release of sample S4 did not exceeded the maximum limit of 20 μg/day. From figure 6, sample S3 and S4 Ni release curve turns into a asymptotic line since 6 days. In vivo, nitinol implanted in the human cardiovascular system first comes into contact with blood, with its progressive encapsulation as it continues to endothelialise, followed by reduced contact with serum, and with its eventual complete endothelialisation, it comes into contact with human body fluids only. This keeps Ni release almost in a stable line. So selecting 41 days for the investigation. 3.8 Formation of in vitro evaluation guidelines An appropriate amount of Ni-Ti alloy in vivo implanted product was selected and divided into two groups. Each group was added to 0.005% HCl at a ratio of 10 g/mL and ensure that the 0.005% HCl was sufficient to soak through the product and incubated at 37 ℃,180 r/min, 0.005% HCl was removed and replenished with fresh 0.005% HCl daily until seven days. The daily Ni content of the extract was measured. A maximum limit is set at 50 μg/mL. 4. Discussion There are no standards or guidelines to control the Nickel release in the medical device field, and the FDA has only been concerned about it from implanted metals in the last year or two. Although relevant articles have been published, certain normative regulations and standards still need to be formed, and there is a gap in market regulation, but the actual situation also urgently needs to strengthen the regulation of it. Allergic reactions to Ni have been identified in the international jeweler and textile industry and regulations have been enacted to avoid its risk [16,17]. Based on their experience, there is a strong need to establish a safety evaluation system for Ni ions in the medical device sector. In the process of medical device registration and management, regulatory authorities are also paying increasing attention to implantable metallic materials, including the need to provide data on the characterization of material composition, as well as data on corrosion resistance studies. The quality control of the products was also controlled by the regulatory authorities only from the raw material of the Ni-Ti alloy, for example GB 24627-2009, corresponding to the Gomez standard ASTM F2063-05, which controls the quality from the content of the elements in the Ni-Ti alloy. The breakdown potential of products supplied by manufacturers is measured using electrochemical workstations and varies from product to product[18-21]. In fact, the breakdown potential, a characteristic parameter of corrosion resistance, is related to many factors, for example, the results of two products from Shsma (Table 4) . The breakdown potential of the product simulating an in vivo environmental extraction increased, which may contribute to the corrosion resistance of the implanted metal by effective passivation in vivo[22]. Nitinol implanted in the human cardiovascular system first comes into contact with blood, with its progressive encapsulation as it continues to endothelialise, followed by reduced contact with serum, and with its eventual complete endothelialisation, it comes into contact with human body fluids only. So initially seven media were selected for the extraction of Ni-Ti wires, namely goat whole blood, goat serum, 1% HNO 3 , 1% HCL, PBS buffer solution, simulated artificial body fluids, and water. The release of nickel from t seven extraction media was examined and it was found that 0.005% HCl could be substituted for goat blood. The extraction medium is specific for Ni-Ti alloys, which have a release rate more than 10 times that of Ni-Cr alloys, probably because the other element of the alloy, especially Cr element, Ti hardly reacts with diluted HCl. PDE value for Ni is of 50 μg/d[23]. The amount of Ni released from sample S3 exceeded the PDE limit of 20μg/day for Class III elements in ICH-Q3D, but did not exceed the PDE value of 50μg/day for Ni in USP232, and as to whether it is clinically hazardous or not, at present Our study does not allow us to draw definite conclusions, but we can tentatively conclude that the clinical application of sample S3 is risky. The blockers used in our study were all used in adults and had a PDE of 20 μg/day. using 0.005% hydrochloric acid as the extraction medium, the release of Ni was 2.5 times greater than that of whole goat blood and 2.5 times greater than that of the normal in vivo environment. The maximum daily release of Ni ions from the S3 product is 38.7 μg, which translates into an release of 15.5μg in vivo. The maximum daily release of Ni ions from the S1 product is 13.36 μg, which translates into a release of 5.4 μg under normal in vivo environmental conditions. 5. Conclusions The extraction medium screened in this study, a 0.005% solution of hydrochloric acid, is a complete substitute for the in vivo environment for the effective and safe evaluation of Ni-Ti products. The extraction medium is clinically equivalent to blood for the evaluation of Ni-Ti cardiovascular products, but the extraction medium is simple to prepare and easy to handle, and the extraction solution is also simple and easy to use for the determination of Ni content. A preliminary guideline for the in vitro safety evaluation of Ni release from Ni-Ti alloy metal implants has been developed for the reference of quality regulators. Declarations Author Contributions: Conceptualization, Resources, KX.; Methodology, Formal analysis, Data curation, B.Z.; Software , D.L.; Formal analysis, Validation, C.W; Supervision, Project administration, B.L.; Visualization, Validation, X.H. and P.H.; Writing— original draft, Writing—review & Editing, Y.H. data curation, J.L. and N.H. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement: Not applicable Informed Consent Statement: Not applicable Data Availability Statement: Data are contained within the article. Conflicts of Interest: We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References A. Biesiekiersk, J. Wang, M.A.-H. Gepreel, C. Wen, A new look at biomedical Ti-based shape memory alloys, Acta Biomater, 8(5), 1661-1669 (2012) W.H. Organization, "Carcinogenic list," International Agency for Research on Cancer 1987 Ganavi Ramagopal, Bhanu Duggal, N.O. Bansal，, Ganesh Narayana, Study of Nickel Levels in Patients with Atrial Septal Defect Undergoing Amplatzer Device Closure, Heart Views, 19(3), (2018) O. Elkiran, C. Karakurt, G. Koca, C. Taskapan, Serum Nickel and Titanium Levels after Transcatheter Closure of Atrial Septal Defects with Amplatzer Septal Occluder, Cardiol Res Pract, 2019, 7891746 (2019) Z. Zhang, B. Fu, D. Zhang, Z. Zhang, Y. Cheng, L. Sheng, C. Lai, T. 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Is the nickel hypersensitivity the start of everything? , Med Hypotheses, 146, 110442 (2021) Center for Devices and Radiological Health, "Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems," Dec 18 2018 D.A. Siddiqui, S. Sivan, J.D. Weaver, M.D. Prima, Effect of wire fretting on the corrosion resistance of common medical alloys, J Biomed Mater Res B Appl Biomater, 105(8), 2487-2494 (2017) Commission Regulation (EC) No. 552/2009 of 22 June 2009 amending Regulation (EC), No. 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards Annex XVII, Annex: Entry 27. Official J Eur Union. , L164:7‐9, (2009) N.m.P. Administration, "Standard specification for wrought Nickel-Titanium shape memory alloys for medical devices and surgical implants," GB24627-2009, Standards Press of China 2009 L.-H. Jia, Y. Li, Y.-Z. Li, Determination of wholesome elements and heavy metals in safflower (Carthamus tinctorius L.) from Xinjiang and Henan by ICP-MS/ICP-AES, Journal of Pharmaceutical Analysis, 1(2), 100-103 (2011) The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, "Guideline for elemental impurities," 2014 General Administration of Quality Supervision, Jewellery-Determination of the release of Nickel-Method of spectrometry, GB/T19719-2005, Standards Press of China, (2005) General Administration of Quality Supervision, Determination of nickel released from accessories on textile products, GB/T30158-2013, Standards Press of China, (2013) M. Talha, Y. Ma, Y.L. a, A.K. Mandal, O.P. Sinha, X. Kong, Corrosion performance of various deformed surfaces of implant steel for coronary stent applications: Effect of protein concentration, Colloids Surf B Biointerfaces, 197, 111407 (2021) Z. Feng, J. Li, Z. Yang, R. Buchheit, The Effect of Vanadate, Phosphate, Fluoride Compounds on the Aqueous Corrosion of Magnesium Alloy AZ31 in Dilute Chloride Solutions, Materials, 13(6), (2020) M. Aparicio，, J. Mosa, G. Rodriguez, J. Guzman, Q. Picard, L.C. Klein, A. Jitianu, Consolidated Melting Gel Coatings on AZ31 Magnesium Alloy with Excellent Corrosion Resistance in NaCl Solutions: An Interface Study, Appl Mater Interfaces, 11(3), 3493-3505 (2019) Z. Yang, B. Kan, J. Li, Y. Su, L. Qiao, A.A. Volinsky, A Statistical Study on the Effect of Hydrostatic Pressure on Metastable Pitting Corrosion of X70 Pipeline Steel, Materials (Basel), 10(11), (2017) J. Scherer, B.M. Ocko, O.M. Magnussen, Structure, dissolution, and passivation of Ni(111) electrodes in sulfuric acid solution: an in situ STM, X-ray scattering, and electrochemical study, Electrochimica Acta, 48(9), 1169-1191 (2003) The United States Pharmacopeial Convention., U.S. Pharmacopeia / National Formulary, 2013 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4057011","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":278514811,"identity":"fe960a32-6c50-48cc-8fba-809c9867fe36","order_by":0,"name":"Bin Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYBACeWb+h49//LCR4ydai2E7D7MxY0+asWQD0XrO87AJM7AdTtxwgFgdjM28x5gLeNISNx9P3sDwo2IbYS3szHxpj2dY2BhvO/OsgLHnzG1ibGEwN+DhSZPddiPHgJmxjQgtDIcZzCR42A4zbp5BvBYeM2mgFsUNEsRqMWxmSzacCQxkCaBfDhLlF3n+wwcffABFZXvyxgc/KohxGAIkGBwgST1YC6k6RsEoGAWjYIQAAJYrPHxSpopxAAAAAElFTkSuQmCC","orcid":"","institution":"Shandong Institute of Medical Device and Pharmaceutical Packaging Inspection","correspondingAuthor":true,"prefix":"","firstName":"Bin","middleName":"","lastName":"Liu","suffix":""},{"id":278514812,"identity":"c1dca089-de41-43db-90f4-f900d1c69a61","order_by":1,"name":"Yafan Hu","email":"","orcid":"","institution":"Chinese Academy of Agricultural Sciences, Ministry of Agriculture","correspondingAuthor":false,"prefix":"","firstName":"Yafan","middleName":"","lastName":"Hu","suffix":""},{"id":278514813,"identity":"29a793cf-bf73-4249-ab25-8a2c440d1e89","order_by":2,"name":"Kai Xu","email":"","orcid":"","institution":"Shandong Institute of Medical Device and Pharmaceutical Packaging Inspection","correspondingAuthor":false,"prefix":"","firstName":"Kai","middleName":"","lastName":"Xu","suffix":""},{"id":278514814,"identity":"85e505fa-408e-4ec2-a6e6-eea411802922","order_by":3,"name":"Bo Zhang","email":"","orcid":"","institution":"Shandong Institute of Medical Device and Pharmaceutical Packaging Inspection","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Zhang","suffix":""},{"id":278514815,"identity":"a8e9f04a-2e31-4033-93a9-f3bea411a37b","order_by":4,"name":"Dong Liu","email":"","orcid":"","institution":"Shandong Institute of Medical Device and Pharmaceutical Packaging Inspection","correspondingAuthor":false,"prefix":"","firstName":"Dong","middleName":"","lastName":"Liu","suffix":""},{"id":278514816,"identity":"480d0115-9a4c-48df-bb80-9fd13ef9322b","order_by":5,"name":"Changyan Wu","email":"","orcid":"","institution":"Shandong Institute of Medical Device and Pharmaceutical Packaging Inspection","correspondingAuthor":false,"prefix":"","firstName":"Changyan","middleName":"","lastName":"Wu","suffix":""},{"id":278514818,"identity":"9f554082-4ec8-4db7-a9fc-76dcfbcbd04d","order_by":6,"name":"Xiuyun Han","email":"","orcid":"","institution":"Amhwa biopharm Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Xiuyun","middleName":"","lastName":"Han","suffix":""},{"id":278514824,"identity":"66abb5ef-a39f-4c6a-b2b2-e6911ba34ff9","order_by":7,"name":"Peng Han","email":"","orcid":"","institution":"Amhwa biopharm Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Han","suffix":""},{"id":278514826,"identity":"17362355-d17a-495e-959f-4183fe414402","order_by":8,"name":"Jian Lu","email":"","orcid":"","institution":"Shandong Institute of Medical Device and Pharmaceutical Packaging Inspection","correspondingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"Lu","suffix":""},{"id":278514827,"identity":"698ef2ac-ae71-475f-8d1b-3df2c167de5c","order_by":9,"name":"Naishui Han","email":"","orcid":"","institution":"Shandong Institute of Medical Device and Pharmaceutical Packaging Inspection","correspondingAuthor":false,"prefix":"","firstName":"Naishui","middleName":"","lastName":"Han","suffix":""}],"badges":[],"createdAt":"2024-03-09 14:06:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4057011/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4057011/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52594804,"identity":"5c2ba5b2-2f2b-4eeb-80e9-1a9112670db0","added_by":"auto","created_at":"2024-03-13 11:28:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31099,"visible":true,"origin":"","legend":"\u003cp\u003eRest and breakdown potentialsof six samples before and after extraction\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4057011/v1/da27d83174323abab406ebae.png"},{"id":52595037,"identity":"abfa55e3-5acf-4925-962b-b2a746213ba0","added_by":"auto","created_at":"2024-03-13 11:36:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51648,"visible":true,"origin":"","legend":"\u003cp\u003eTotal Ni release in different media\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4057011/v1/076407e28e2114c9dfa4fc6b.png"},{"id":52594803,"identity":"b7b1e029-9fa8-456c-89c9-cf08101c64cc","added_by":"auto","created_at":"2024-03-13 11:28:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":75814,"visible":true,"origin":"","legend":"\u003cp\u003eTotal Ni release in different concentration of HCl\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4057011/v1/2c75b65e6e2c82609f676a21.png"},{"id":52594806,"identity":"63853871-285e-4ce3-96b8-db4e947e46e7","added_by":"auto","created_at":"2024-03-13 11:28:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":334286,"visible":true,"origin":"","legend":"\u003cp\u003eMorphology of Ni-Ti wire under EM\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4057011/v1/892d2bef60f38ec8fc41b8c1.png"},{"id":52595038,"identity":"8dbfc613-7db6-4602-9795-56e8c8ccfcb4","added_by":"auto","created_at":"2024-03-13 11:36:48","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":27281,"visible":true,"origin":"","legend":"\u003cp\u003eNickel release from Ni-Ti and Ni-Cr alloys in extraction media\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4057011/v1/43105faa9e3df313ffd5fb83.png"},{"id":52595488,"identity":"3bea4ee3-225f-40f9-9917-f13e4981aba5","added_by":"auto","created_at":"2024-03-13 11:44:48","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":32389,"visible":true,"origin":"","legend":"\u003cp\u003edaily release of S3 and S4 in 0.005%HCl\u003c/p\u003e\n\u003cp\u003eS3: VSDO (WXVSDMD-22, Visee, China); S4: ASDO (Shsma, China).\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4057011/v1/4cbe10fc24f422e6000d1662.png"},{"id":56030154,"identity":"b544efad-a017-49f8-9648-192869da161b","added_by":"auto","created_at":"2024-05-07 17:44:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":952268,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4057011/v1/2d331244-c089-4824-a493-6b45ddad5e3f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety Evaluation for Nickel Release of Nickel–Titanium alloys Cardiovascular stents","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eNi-Ti alloys are used in many medical devices in the human body, including cardiovascular blockers and stents, due to their unique strong elasticity and shape memory properties[1]. However, the Ni element in them is a carcinogen[2].According to relevant reports, Ni in jewelry and textile clothing is prone to cause Ni allergic reactions in human skin. Ni is the most common allergenic metal, about 20% of people are allergic to Ni, and the number of female patients is higher than that of male patients. Once sensitization occurs, Ni allergy can persist indefinitely. The Ni released by long-term implantation of NiTi alloy, because of its direct contact with human blood organs and tissues, may bring more serious harm to patients compared to skin and gastrointestinal absorption[3-6], therefore, more attention should be paid to its safety issues. The international jewelry and textile industry has discovered the allergic reaction of Ni and promulgated relevant regulations to avoid its risk. Based on their experiences, it is very necessary to establish a safety evaluation system for Ni in the field of medical devices. \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe release of Ni from cardiovascular devices made of Ni-Ti alloys that are implanted in the human body for long periods of time has caused widespread concern in recent years[7-9]. The domestic NiTi alloy cardiovascular products have developed rapidly, and the domestic market was almost zero before 2000. With the influx of imported products into Chinese market, domestic manufacturers have obtained some technical factors of this kind of products and began to make the same products themselves. Gradually it breaks the monopoly position of foreign products, and also make lower price of such products, so that the poor can also afford this kind of products. In recent years，release of implanted Ni has received attention from regulatory authorities, including Food and Drug Administration (FDA)[10]. For the quality control of this kind of products, the regulatory authorities only control the quality from the raw materials of NiTi alloy, such as GB24627-2009, the corresponding standard is ASTM F2063-18, and the quality is controlled with by the content of various elements in NiTi alloy. Later, with the gradual maturity and development of products, the requirements for products are becoming more and more stringent. With the implementation of ISO16429:2004 in the world, it is required to evaluate the long-term corrosion behavior of metal implant materials, and the main evaluation indexes are corrosion potential and open-circuit potential. The national standard was introduced into domestic standard YY/T 1552-2017. The relevant standard in the United States is ASTM F2129-06, and the evaluation index is a cyclic polarization curve of the product under certain PH condition, which is difficult to interpret (there are three forms, one is the material that shows the protective potential, one is the material that does not show the protective potential, and the other is the material with oxidation on the surface), which is transformed into the domestic standard YY/T0695-2008.Corrosion resistance indicators[11] are currently used to evaluate the risk of unintended corrosion leading to the release of elements from metallic materials into the human body to produce adverse reactions. However, this method is not specific in terms of physiological environment simulation, such as the blood environment, and does not address qualitative\u0026nbsp;and\u0026nbsp;quantitative of the potential risk.\u003c/p\u003e\n\u003cp\u003eTherefore, this issue is currently of more concern to regulatory authorities, which has also received attention in recent years[12], including the U.S. FDA review department, but due to the lack of reliable research models, there are no relevant evaluation standards or guidelines \u0026nbsp;This study proposes to find an extraction medium that can replace blood for simulated extraction tests to specifically and safely evaluate the performance of Ni release from Ni-Ti products in vitro, and to develop an evaluation system for Ni-Ti alloy cardiovascular devices so as to provide effective evaluation guidelines for government regulation and management to evaluate the safety of such products.\u003c/p\u003e\n\u003cp\u003eThe introduction should briefly place the study in a broad context and highlight why it is important. It should define the purpose of the work and its significance. The current state of the research field should be carefully reviewed and key publications cited. Please highlight controversial and diverging hypotheses when necessary. Finally, briefly mention the main aim of the work and highlight the principal conclusions. As far as possible, please keep the introduction comprehensible to scientists outside your particular field of research. References should be numbered in order of appearance and indicated by a numeral or numerals in square brackets\u0026mdash;e.g., [1] or [2,3], or [4\u0026ndash;6]. See the end of the document for further details on references.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e2.1 Materials\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHNO\u003csub\u003e3\u003c/sub\u003e was obtained from J.T. Baker, USA; Ni, Ti, Co, Cr, Cu, Fe, Nb standard solutions were purchased from\u0026nbsp;\u003c/em\u003eCentral Iron \u0026amp; Steel Research Institute，China\u003cem\u003e; Ni-Ti and\u003c/em\u003e Ni-Cr\u003cem\u003e\u0026nbsp;wires were obtained from SHSMA\u003c/em\u003e\u003cem\u003e，China; goat blood was purchased from Yudo Biotech\u003c/em\u003e\u003cem\u003e，China; goat serum was purchased from Yudo Biotech\u003c/em\u003e\u003cem\u003e，China; phosphate buffer solution\u003c/em\u003e\u003cem\u003e（PBS\u003c/em\u003e\u003cem\u003e）was purchased from Sigma, USA; Hydrochloric acid(HCl) was purchased from J.T. Baker, USA. Four alloys that cardiovascular implants were selected for this study\u0026nbsp;\u003c/em\u003e\u003cem\u003e：Samples S1:\u003c/em\u003e \u003cem\u003eLeft\u003c/em\u003e\u003cem\u003e\u0026nbsp;Atrial\u003c/em\u003e \u003cem\u003eAppendage occluder\u003c/em\u003e \u003cem\u003e(LAAO) was obtained from\u0026nbsp;\u003c/em\u003eLAFDQ-26,\u003cem\u003e\u0026nbsp;Shsma\u003c/em\u003e\u003cem\u003e,China; S2: LAAO was obtained from\u0026nbsp;\u003c/em\u003eYFD\u003cem\u003eQ-27-1, Ydb med, China; S3:\u003c/em\u003e \u003cem\u003eVentricular septal defect occluder (VSDO)\u0026nbsp;was obtained from WXVSDMD-22\u003c/em\u003e\u003cem\u003e，Visee,china; S4:atrial septal defect occluder\u0026nbsp;\u003c/em\u003e\u003cem\u003e（ASDO\u003c/em\u003e\u003cem\u003e）was obtained from Shsma, China; S5:Nickel-Nitium wires were obtained from Shsma\u003c/em\u003e\u003cem\u003e,China\u003c/em\u003e\u003cem\u003e; S6:Nickel-Chromium wires were obtained from market.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e2.2 \u003cem\u003eDetermination of\u003c/em\u003e the C, H, N, O content\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe carbon(C) content was measured by Carbon-Sulfur \u003cem\u003eelements\u003c/em\u003e analyzer (CS800, Eltra, Germany), 6 samples were used for each S1, S2. Oxygen(O), nitrogen(N) and hydrogen(H) were measured by oxygen, nitrogen and hydrogen \u003cem\u003eelements\u003c/em\u003e analyzer (Onh600, Eltra, Germany). 8 samples were used for each S1, S2. They were calibrated according to the content of the elements C, O, N and H in \u0026ldquo;Standard Specification for Wrought Ni-Ti Shape Memory Alloys for Medical Devices and Surgical Implants\u0026rdquo; GB24627-2009[13]. YSB C11140-2007 was selected as the standard for the determination of C; the AR650 was selected as the standard for the determination of O, N and H elements.\u003c/p\u003e\n\u003cp\u003e2.3 Determination of metal element content\u003c/p\u003e\n\u003cp\u003eThe metal content was determined by electron-cloupled plasma atomic emission spectrometry (ICP-AES) with modifications[14].\u003c/p\u003e\n\u003cp\u003eWeigh 0.20 g of Ni-Ti alloy S1 and S2, (each S1sample\u0026rsquo;s weight is 0.56647g, each S2 sample\u0026rsquo;s weight is 0.46855g, so S1 and S2 must to be divided into small parts) place them in poly tetra fluoroethylene (PTFE) digestion tank, add 10 mL of aqua regia, mix well, soak overnight and place in an ultra-high pressure microwave system (Multiwave Pro, Austria), see Table 1 for digestion parameters. The solution was transferred to a 25 mL measuring flask with 2% HCl and diluted to the scale with shaking. The same method was used to prepare the reagent blank solution as a blank correction. The standard solutions of Ni, Ti, Co, Cr, Cu, Fe and Nb were all pipetted separately at 1,000 mg/L and diluted with 2% HNO\u003csub\u003e3\u003c/sub\u003e to make a mixed standard stock solution containing 10 \u0026mu;g/mL of Ni, Ti, Co, Cr, Cu, Fe and Nb. The mixed standard stock solution was diluted with 2% HNO\u003csub\u003e3\u003c/sub\u003e to make the control solution containing 0.1 \u0026mu;g/mL, 0.2 \u0026mu;g/mL, 0.5 \u0026mu;g/mL, 1.0 \u0026mu;g/mL and 2.0 \u0026mu;g/mL of Ni, Ti, Co, Cr, Cu, Fe and Nb respectively. Prepared and used as needed.\u003c/p\u003e\n\u003cp\u003eThe test solution and the control solution were taken in appropriate amounts and analyzed using ICP (Thermo, USA) with a pump speed of 50 rpm; RF frequency of 27.12 MHz; RF power of 1150 w; auxiliary gas of 0.5 L/min; glass concentric atomizer with a cyclonic fog chamber; and wavelengths of Ni 221.647 nm, Cr 283.616 nm, Cu 324.754 nm, Fe 259.940 nm, Nb 309.418 nm, Co 228.616 nm, Cu 324.754nm, Fe 259.940nm, Nb 309.418nm and Co 228.616nm. The net intensity value was used as the integration method and calculated.\u003c/p\u003e\n\u003cp\u003eTable 1. Microwave digestion conditions for Ni-Ti products\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"676\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.896602658788774%\"\u003e\n \u003cp\u003estage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.884785819793205%\"\u003e\n \u003cp\u003epower/W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.054652880354507%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.054652880354507%\"\u003e\n \u003cp\u003eramp time/ min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.56573116691285%\"\u003e\n \u003cp\u003etemperature/℃\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.54357459379616%\"\u003e\n \u003cp\u003eholding time/s\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.896602658788774%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.884785819793205%\"\u003e\n \u003cp\u003e1600\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.054652880354507%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.054652880354507%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.56573116691285%\"\u003e\n \u003cp\u003e120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.54357459379616%\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.896602658788774%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.884785819793205%\"\u003e\n \u003cp\u003e1600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.054652880354507%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.054652880354507%\"\u003e\n \u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.56573116691285%\"\u003e\n \u003cp\u003e150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.54357459379616%\"\u003e\n \u003cp\u003e2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.896602658788774%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.884785819793205%\"\u003e\n \u003cp\u003e1600\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.054652880354507%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.054652880354507%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.56573116691285%\"\u003e\n \u003cp\u003e180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.54357459379616%\"\u003e\n \u003cp\u003e20\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e2.4 Corrosion resistance\u003c/p\u003e\n\u003cp\u003eThe sample to be tested is placed in a suitably De-oxygenated phosphate buffered saline (PBS) solution and the resting potential (Er) is recorded for 1h, followed by a scan in the anodic direction or forward from Er. When the peak potential is reached or the current density reaches two orders of magnitude of the current density corresponding to the breakdown potential (Eb), the scan is reversed. The reverse scan stops when the current density is less than the value in the forward scan or when the potential reaches Er. 2 samples were used for each S1,S3,S4.\u003c/p\u003e\n\u003cp\u003e2.5 Screening of extraction media\u003c/p\u003e\n\u003cp\u003eWeigh 1.2 g of Ni-Ti wire (S5) and add 12 mL of goat blood and goat serum respectively; weigh 2.0 g of Ni-Ti wire(S5) and add 20 mL of 1% HNO\u003csub\u003e3\u003c/sub\u003e, 1% HCL, PBS, artificial simulated body fluid (MBF ) and water respectively. Shake at 37\u0026deg;C, 180 r/min and remove all the extraction medium at 1, 6, 24, 48, 72, 120 and 168 h. Then extracting medium was replenished with fresh extracting medium and shaking was continued.\u003c/p\u003e\n\u003cp\u003e2.5.1 Determination of Ni in goat blood\u003c/p\u003e\n\u003cp\u003eThe standard stock solution containing 1.0 \u0026mu;g /mL was prepared and diluted three times with water to make a control solution containing 0. 01 \u0026mu;g/mL, 0. 05 \u0026mu;g/mL, 0.15 \u0026mu;g/mL, 0.3 \u0026mu;g/mL and 0. 5 \u0026mu;g/mL of Ni. Prepared and used as needed.\u003c/p\u003e\n\u003cp\u003e2 ml of goat blood was measured and placed in PTFE digestion tank. Add 5 mL of HNO\u003csub\u003e3\u003c/sub\u003e and 2 mL of H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e, mix well, soak overnight, place in a microwave digestion system and digest according to the procedure in Table 2. After digestion, the inner jar was removed and placed on an electric heater, heated at 120\u0026deg;C until the red-brown vapor evaporated and nearly dried, transferred to a 25 mL measuring flask with three times water and diluted to the scale, shaken well and used as the test solution. The same method was used to prepare a reagent blank solution as a blank correction.\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;2. Microwave digestion conditions for goat blood\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"548\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.226277372262773%\"\u003e\n \u003cp\u003estage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.153284671532848%\"\u003e\n \u003cp\u003epower/W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.357664233576642%\"\u003e\n \u003cp\u003eramp time/ min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.45985401459854%\"\u003e\n \u003cp\u003etemperature/℃\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.802919708029197%\"\u003e\n \u003cp\u003eholding time/s\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.226277372262773%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.153284671532848%\"\u003e\n \u003cp\u003e900\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.357664233576642%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.45985401459854%\"\u003e\n \u003cp\u003e120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.802919708029197%\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.226277372262773%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.153284671532848%\"\u003e\n \u003cp\u003e900\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.357664233576642%\"\u003e\n \u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.45985401459854%\"\u003e\n \u003cp\u003e150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.802919708029197%\"\u003e\n \u003cp\u003e2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.226277372262773%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.153284671532848%\"\u003e\n \u003cp\u003e900\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.357664233576642%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.45985401459854%\"\u003e\n \u003cp\u003e180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.802919708029197%\"\u003e\n \u003cp\u003e90\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e2.5.2 Determination of Ni in goat serum\u003c/p\u003e\n\u003cp\u003eThe ICP working conditions were the same as in method 2.3, and control solutions containing 0. 02 \u0026mu;g /mL, 0. 05 \u0026mu;g /mL, 0. 15 \u0026mu;g /mL, 0. 3 \u0026mu;g /mL and 0. 5 \u0026mu;g /mL of Ni were prepared using the dilution method. Prepared and used as needed.\u003c/p\u003e\n\u003cp\u003eThe solution of the test sample was prepared by taking 5 mL of goat serum extract, fixing it with three times of water into a 20 mL measuring flask and shaking well. In the same way, 5 mL of blank goat serum was fixed into a 20 mL flask and used as blank calibration.\u003c/p\u003e\n\u003cp\u003e2.5.3 Determination of Ni in 1% HNO\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\n\u003cp\u003eThe ICP working conditions were the same as in method 2.3, and the control solution was the same as in method 2.5.1. 1% HNO\u003csub\u003e3\u003c/sub\u003e was diluted one hundredfold and then directly injected into the sample. 1% HNO\u003csub\u003e3\u003c/sub\u003e was used as a blank calibration.\u003c/p\u003e\n\u003cp\u003e2.5.4 Determination of Ni in 1% HCl\u003c/p\u003e\n\u003cp\u003eA control solution containing 10 \u0026mu;g /mL, 20 \u0026mu;g /mL, 40 \u0026mu;g /mL, 80 \u0026mu;g /mL and 100 \u0026mu;g /mL was prepared using the same ICP working conditions as in method 2.3. \u0026nbsp;The 1% HCl extract was fed directly into the sample and 1% HCl was used for the blank.\u003c/p\u003e\n\u003cp\u003e2.5.5 Determination of Ni in PBS\u003c/p\u003e\n\u003cp\u003eThe ICP working conditions were the same as method 2.3 and the control solution was the same as method 2.5.1. The PBS extract was injected directly and the blank was used directly with PBS.\u003c/p\u003e\n\u003cp\u003e2.5.6 Determination of Ni in SBF\u003c/p\u003e\n\u003cp\u003eThe ICP working conditions were the same as method 2.3 and the control solution was the same as method 2.5.1. The SBF were injected directly into the sample and the blank was used directly with SBF.\u003c/p\u003e\n\u003cp\u003e2.5.7 Determination of Ni in water\u003c/p\u003e\n\u003cp\u003eThe ICP working conditions were the same as method 2.3 and the control solution was the same as method 2.5.1. The aqueous extract was directly injected and the blank was directly used with water.\u003c/p\u003e\n\u003cp\u003eThe Ni content in the extracted medium was calculated by integrating the net intensity value.\u003c/p\u003e\n\u003cp\u003e2.6 Recovery of Ni from extraction media\u003c/p\u003e\n\u003cp\u003ePrecisely measure 2.0mL of goat blood extract and add 1,000 \u0026mu;g/mL of Ni standard stock solution 2.5\u0026mu;L and 25\u0026mu;L to the solution for determination according to the aforementioned preparation method and ICP conditions. Precisely measure 2mL of goat serum extract and add 2.0 \u0026mu;L of 1000 \u0026mu;g/mL of Ni standard stock solution; Precisely measure 1mL of 1% \u003cem\u003eHNO\u003csub\u003e3\u003c/sub\u003e\u003c/em\u003e extract and add 50\u0026mu;L of 1,000 \u0026mu;g/mL of Ni standard stock solution; Precisely measure 10mL of 1% HCl extract and add 10\u0026mu;L of 1,000 \u0026mu;g/mL of Ni standard stock solution; Precisely measure 10mL of PBS 10 mL of PBS extract and add exactly 5 \u0026mu;L of 1000 \u0026mu;g/mL of Ni standard stock solution. Precisely measure 10mL of SBF extract and add 5\u0026mu;L of Ni standard stock solution at 1000 \u0026mu;g/mL; precisely measure 10mL of the water extract and add 10\u0026mu;L of Ni standard stock solution at 1000 \u0026mu;g/mL. The Ni content was determined according to the aforementioned method of preparation of the test solution and ICP conditions.\u003c/p\u003e\n\u003cp\u003e2.7 Confirmation of HCl concentration\u003c/p\u003e\n\u003cp\u003eHCl at 0.01%, 0.05%, 0.1%, 0.2%, 0.005% and 0.007% by mass were prepared and the extracts were removed at 1, 6, 24, 48, 72, 120 and 168 hours and stored in the refrigerator while being replenished with fresh extracts. The amount of Ni in the hydrochloric acid extracts was determined for each concentration according to the procedure in 2.4.3.6 and the total amount of Ni released at each time point was calculated. The samples are Ni-Ti wire(S5).\u003c/p\u003e\n\u003cp\u003e2.8 Microscopic observation of samples\u003c/p\u003e\n\u003cp\u003eA field emission scanning electron microscope (EM) (model Hitachi SU8010) was used to observe the secondary electron image morphology of the sample at a voltage of 1 kV at a magnification of between 500x and 1000x.\u003c/p\u003e\n\u003cp\u003e2.9 Specificity verification\u003c/p\u003e\n\u003cp\u003eThe 0.005% HCl extraction medium was used to extract a Ni-chromium alloy, Cr15 Ni60(S6),\u0026nbsp;at the same extraction ratios and under the same extraction conditions as a comparison, and its solution was taken at 1, 6, 24, 48, 72, 120 and 168h to determine the concentration of Ni and to find the total release versus time release curve, compared to the release curve of a Ni-Ti alloy under the same conditions.\u003c/p\u003e\n\u003cp\u003e2.10 Safety evaluation\u003c/p\u003e\n\u003cp\u003eThe samples were then incubated in a constant temperature shaker at 37\u0026deg;C,180r/min. 41 days after the investigation period, the extracts were removed and the Ni content of the extracts was measured by ICP to calculate the daily release of Ni from the product. The ICH regulations state that the maximum intravenous dose of Ni is 20\u0026mu;g/day, and this was used as a benchmark to investigate the safety of Ni release from the product. 2 samples were used for each S1, S3, S4.\u003c/p\u003e\n\u003cp\u003eThis was used as a benchmark to investigate the safety of Ni release.\u003c/p\u003e\n\u003cp\u003e2.11 Statistical analysis\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Statistical analysis was performed using GraphPad Prism（version 8.0.1）. p value \u0026lt; 0.05 was considered statistically significant (Wilcoxon Test). n=3.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e3.1 Determination of C, H, N, O and metal elements\u003c/p\u003e\n\u003cp\u003eTable 3. the standard curve and correlation coefficient of Ni、Ti、Co、Cr、Cu、Fe、Nb\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.01125703564728%\" valign=\"top\"\u003e\n \u003cp\u003eElement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.08255159474672%\" valign=\"top\"\u003e\n \u003cp\u003eStandard curve equation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003eDensity scope ug/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003eCorrelation coefficient\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.01125703564728%\" valign=\"top\"\u003e\n \u003cp\u003eNi-221\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.08255159474672%\" valign=\"top\"\u003e\n \u003cp\u003eY=1710X+1.609\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e0~2. 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.01125703564728%\" valign=\"top\"\u003e\n \u003cp\u003eTi-334\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.08255159474672%\" valign=\"top\"\u003e\n \u003cp\u003eY=12050X+8.186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e0~2. 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e0.9999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.01125703564728%\" valign=\"top\"\u003e\n \u003cp\u003eCo-228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.08255159474672%\" valign=\"top\"\u003e\n \u003cp\u003eY=1910X-1.348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e0~2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.01125703564728%\" valign=\"top\"\u003e\n \u003cp\u003eCr-283\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.08255159474672%\" valign=\"top\"\u003e\n \u003cp\u003eY=4605X+27.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e0~2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.01125703564728%\" valign=\"top\"\u003e\n \u003cp\u003eCu-324\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.08255159474672%\" valign=\"top\"\u003e\n \u003cp\u003eY=4956X+13.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e0~2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.01125703564728%\" valign=\"top\"\u003e\n \u003cp\u003eFe-259\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.08255159474672%\" valign=\"top\"\u003e\n \u003cp\u003eY=2737X+12.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e0~2. 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.01125703564728%\" valign=\"top\"\u003e\n \u003cp\u003eNb-309\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.08255159474672%\" valign=\"top\"\u003e\n \u003cp\u003eY=2803X-21.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e0~2. 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.953095684803003%\" valign=\"top\"\u003e\n \u003cp\u003e0.9985\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 4. the limits of detection and the limits of quantification about Ni、Ti、Co、Cr、Cu、Fe、Nb\u003c/p\u003e\n\u003cp\u003eTable 5. Ni-Ti alloy cardiovascular products with C, H, N, O and metal elements\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eS1:LAAO (\u003c/em\u003e LAFDQ-26,\u003cem\u003e\u0026nbsp;Shsma\u003c/em\u003e\u003cem\u003e，\u003c/em\u003e\u003cem\u003eChina); S2: LAAO (\u003c/em\u003eYFD\u003cem\u003eQ-27-1, Ydb med, Ch\u003c/em\u003eina). n=3\u003c/p\u003e\n\u003cp\u003eThe table 5 above illustrates the element of Ni-Ti alloys. The results of S1 and S2 were in full compliance with the provisions of GB24627-2009, where the elemental content of metallic Ni was below 57.0%. The standard curves for the samples are shown in Table 3, the limits of detection and the limits of quantification are shown in Table 4.\u003c/p\u003e\n\u003cp\u003e3.2 Evaluation of corrosion resistance\u003c/p\u003e\n\u003cp\u003eA represents rest potentials; b represents breakdown potentials. Before means the original sample; after means the samples were extracted by PBS. Er means the resting potentials; Eb means breakdown potentials.S1: LAAO, (LAFDQ-26, Shsma, China); S3: VSDO (WXVSDMD-22,Visee, China); S4: ASDO (Shsma, China).1 and 2 means different batches of the same type of sample.\u003c/p\u003e\n\u003cp\u003eFig.1a shows that there is no significant difference of rest potentials before and after extraction in simulated media in vitro. Fig.1b shows that the breakdown potential increases after extraction, with the exception of sample S3-1. It is suggested that S3 has better corrosion resistance.\u003c/p\u003e\n\u003cp\u003e3.3 Recovery rate of extraction media\u003c/p\u003e\n\u003cp\u003eTable 6. Recovery of Ni in different media\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"265\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003eextraction media\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003erecovery rate /%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003egoat blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e97.5\u0026plusmn;1.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003egoat serum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e89.3\u0026plusmn;0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e1% HNO\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e100.76\u0026plusmn;0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e1% HCL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e91.64\u0026plusmn;1.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003ePBS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e110.48\u0026plusmn;0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003eSBF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e85.22\u0026plusmn;0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e110.74\u0026plusmn;0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAs shown in Table 6, the spiked recoveries of Ni metal ranged from 85.22 % to 110.74%，indicating that the results were accurate and reliable for the seven media measured by the three methods of digestion, dilution and direct injection.\u003c/p\u003e\n\u003cp\u003e3.4 Nickel release curves from samples\u003c/p\u003e\n\u003cp\u003eFrom the release time curves of the Ni content in the seven extraction media (Fig.2), it is evident that 1% HNO\u003csub\u003e3\u003c/sub\u003e and 1% HCl, as the extraction media examined in vitro, have a very large release of Ni compared to goat blood and cannot be used as reference extraction media. Goat blood, as the closest physiological environment to the body, is undoubtedly the most ideal extraction medium to examine in vitro, but its non-storability and complex matrix nature promoted us to look for solutions comparable to its Ni release as a reliable extraction medium to examine the safety of Ni release risk. The difference in Ni release between water, PBS and SBF was not significant, however, compared to goat whole blood, the Ni release from goat whole blood was 3-4 times higher than that from water, PBS and SBF, so water, PBS and SBF were not suitable as media for investigating extraction in vitro. Considering the safety and simplicity of preparation, HCl was chosen as the extraction medium, but and further dilution of 1% HCl was required to investigate whether the release of Ni at 168h was compared to that of goat blood at 168h.\u003c/p\u003e\n\u003cp\u003eFrom Fig.3, it can be seen that the Ni release at a reduced HCl concentration of 0.01% was still more than 6 times the Ni release from goat blood, and continued to dilute the HCl to 0.005% and 0.007% to examine the Ni release. From the above results, it can be seen that the mass percentage concentration of 0.005% HCl, its Ni release at 168h is 2.55 of the release from goat blood. Considering the error, offset and addition of strict, so 0.005% HCl was chosen as the best extraction medium, which can completely and effectively replace goat whole blood, to examine the biosafety evaluation of Ni-Ti metal implanted into human body.\u003c/p\u003e\n\u003cp\u003e3.5 EM observation of the surface morphology of Ni-Ti alloy wires in seven extraction media\u003c/p\u003e\n\u003cp\u003e(a) Unleached NiTi wire (b) Goat blood (c) Goat serum (d) 1% HNO\u003csub\u003e3\u003c/sub\u003e(e)1% HCl (f)PBS (g)SBF(h)H\u003csub\u003e2\u003c/sub\u003eO (i)0.005% HCl\u003c/p\u003e\n\u003cp\u003eAs can be seen in Fig.4, the Ni-Ti wire corroded most severely in the 1% HNO\u003csub\u003e3\u003c/sub\u003e and 1% HCl extraction media, with the surface layer showing severe peeling. In the goat blood Ni-Ti wire surface appears more obvious corrosion spots, in 0.005% HCl also have more serious corrosion surface, other extraction media surface smooth, no obvious corrosion characteristics. It can also be seen from Fig.1 that the Ni-Ti wire precipitated the most Ni in the 1% HNO\u003csub\u003e3\u003c/sub\u003e and 1% HCl extraction media, which is consistent with the EM photographs of its most severe corrosion. There was also a higher release of Ni from goat blood, so there were also more obvious corrosion spots in the electron micrographs, while in the other media there was a small amount of Ni precipitation, but no obvious corrosion in the electron micrographs and the surface was smooth.\u003c/p\u003e\n\u003cp\u003eFig 5 compares the experimental data on different alloys. Under the same extraction medium of 0.005% HCl and the same extraction conditions of 37\u0026deg;C and 180 r/min, the release of Ni from Ni-Cr and Ni-Ti alloys is very different, with Ni-Ti being more than 10 times the release rate of Ni-Cr. Therefore, the media selected for this method and the associated experimental conditions and evaluation criteria are closely related to the type of alloy tested and are clearly specific.\u003c/p\u003e\n\u003cp\u003e3.7 Evaluation of safety\u003c/p\u003e\n\u003cp\u003eTable 7. Nickel release in 0.005%HCl\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"532\" height=\"191\"\u003e\u003c/p\u003e\n\u003cp\u003eS1: LAAO (LAFDQ-26, Shsma, China); S3: VSDO (WXVSDMD-22, Visee, China); S4: ASDO (Shsma, China).\u003c/p\u003e\n\u003cp\u003eTable 8. Sample S3 and S4 nickel release in 0.005%HCl\u003c/p\u003e\n\u003cdiv\u003e\u003cimg src=\"data:image/png;base64,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\" width=\"537\" height=\"167\"\u003e\u003c/div\u003e\n\u003cp\u003eTable 8、Fig.6 and table 6 provides the summary statistics for total and daily Ni release of different samples. According to the permitted daily exposure（PDE）value for Group III elements in ICH-Q3D[15], the PDE value for Ni is 20 \u0026mu;g/day. The total release of Ni from sample S1 for 41 days was less than 2 \u0026mu;g, which is clearly safe. The total Ni release for samples S3 and S4 for forty-one days was over seventy to eighty micrograms respectively, with the average daily release not exceeding the maximum limit of 20 \u0026mu;g/day, but it is to be further confirmed whether the exact daily release exceeds 20 \u0026mu;g/day. In order to further evaluate whether the daily release of Ni from samples S3 and S4 exceeded the limit value of 20 \u0026mu;g/day, samples S3 and S4 were taken for daily Ni release extraction experiments and the results are shown in table 6the graph. Release exceeded the maximum limit of 20\u0026mu;g/day for each of the first 4 days about sample S3. The amount we got should be sufficient to cause concern. And the average daily release of sample S4 did not exceeded the maximum limit of 20 \u0026mu;g/day. From figure 6, sample S3 and S4 Ni release curve turns into a asymptotic line since 6 days. In vivo, nitinol implanted in the human cardiovascular system first comes into contact with blood, with its progressive encapsulation as it continues to endothelialise, followed by reduced contact with serum, and with its eventual complete endothelialisation, it comes into contact with human body fluids only. This keeps Ni release almost in a stable line. So selecting 41 days for the investigation.\u003c/p\u003e\n\u003cp\u003e3.8 Formation of in vitro evaluation guidelines\u003c/p\u003e\n\u003cp\u003eAn appropriate amount of Ni-Ti alloy in vivo implanted product was selected and divided into two groups. Each group was added to 0.005% HCl at a ratio of 10 g/mL and ensure that the 0.005% HCl was sufficient to soak through the product and incubated at 37 ℃,180 r/min, 0.005% HCl was removed and replenished with fresh 0.005% HCl daily until seven days. The daily Ni content of the extract was measured. A maximum limit is set at 50 \u0026mu;g/mL.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThere are no standards or guidelines to control the Nickel release in the medical device field, and the FDA has only been concerned about it from implanted metals in the last year or two. Although relevant articles have been published, certain normative regulations and standards still need to be formed, and there is a gap in market regulation, but the actual situation also urgently needs to strengthen the regulation of it. Allergic reactions to Ni have been identified in the international jeweler and textile industry and regulations have been enacted to avoid its risk [16,17]. Based on their experience, there is a strong need to establish a safety evaluation system for Ni ions in the medical device sector. In the process of medical device registration and management, regulatory authorities are also paying increasing attention to implantable metallic materials, including the need to provide data on the characterization of material composition, as well as data on corrosion resistance studies.\u003c/p\u003e\n\u003cp\u003eThe quality control of the products was also controlled by the regulatory authorities only from the raw material of the Ni-Ti alloy, for example GB 24627-2009, corresponding to the Gomez standard ASTM F2063-05, which controls the quality from the content of the elements in the Ni-Ti alloy. The breakdown potential of products supplied by manufacturers is measured using electrochemical workstations and varies from product to product[18-21]. In fact, the breakdown potential, a characteristic parameter of corrosion resistance, is related to many factors, for example, the results of two products from \u003cem\u003eShsma (Table 4)\u003c/em\u003e. The breakdown potential of the product simulating an in vivo environmental extraction increased, which may contribute to the corrosion resistance of the implanted metal by effective passivation in vivo[22].\u003c/p\u003e\n\u003cp\u003eNitinol implanted in the human cardiovascular system first comes into contact with blood, with its progressive encapsulation as it continues to endothelialise, followed by reduced contact with serum, and with its eventual complete endothelialisation, it comes into contact with human body fluids only. So initially seven media were selected for the extraction of Ni-Ti wires, namely goat whole blood, goat serum, 1% HNO\u003csub\u003e3\u003c/sub\u003e, 1% HCL, PBS buffer solution, simulated artificial body fluids, and water. The release of nickel from t seven extraction media was examined and it was found that 0.005% HCl could be substituted for goat blood. The extraction medium is specific for Ni-Ti alloys, which have a release rate more than 10 times that of Ni-Cr alloys, probably because the other element of the alloy, especially Cr element, Ti hardly reacts with diluted HCl.\u003c/p\u003e\n\u003cp\u003ePDE value for Ni is of 50 \u0026mu;g/d[23]. The amount of Ni released from sample S3 exceeded the PDE limit of 20\u0026mu;g/day for Class III elements in ICH-Q3D, but did not exceed the PDE value of 50\u0026mu;g/day for Ni in USP232, and as to whether it is clinically hazardous or not, at present Our study does not allow us to draw definite conclusions, but we can tentatively conclude that the clinical application of sample S3 is risky. The blockers used in our study were all used in adults and had a PDE of 20 \u0026mu;g/day. using 0.005% hydrochloric acid as the extraction medium, the release of Ni was 2.5 times greater than that of whole goat blood and 2.5 times greater than that of the normal in vivo environment. The maximum daily release of Ni ions from the S3 product is 38.7 \u0026mu;g, which translates into an release of 15.5\u0026mu;g in vivo. The maximum daily release of Ni ions from the S1 product is 13.36 \u0026mu;g, which translates into a release of 5.4 \u0026mu;g under normal in vivo environmental conditions.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eThe extraction medium screened in this study, a 0.005% solution of hydrochloric acid, is a complete substitute for the in vivo environment for the effective and safe evaluation of Ni-Ti products. The extraction medium is clinically equivalent to blood for the evaluation of Ni-Ti cardiovascular products, but the extraction medium is simple to prepare and easy to handle, and the extraction solution is also simple and easy to use for the determination of Ni content. A preliminary guideline for the in vitro safety evaluation of Ni release from Ni-Ti alloy metal implants has been developed for the reference of quality regulators.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Conceptualization, Resources, KX.; Methodology, Formal analysis, Data curation, B.Z.; Software , D.L.; Formal analysis, Validation, C.W; Supervision, Project administration, B.L.; Visualization, Validation, X.H. and P.H.; Writing\u0026mdash; original draft, Writing\u0026mdash;review \u0026amp; Editing, Y.H. data curation, J.L. and N.H. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e Data are contained within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclaimer/Publisher\u0026rsquo;s Note:\u003c/strong\u003e The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eA. Biesiekiersk, J. Wang, M.A.-H. Gepreel, C. Wen, A new look at biomedical Ti-based shape memory alloys, Acta Biomater, 8(5), 1661-1669 (2012)\u003c/li\u003e\n\u003cli\u003eW.H. Organization, \u0026quot;Carcinogenic list,\u0026quot; International Agency for Research on Cancer 1987\u003c/li\u003e\n\u003cli\u003eGanavi Ramagopal, Bhanu Duggal, N.O. Bansal，, Ganesh Narayana, Study of Nickel Levels in Patients with Atrial Septal Defect Undergoing Amplatzer Device Closure, Heart Views, 19(3), (2018)\u003c/li\u003e\n\u003cli\u003eO. Elkiran, C. Karakurt, G. Koca, C. 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Magnussen, Structure, dissolution, and passivation of Ni(111) electrodes in sulfuric acid solution: an in situ STM, X-ray scattering, and electrochemical study, Electrochimica Acta, 48(9), 1169-1191 (2003)\u003c/li\u003e\n\u003cli\u003eThe United States Pharmacopeial Convention., U.S. Pharmacopeia / National Formulary, 2013\u003c/li\u003e\n\u003c/ol\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ni release, safety evaluation, extraction media, Ni-Ti alloys cardiovascular stents, in vitro","lastPublishedDoi":"10.21203/rs.3.rs-4057011/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4057011/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Nickel (Ni) is a major element of several alloys for implantable cardiovascular devices (stents and blockers).Due to the lack of reliable research models, there is no domestic and international evaluation system for Ni release in the medical device field before 2018.Now, there are some standards such as ASTM F3306-19 and ISO 10993 appeared. They should help us to control and analyze the Ni ion release from the implant medical devices. But all these standards are short of a solution that it can take the place of the complex simulated body solutions and blood, serum. Our aim is to discover the easy solution. It should make the evaluation of Ni release easy to do. Nickel-Titanium (NiTi) cardiovascular alloy products with registration certificate in National Medical Product Administration in China were chosen as samples in the investigation. In this study, C, H, N, O was measured by oxygen, nitrogen and hydrogen elements analyzer and mental element content was determined by Electron - coupled plasma atomic emission spectrometry (ICP-AES). While corrosion resistance was evaluated by electrochemistry. Ni release curves were plotted by measuring the amount of Ni released from seven extraction media. All the metallic and non-metallic content of samples were qualified with GB24627-2009. Wilcoxon Test showed that HCl was identified as a possible alternative to blood. The extraction medium was determined to be 10mL 0.005% HCl with a limit 50μg /d while time was 7 consecutive days with the temperature at 37°C.It was proved with a high degree of specificity and reliability. The evaluation guideline provides technical support for the review and regulatory authorities, and is of great significance in improving the quality and safety of such products, providing guidance for the standardized development of the Ni-Ti alloy cardiovascular product industry in China, with significant social benefits.","manuscriptTitle":"Safety Evaluation for Nickel Release of Nickel–Titanium alloys Cardiovascular stents","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-13 11:28:43","doi":"10.21203/rs.3.rs-4057011/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b6794cce-a225-4b34-9be6-00f48b7c0bbb","owner":[],"postedDate":"March 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-07T16:05:43+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-13 11:28:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4057011","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4057011","identity":"rs-4057011","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}