Mechanism of Acceleration of Iron Corrosion by a Polylactide Coating

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Biological and Medical Applications of Materials and Interfaces

Mechanism of Acceleration of Iron Corrosion by a Polylactide Coating Yongli Qi, Xin Li, Yao He, Deyuan Zhang, and Jiandong Ding ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b17125 • Publication Date (Web): 04 Dec 2018 Downloaded from http://pubs.acs.org on December 13, 2018

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ACS Applied Materials & Interfaces

Mechanism of Acceleration of Iron Corrosion by a Polylactide Coating

Yongli Qi1), Xin Li1), Yao He1), Deyuan Zhang2), Jiandong Ding1)*

1)

State Key Laboratory of Molecular Engineering of Polymers, Department of

Macromolecular Science, Fudan University, Shanghai 200438, CHINA

2) R&D

Center, Lifetech Scientific (Shenzhen) Co., Ltd., Shenzhen 518057, CHINA

KEYWORDS: biodegradable polymer; iron-based stent; surface coating; metalpolymer composite; corrosion mechanism.

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ABSTRACT: Strong and biodegradable materials are the key to the development of next-generation medcial devices for interventional treatment. Biodegradable polymers such as polylactide (PLA) have controllable degradation profiles, but the mechanical strength is much weaker than some metallic materials such as iron; on the other hand, tuning the corrosion rate of iron to a proper time range for biomedical applications has always been a challenge. Very recently, we have achieved a complete corrosion of iron stent in vivo within clinically required time frame by combining a PLA coating, which provides a new biomaterial type for the next-generation biodegradable coronary stents termed as metal-polymer composite stent (MPS). The underlying mechanism of accelerating of iron corosion by a PLA coating remains an open fundamental topic. Herein, we investigated the corrosion mechanism of an iron sheet under a PLA coating in the biomimetic in vitro condition. The Pourbaix diagram (potential versus pH) was calculated to present the thermodynamic driving force of iron corrosion in the biomimetic aqueous medium. Electrochemical methods were applied to track the dynamic corrosion process and inspect various potential cues influencing iron corrosion. The present work reveals that acceleration of iron corrosion by the PLA coating arises mainly from decreasing the local pH owing to PLA hydrolysis and from alleviating the deposition of the passivation layer by the polymer coating.


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1. INTRODUCTION Biodegradable materials for regenerative medicine should possess befitting mechanical properties and degradation profiles to match the native tissue healing.1-6 Two material classes have been the focus of the biodegradable materials for cardiovascular treatments: polymer and metal. In general, polymer exhibits more adjustable degradation rate while metal shows better mechanical strength.7-12 In particular, strong biodegradable materials have been the wave of the future in the percutaneous intervention. Degradable scaffolds should provide sufficiently temporary strength to resist vessel recoil at the early stage while long-term complications could be eliminated after the degradation of the implanted biomaterials.3, 13-15 The key to the development of biodegradable stents is finding appropriate materials

to achieve an ideal balance between mechanical properties and degradation profiles besides biocompatibility. Among the current biodegradable stents, ABSORB BVS (Abbott Vascular, Santa Clara, USA) made of polylactide (PLA) is still troubled by its relative weak mechanical properties16-19, and DREAMS (Biotronik AG, Buelach, Switzerland) made of magnesium alloy is expected with a slower corrosion rate20-22, both of which result in larger strut thicknesses compared to durable metal stents used in clinic.23 Iron stents exhibit better mechanical performance than stents made of bioresorbable polymers and other biocorrodible metals.24 In 2001, Peuster et al. implanted an iron stent into the descending aorta of a rabbit and proved its feasibility as a biodegradable stent. However, most of the iron struts still uncorroded 18 months after implantation, and thus a faster corrosion rate of iron has been much desired.25 The subsequent animal studies showed no local or systemic toxicity of iron stents, yet the development of biodegradable iron stents has been hindered by their slow corrosion rates.26-30 Some efforts have been made to accelerate iron corrosion using methods of alloying31-35, composite with ceramics36 and surface modification37-41. Even though a relative faster corrosion rate has been demonstrated in vitro by these means, a complete corrosion of an iron stent in vivo has never been achieved until our report on a metalpolymer composite stent (MPS) made of iron substrate and PLA coating.42



It seems worthy of noting that the term “composite” is justified to describe a material system with component A coating on component B if the system exhibits some property beyond a normal coating, despite of no structure of an ordinary composite with A dispersed in B. As defined in the book “Mechanics and Analysis of Composite Materials”, “Generally speaking, any material consisting of two or more components with different properties and distinct boundaries between the components can be referred to as a composite material.”43 Combined with another book “Composite materials: science and engineering”44 and a recent paper in Nature Materials titled “The development of bioresorbable composite polymeric implants with high mechanical strength” (actually a polymer coating on another polymer)3, a composite indicates a material system composed of two or more classes of materials in contact and exhibits new or significantly enhanced properties beneficial for mankind. Utilizing the facile composite design, our MPS can maintain sufficient scaffolding strength at the early stage and possess controllable degradation rate. Complete corrosion of iron struts has been achieved in 3-6 months by adjusting the composition of the PLA coating. PLA is a popular hydrolytically biodegradable polyester and has been approved by Food and Drug Administration (FDA) for application in bioresorbable stents.45-46 Painting and coating with organic materials is a widespread method to provide corrosion protection.47-48 It is surprising that our previous work42 has illustrated that a PLA coating could dramatically accelerate iron corrosion both in vitro and in vivo much beyond the normal function as a layer for drug eluting. A successful first-in-man implantation of iron-based bioabsorbable scaffold (IBS) applying the ironPLA composite technique has been presented in the opening ceremony of China Interventional Therapeutics Congress in March 2018.49 The exciting clinical trial strongly calls for extensive fundamental research to explore the mechanism of iron corroison under a PLA coating, which is the theme of the present report. Herein, Pourbaix diagram for Fe-H2O system under a biomimetic aqueous condition was calculated by us to illustrate the effect of pH on iron corrosion thermodynamically. Then we designed a series of in vitro experiments to inspect the iron corosion profiles. In order to well control the in vitro experiments, we examined


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iron sheets instead of three-dimensional stents. Considering that the implanted iron stents may contact with weak alkaline, oxygen and inorganic ions rich arterial blood, we employed Hank’s solution, which is of the similar pH and inorganic ions to plasma, to mimic the arterial blood environment. The effect of a PLA coating on iron corrosion was investigated using electrochemical methods mainly including potentiodynamic polarization curves for assessment of corrosion rate and electrochemical impedance spectroscopy (EIS) for analysis of coating evolution. Besides the experimental group of PLA-coated iron, we set bare iron and PMMA-coated iron as two control groups. Here, PLA and poly(methyl methacrylate) (PMMA) represent biodegradable and nonbiodegradable polymers, respectively. Local pH values in the interfaces between iron and polymer coatings were measured. As PLA can be hydrolyzed to produce terminal carboxyl groups, the effects of H+ and lactate ions on iron corrosion were further examined independently. In addition, a passive layer formed on iron surface plays an important role in the slow corrosion rate, so the effects of calcium ions and phosphate ions in the corrosive medium were also examined. Based on the theoretical calculation and experimental analysis, the mechanism of acceleration of iron corrosion by the PLA coating was finally discussed.

2. MATERIALS AND METHODS 2.1 Calculation of Pourbaix Diagram for Fe-H2O System under Biomimetic Environment. Main reactions related to iron corrosion are listed in Table S1, and were used to construct the Pourbaix diagram for Fe-H2O system. For reactions with z electrons involved (z ≠ 0), the relationship between Gibbs free energy G and potential Ψ is written as △ r𝐺 = ―𝑧𝐹𝛹 Here, F is the Faraday’s constant, namely, the amount of charges per molar electrons (96 494 C). Then, 𝑧𝐹𝛹 = ― △ r𝐺θ + 𝑅𝑇ln[𝛼𝑎A/𝛼𝑏B] ― 2.303𝑛𝑅𝑇 ∙ pH



△ r𝐺θ = ―𝑧𝐹𝛹θ Here,  refers to activity of the corresponding species, R and T are gas constant and absolute temperature, respectively, and Ψθ indicates the standard electrode potential. The potential is related to the inherent property of a cell and the activities of the electrolytes by Nernst equation, which is expressed as 𝛹 = 𝛹θ + 𝑅𝑇ln[𝛼𝑎A/𝛼𝑏B]/𝑧𝐹 ― 2.303𝑛𝑅𝑇 ∙ pH/𝑧𝐹 For reactions involving H+ but not involving any electrons, z = 0, n ≠ 0. Then, ― △ r𝐺θ

1 𝛼𝑏B pH = ― lg 2.303𝑛𝑅𝑇 𝑛 𝛼𝑎A The general relations between electrode potentials and pH for each reaction are summarized in Table S2. The standard Gibbs free energy for a reaction at the body temperature is ready from △ r𝐺θ(310 K) = △ r𝐻θ(310 K) ― 310 × △ r𝑆θ(310 K) The standard enthalpy of the reaction at 37C (△r Hθ(310 K)) and the standard entropy of the reaction at 37C (△r Sθ(310 K)) were calculated from those at 25C. For simplifying the operation, heat capacities between 25°C (298 K) and 37°C (310 K) were assumed constants, and a constant approximation was also made for enthalpy between 298 K and 310 K. The enthalpies, entropies and heat capacities at constant pressure for each reaction equation at 25°C, namely, △r Hθ(298 K), △r Sθ(298 K), Cp(298 K), were calculated from the standard thermodynamic quantities of formation of reactants and chemicals involved in the reactions. The reported standard enthalpies, entropies and heat capacities of formation of the components (25°C) are summarized in Table S3. The final results of △r Hθ(310 K), △r Sθ(310 K) and △r Gθ(310 K) are listed in Table S4. The potential-pH relations for each reaction under physiological condition were obtained by taking the physiological parameters into the equations listed in Table S2. Here, the partial pressure of oxygen was taken as 13.3 kPa according to the physiological conditions of human arterial blood50, the pressure of hydrogen was set as the blood pressure (760+100) mmHg, the activity of Fe3+ was set as 3×10-5 mol/L


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according to its content in plasma, and the activity of Fe3+ was set as 1×10-6 mol/L, which is the detection limit of most instruments. Potentials of any electrodes are compared with that of the standard hydrogen electrode (SHE). SHEs at all temperatures are defined as zero volts. The relations of potential (vs SHE)-pH are listed in Table S5. The Pourbaix diagram presenting relations of pH and potential was constructed by the equations in Table S5. We introduced a hydrogen overpotential into the hydrogen line. The value of the hydrogen overpotential was taken as 0.2 V, and thus the hydrogen line in the modified Pourbaix diagram was moved down 0.2 V for intuitive guidance of engineering use. 2.2 Preparation of Iron Sheets and Bare Iron Electrodes. The 10 mm × 10 mm samples were cut from an iron sheet (pure iron, > 99.9 wt%) with a thickness of 0.2 mm and welded onto copper wires. Then the samples were sealed by epoxy resin, leaving only one surface exposed. The embedded samples were polished by SiC papers of grit sizes from 800, 1500, 2000 to 3000 followed by ultrasonic cleaning in acetone and anhydrous ethanol successively. After quickly dried by nitrogen gas, the sealed 10 mm × 10 mm iron sheets were used as the bare iron electrodes. The iron sheets used in other experiments were polished, cleaned and dried with the same method as for treatment of the bare iron electrodes. 2.3 Preparation of Polymer Coatings. PMMA-coated iron electrodes and PLAcoated iron electrodes were prepared by ultrasonic spray coating of the corersponding polymer solutions on the bare iron electrodes. In detail, granules of PMMA (weightaverage molecular weight Mw : 128 kDa) and PLA (Mw : 60 kDa) were dissolved in ethyl acetate to prepare 0.01 g/mL polymer solution. The solution was ultrasonically sprayed on the exposed surfaces of bare iron electrodes using an unltrasonic spray integration system (Ruidu Photoelectric, Shanghai, China). The syringe pump dispense rate of the polymer solution was 0.10 mL/min, and the ultrasonic power was 4.75 W. PMMA-coated iron sheets and PLA-coated iron sheets for charaterizations of surface properties and hydrogen release test were prepared by the same method as the polymer-coated electrodes. The polymer-coated iron sheets used for PLA degradation



test, pH measurement and element distribution analysis were prepared by casting 200 μL ethyl acetate solution of the polymer (0.1 g/L) on each iron sheet with a size of 22 mm × 26 mm. The back side and peripheral edges of bare iron sheets and polymer-coated iron sheets were sealed by silicone before immersed in Hank’s solution for hydrogen release test, PLA degradation test, pH measurement and element distribution analysis. One liter of Hank’s solution contained 0.14 g CaCl2, 0.4 g KCl, 0.06 g KH2PO4, 0.1 g MgCl2·6H2O, 0.1 g MgSO4·7H2O, 8.0 g NaCl, 0.35 g NaHCO3, 0.12 g Na2HPO4·12H2O, and 1.0 g D-glucose. 2.4 Effect of Dissolved Oxygen on Corrosion Current Density. In the test of the effect of dissolved oxygen (DO), the DO concentration in normoxic Hank’s solution was about 8 mg/L. The Hank’s solution was deaerated by bubbling nitrogen gas into the normoxic Hank’s solution for 30 min. The DO concentration was monitored by a portable DO meter (Orion Star A, Thermo Scientific) and the final concentration in the deaerated solution was about 0.05 mg/L. The normoxic and deaerated Hank’s solutions of different pH's adjusted by adding lactic acid were used as electrolytes for the potentiodynamic scanning tests. The tests were conducted using a typical three electrodes cell with bare iron as the working electrode, a saturated calomel electrode (SCE) as the reference electrode, and a platinum sheet as the counter electrode. We carried out the potentiodynamic scanning tests in 500 mL Hank’s solution at 37°C, using an electrochemical workstation CHI760E (Shanghaichenhua, China). Before the tests, the samples were immersed in Hank’s solution for 30 min to obtain a steady open circuit potential (OCP). The working electrode was first polarized cathodically to -400 mV vs. OCP, and then anodically to +400 mV vs. OCP with a scanning rate of 0.33 mV/s. During the experiments, the exposed area of the work electrode was 1 cm2. Corrosion current densities of bare iron in different electrolytes were calculated by Tafel curve fitting with the included software of the electrochemical workstation. 2.5 Hydrogen Release Experiments. Hydrogen evolution experiments were carried out by immersing polished bare iron sheets of 30 mm × 30 mm in Hank’s


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solutions at pH 4.0, 5.0, 6.0 and 7.4, and PLA-coated iron sheets or AZ31 magnesium alloy sheets of the same size in Hank’s solution at pH 7.4. Each sample was immersed in 200 mL Hank’s solution in a glass beaker. The experiments were conducted in a water bath shaker (37°C, 50 rpm). The hydrogen gas was collected at the end of the funnel. Its volume was recorded at the scheduled time. The immersion solution was refreshed every 24 h. 2.6 Degradation of the PLA Coating on Iron. Each PLA-coated iron sheet was immersed in 10 mL Hank’s solution, and the solution was refreshed every 24 h. Degradation lasted for 28 days in a water bath shaker (37°C, 50 rpm). After 7, 14, 21 and 28 days of immersion, the samples were taken out, and the PLA coating was peeled off for characterization of molecular weight (MW) and its dsitribution with gel permeation chromatography (GPC, Agilent/Wyatt, USA). The GPC measurement was carried out at a flow rate of 1 mL/min using tetrahydrofuran as the mobile phase. Polystyrene standards were used for calibration. 2.7 Measurement of Local pH on the Surface of Bare Iron and the Interfaces of Polymer-Coated Iron. Each piece of bare iron, PMMA-coated iron or PLA-coated iron sheet was immersed in 10 mL Hank’s solution and put in the water bath shaker (37°C, 50 rpm). After 24 h, the iron sheets were taken out for surface pH measurements. Hank’s solution on the surfaces of the iron sheets was removed gently by paper before pH tests. For bare iron sheet, some points were drawn on its surface directly using a pH tester pen (DW-1k, Nikken Chemical Laboratory Co., Ltd.) with a scale range of 5.8 ~ 8.2. For PMMA-coated iron and PLA-coated iron, the polymer coatings were peeled off by first cutting off the peripheral edges of the polymer-coated iron sheets and then using thin-tipped tweezers stripping the polymer coatings from the edges. Both the surfaces of iron substrates and the surfaces of the polymer coatings adjacent to iron substrates (original interior surfaces of the polymer coatings) were drawn on points using the pH tester pen. The pH values of the tested surfaces were determined by comparing the color of the points drawn on the surfaces with the pH color scale on the pen. The tested surfaces



were photographed immediately after the points were drawn on, and the color scale of the pH tester pen was photographed under the same light conditions. We used the software of ColorPix to pick the color in the photograph of the pH tester pen. 2.8 Characterization of the Surface Properties. We evaluated the surface wettability of bare iron, PMMA-coated iron and PLA-coated iron via water contact angles. Two microliters of Milli-Q water was dropped onto the sample surfaces automatically using a contact-angle-measuring device (JC2000DM, Zhongchen). Three points on each sample were detected, and three samples were measured for each group. We employed Fourier transform infraed (FTIR) spectroscopy to characterize the chemical groups on the surfaces. FTIR spectra of bare iron sheet, PMMA-coated iron sheet and PLA-coated iron sheet were measured with Nicolet 6700 (Thermo Fisher). The samples were placed on and contacted directly with an attenuated total reflectance (ATR) crystal. The FTIR spectra between wavenumber of 4000 and 500 cm−1 were recorded. The spectra were analyzed by Omnic 8.2 software. The surface mophologies of bare iron, PMMA-coated iron and PLA-coated iron were observed with a ﬁeld-emission scanning electron microscope (FE-SEM, Ultra 55, Zeiss, Germany). 2.9 Immersion Test under Biomimetic Aqueous Condition. The electrodes of bare iron, PMMA-coated iron and PLA-coated iron were hung and immersed in 500 mL Hank’s solution incubated in water bath shaker (37°C, 50 r/min) for 28 days. The Hank’s solution was refreshed every two days. At assigned time, the samples were taken out for photographing and electrochemical tests. Potentiodynamic scanning tests were performed after the work electrodes immersed in Hank’s solution for 0, 0.5, 1, 3, 5, 7 ,10, 14, 21 and 28 days. The testing parameters and calculation methods of corrosion potential (Ecorr) and corrosion current density (icorr) were the same as described in 2.4. All the electrochemical tests were conducted at 37°C in an electrolytic cell containing 500 mL Hank’s solution. 2.10 EIS Tests. Prior to the immersion test and after 3, 14, 28 days of immerison in Hank’s solution, EIS tests were carried out using the single AC model to monitor the


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corrosion process of the bare iron, PMMA-coated iron and PLA-coated iron. All the EIS measurements were performed at OCP with alternating current amplitude of 20 mV, and the applied frequencies varied from 100 kHz to 0.01 Hz. The impendance spectra of the samples were analyzed in Nyquist and Bode plots. Four samples of each group were used for EIS tests. The ZSimpWin software was used to analyze the impedance data, by which the equivalent electrical circuit and the parameters were obtained. 2.11 Examination of Effects of pH and Lactate Concentration on Iron Corrosion. For the pH effect tests, the Hank’s solution was adjusted to pH 7.4, 6.5, 6.0, 5.5, 5.0 4.5, 4.0 and 3.0, using 0.05 g/mL and 0.30 g/mL lactic acid solution. The concentration of lactate ions in Hank’s solutions of different pH values could be calculated from the amount of added lactic acid. For the effect of lactate concentration tests, Hank’s solutions containing 0, 0.01, 0.1, 0.2, 0.5, 1.0 and 2.0 mol/L lactate ions were obtained by adding lactic acid and then adjusting pH to 7.4 using NaOH. The Hank’s solutions of different pH's and of pH 7.4 containing different concentrations of lactate ions were used as electrolytes for potentiodynamic scanning tests. The corrosion potential and corrosion current density were obtained using the same method as described in 2.4. 2.12 Element Distribution on Bare Iron and PLA-Coated Iron. Samples of bare iron and PLA-coated iron were taken out for morphology observations and element analysis after 72 h of immersion in Hank’s solution. The surfaces of bare iron and PLAcoated iron were rinsed by deionized water and ethyl alcohol successively. After vacuum drying, the PLA coating was peeled off. Then the bare iron surface, iron surface under a PLA coating and the PLA coating surface adjacent to the iron were observed under FE-SEM (Ultra 55, Zeiss, Germany) equipped with energy-dispersive X-ray spectrometer. 2.13 Examination of Effects of Calcium Ions and Phosphate Ions on Iron Corrosion. After immersed for 0, 3 and 14 days in Hank’s solution and D-CaP (free of calcium and phosphate ions) Hank’s solution, the electrodes of bare iron, PMMAcoated iron and PLA-coated iron were taken out for potentiodynamic scaning tests in



Hank’s solution and D-CaP Hank’s solution. Compositions of the Hank’s solution and D-CaP Hank’s solution are listed in Table S6. While the Hank’s solution contained the same salts as decribed in 2.5, the D-CaP Hank’s solution was prepared without addition of CaCl2, Na2HPO4·12H2O and KH2PO4. The immersion experiment was conducted in the water bath shaker as decribled in 2.9, and the corrosion current density was obtained using the same method as described in 2.4. 2.14 Statistical Analysis. Three independent samples in each group were examined in the hydrogen release tests and potentiodynamic scanning tests. The results of hydrogen volume, corrosion current density and corrosion potential were expressed as mean ± standard deviation (SD). In the tests of the effects of pH, lactate ions, and those of the calcium and phosphate ions on iron corrosion, the student t-tests were used to estimate a significant difference, which was denoted as “*” (p < 0.05), “**” (p < 0.01) or “***” (p < 0.001).

3. RESULTS 3.1 Calculated Pourbaix Diagram for Fe-H2O System under Biomimetic Condition. Pourbaix diagram, or potential-pH diagram, reveals the thermodynamics of metal corrosion in a compact way.51 It is a fundamental tool for corrosion studies. A Pourbaix diagram for Fe-H2O system was calculated at 37°C (Figure 1A) and the calculation procedure was described in the part of S1 in Supporting Information. As the values of partial oxygen pressure and Fe3+ concentration were assigned according to the arterial blood component of human, this modified Pourbaix diagram could predict the corrosion tendency of iron under the physiological condition to some extent. From the diagram, a stronger thermodynamic driving force can be seen for both hydrogen evolution reaction and oxygen reduction reaction with the decrease of pH, indicating a greater tendency of iron corrosion. As PLA hydrolysis may produce a local acidic microenvironment, we assumed that a PLA coating could accelerate iron corrosion.


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Figure 1. Schematic illustration of the corrosion profiles of bare iron and PLA-coated iron. (A) Calculated Pourbaix diagram for Fe-H2O system at 37°C. We set p(O2) = 13.3 kPa, c(Fe2+) = 1×10-6 mol/L, c(Fe3+) = 3×10-5 mol/L according to the corresponding contents in human arterial blood. Hydrogen gas pressure in the blood is set as the average blood pressure, namely, p(H2) = (760+100) mmHg. We modify the Pourbaix diagram by considering hydrogen overpotential, and thus the hydrogen line is moved down for 0.2 V. (B) The upper row indicates the electrode reactions of iron corrosion in alkaline, near-neutral and acidic corrosion media; the lower row illustrates the electrode processes and the adjacent environment of iron and PLA-coated iron. Oxygen reduction happens in the near-neutral microenvironment under a PLA coating.

Corrosion of iron in physiological conditions involves setting-up of electrochemical corrosion cells.52 Anodic reactions and cathodic reactions are always coupled with each other during an electrochemical corrosion process. When iron corrodes in an aqueous solution, iron loses electrons and generates ferrous ions at anodic areas. At cathodic areas, reactions of oxygen molecules and hydrogen ions depend on the pH of the corrosion medium, as presented in the upper row of Figure 1B. In an alkaline or near-neutral environment, oxygen is reduced to generate OH-; in an acidic environment, oxygen is reduced to generate water, and hydrogen ions may accept electrons to generate hydrogen gas. Although PLA hydrolysis must lead to lowering the local pH, the OH- produced



by oxygen reduction shall result in partial neutralization. Considering that the PLA coating is adjacent to a weak alkaline solution in the biomimetic environment, the very local microenvironment of the iron surface in the PLA-coated iron is probably nearneutral, as schematically indicated in Figure 1B.

3.2 Tests of Oxygen Effect on Corrosion Current Density and Tests of Release of Hydrogen Gas during Metal Corrosion. As the cathodic reactions include oxygen reduction and hydrogen evolution in acidic solution when iron corrodes, we examined corrosion current densities (icorr) in normoxic and deaerated Hank’s solutions under different pH values by potentiodynamic scanning tests. A typical three-electrode system as diagramed in the left of Figure 2A was applied in the tests, and the results of icorr are presented in the right of Figure 2A. In the normoxic Hank’s solution, icorr increased sharply with the decrease of pH, which might result from the acceleration of both oxygen reduction and hydrogen evolution reactions in the cathode. After deaerating, icorr decreased compared with that of normoxic Hank’s solution in the pH range of 6.5 and 4.5, illustrating that oxygen reduction played an important role in the cathodic reactions when the pH value was higher than 4.5. The icorr underwent a sudden increase at pH 4.0 with further decrease of pH in the deaerated Hank’s solution, indicating that hydrogen evolution started to dominate the cathodic process under this condition.


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Figure 2. (A) Schematic diagram of a three-electrode system for electrochemical test (left) and corrosion current densities (icorr) of bare iron in normoxic and deaerated Hank’s solutions of different pH's (right). The icorr was calculated by Tafel curve fitting. The dissolved oxygen concentrations of normoxic and deaerated groups were about 8.0 mg/L and 0.05 mg/L, respectively. (B) Detection of hydrogen evolution of bare iron at indicated different pH's, PLA-coated iron and AZ31 magnesium alloy at pH 7.4. The top left is a schematic diagram of H2 gas collection device. The surface area of each sample was 9 cm2.

We also measured the volume of hydrogen gas by immersing the samples in normoxic Hank’s solution using a collection device as shown in the top left of Figure 2B. Hydrogen gas was collected during the corrosion of bare iron in different pH's and PLA-coated iron in Hank’s solution at pH 7.4. A magnesium alloy in Hank’s solution of pH 7.4 was also tested as a control.



As shown in Figure 2B, the volume of collected hydrogen gas increased slowly and continuously during the corrosion of bare iron in pH 4.0, and no more than 3 mL was collected for 7 days. Compared with that at pH 4.0, corrosion of bare iron at pH 5.0 and pH 6.0 produced little hydrogen gas for 7 days of immersion, which was consistent with the results of icorr in Figure 2A. No hydrogen gas was collected for bare iron and PLA-coated iron at pH 7.4. In contrast, the corroison of magenisuim alloy in Hank’s solution at pH 7.4 released much more hydrogen gas than bare iron at pH 7.4 4.0, indicating not only a faster corrosion rate of magenisium alloy than bare iron but also the predominent corrosion mechnaism via hydrogen evolution. Even though the results could not certify that no hydrogen reduction occured at all during iron corrosion under a PLA coating, it is conclusive that hydrogen bubbles are, if any, insignificant, and thus may not be a problem for the PLA-coated iron when applied in vascular stents. It is noteworthy that pH 4.0 seems like a turning point of iron corrosion in Hank’s solution, lower than which hydrogen evolution starts dominating in cathodic reactions. 3.3 Degradation of PLA Coating on Iron and Measurements of Surface/Interface pH Values. PLA can be hydrolyzed to produce carboxyl terminal chains and hydroxyl terminal chains as shown in Figure 3A, and thus a PLA coating on iron was supposed to degrade to polymer segments of low molecular weight under a biomimetic condition. Evolution of molecular weight distribution (MWD) of the PLA coating on iron was examined via GPC, with results shown in Figure 3B. The GPC curves of the initial PLA coating (without immersed in Hank’s solution) exhibited a higher peak at short elution time and weak peaks at longer elution time, indicating that most of the PLA chains were of high molecular weight. With the immersion time prolonging, the peak at left became lower and wider, while the peak at right became higher, manifesting that PLA had degraded to produce more chains of low molecular weight or small molecules of lactic acid. As a control, we also exmained the degradation of a PLA coating on glass. The GPC profiles in Figure S1 showed a faster degradation of the PLA chains coating on glass than on iron at the late immersion stage. The relatively slower degradation of the


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PLA macromolecules coated on iron might arise from the alkaline microenvironment produced by corrosion products of iron. Given that the PLA coating could degrade to produce acidic products on iron, we measured the pH of the interface of PLA-coated iron sheet and the pH of the bare iron surface. PMMA, a typical non-biodegradable polymer, was also coated on iron as a control. The pH's of the interfaces were determined by examining both the surfaces of iron substrates and the surfaces of polymer coatings adjacent to iron. The results showed that the tested surfaces of the PMMA-coated iron were weak alkaline and the surface of the bare iron was more alkaline than the interface of the PMMA-coated iron (Figure 3C). For the PLA-coated iron, both the tested surfaces were confirmed to be acidic. The pH value on the interface of the iron substrate and the PLA coating was about 5.6, which was further confirmed by the measurement results of another pH tester pen (Figure S2). Even though this method was unavailable for long time tracking because of the interferences of the dark corrosion products, we can conclude that the lower pH under the PLA coating might contribute to a faster corrosion rate of the PLA-coated iron from the results of the 24 h immersion test.



Figure 3. Degradation of PLA coating on iron, local pH measurements, surface properties, and corrosion morphologies of iron. (A) The reaction formula of hydrolysis of PLA. (B) GPC curves of


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remaining macromolecules in PLA coatings on iron sheets at the indicated degradation times. The in vitro degradation experiments were conducted in a standard Hank’s solution at 37°C. The initial pH of Hank’s solution was 7.4, and the solution was refreshed every 24 h. (C) Local pH measurements on the surface of bare iron and the interfaces of polymer-coated iron. Both the surfaces of the iron substrates and the original interior surfaces of the polymer coatings adjacent to iron were tested to determine the interface pH's. The measurements were conducted after 24 h immersion in Hank’s solution. (D) Optical micrographs to detect water contact angles (upper row) and SEM images to observe surface morphologies (lower row) of bare iron, PMMA-coated iron and PLA-coated iron. The microparticles on the top surfaces of PMMA-coated iron and PLA-coated iron were caused by the scattered atomized droplets of the polymer solution. (E) ATR-FTIR spectra of the three surfaces. (F) Photographs of specimens for global observations of corrosion morphologies of iron electrodes with and without polymer coatings after immersed in Hank’s solution for the indicated times. The size of the iron sheet mounted on the epoxy resin was 10 mm × 10 mm. These results demonstrated that the PLA coating accelerated iron corrosion significantly.

3.4 Surface Properties and Corrosion Morphologies of Iron with and without Polymer Coatings. For both short time and long time trackings, we prepared PMMA coating and PLA coating on iron by ultrasonic spraying, which is a popular method of coating prepration for vascular stents. The PMMA and PLA coatings were both with a thickness of about 1.5 μm, as calibrated with a stylus profiler (Figure S3). The results of water contact angles illustrated that the surfaces of PMMA-coated iron and PLAcoated iron were more hydrophobic than that of bare iron (Figure 3D). We also prepared a PLA film on glass, representing the bulk PLA (Figure S4), and we confirmed that the PLA coating on iron had similar properties to the bulk PLA. SEM micrographs showed a scratched surface of bare iron, resulting from the polishing treatment. The PMMA coating and PLA coating exhibited similar surface topographies, which might result from the same coating preparation technology and the similar surface chemistry. We also carried out the FTIR measurments. Compared with the bare iron of scarce absorption peaks, the FTIR spectra in Figure 5E confirmed the formation of polymer coatings on iron sheets. The bulk PLA film (Figure S4B) showed similar absorption



characteristic peaks to those of the PLA coating on iron, illustrating no noticable chemical interaction between the iron substrate and the PLA coating. The immersion test is the most traditional and visual method for the study of metal corrosion. The surface morphologies of bare iron, PMMA-coated iron and PLA-coated iron after immersed in Hank’s solution for scheduled time are presented in Figure 3F. The PMMA coating and PLA coating prepared by ultrasonic spraying were both trasparent on iron. At the early stage, bare iron started corroding at a few local spots preferring at the sealed edges. Then the corrosion spot grew over time and brownish corrosion products accumulated at the local sites. Even after 28 days of immersion, most of the bare iron surface still uncorroded and showed metallic luster. For the PMMA-coated iron, a few corrosion spots appeared after 6 h of immersion and the corrosion sites extended over immersion time. On day 28, most parts of the iron surface beneath the PMMA coating turned to green and started corroding. For the PLA-coated iron, many corrosion spots appeared on the iron surface after merely 6 h immersion. The color of the iron surface turned darker and the corrosion area became larger over immerison time. On day 28, the entire surface of iron substrate beneath the PLA coating corroded seriously, and some brown corrosion products accumulated outside the coating. As a result, the PMMA coating could make iron corrode a bit faster, and the biodegradable PLA coating accelerated iron corrosion dramatically. The effect of the PLA coating on accelerating iron corrosion is surprising and important for the development of a new-generation coronary stent. A study of the underlying eletrochemical mechanism is thus very necessary. 3.5 Measurements of Potentiodynamic Polarization Curves. We then employed electrochemical methods to track the corrosion profiles of bare iron, PMMAcoated iron, and PLA-coated iron. At first, the time-dependent open circuit potential (OCP) was monitored for 24 h (Figure S5). The OCPs of bare iron and PLA-coated iron both decreased sharply and reached stabilization in 1 h and 4 h, respectively. In contrast, the OCP of PMMA-coated iron fluctuated seriously and had not reached equilibrium after 24 h immersion. The faster OCP stabilization of the PLA-coated iron than that of


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the PMMA-coated iron implied easier permeation of electrolytes through the PLA coating. To investigate the long-term effect of the PLA coating on iron corrosion, polarization curves were measured. The corrosion potential (Ecorr) and corrosion current density (icorr) were calculated using Tafel extrapolation, as schematically presented in Figure 4A. The typical polarization curves of samples before and after the immersion test in Hank’s solution are shown in Figure 4(B). Initially, the current density of the anodic branch of PMMA-coated iron was significantly lower than that of the bare iron, while the current density of the PLA-coated iron was similar to that of the bare iron. This indicated a strong inhibition of iron corrosion by the PMMA coating. On day 28, the current density of both cathodic and anodic branches of the PLA-coated iron were significantly increased compared with that of the bare iron, showing an acceleration of iron corrosion in the presence of a PLA coating.



Figure 4. Potentiodynamic polarization curve tests. (A) Schematic presentation of polarization curve (left) and the determination of corrosion potential (Ecorr) and corrosion current density (icorr) with Tafel curve fitting (right). The terms ia and ic denote the current densities of anodic reaction and cathodic reaction, respectively. (B) Potentiadynamic polarization curves of bare iron, PMMAcoated iron and PLA-coated iron prior to the immerison test (left) and after immersed for 28 days (right). (C) Corrosion potential Ecorr (left) and corrosion current density icorr (right) of bare iron, PMMA-coated iron and PLA-coated iron as a function of immersion time. Ecorr in presence of the PLA and PMMA coatings became lower than that of bare iron at about day 2 and day 4, respectively.


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Figure 4C gives the Ecorr and icorr values of the three groups after assigned immersion time. The PMMA coating led to a shift of Ecorr to less negative potentials at the initial time, which was in agreement with the OCP results (Figure S5). The Ecorr of bare iron decreased dramatically over time and rapidly stabilized at about -800 mV with respect to SCE. In presence of the PLA coating, the Ecorr decreased slower than that of the bare iron but reached a stable value more rapidly than in presence of the PMMA coating, which manifested a better permeation of electrolytes through the PLA coating. As corrosion rate is proportional to icorr, the icorr was employed to characterize the effect of polymer coatings on iron corrosion rates. At the initial time, the icorr of the bare iron was greater than that of the PMMA-coated iron and similar to that of the PLAcoated iron, indicating that the PMMA coating prevented iron from corroding while the PLA coating nearly not. After 12 h immersion, the icorr of the bare iron decreased to 3.1 μA/cm2 from 7.9 μA/cm2 and maintained at this level till 28 days, postulating that a passivation layer resided on the iron surface and slowed down the corrosion rate of iron. Except at the initial time, the icorr of the PMMA-coated iron fluctuated but kept a similar level to that of the bare iron or was slightly greater than that of the bare iron over time. For the PLA-coated iron, the icorr increased over time and its value was far greater than that of the bare iron, e.g. 14.3 μA/cm2 vs 2.0 μA/cm2 on day 14, indicating that iron corrosion has been accelerated in the presence of the PLA coating. The quantitative results in Figure 4 are well consistent with the surface morphologies in Figure 3F. 3.6 Analysis of EIS Spectra. EIS is a powerful electrochemical method for assessing the relative corrosion protection of coatings. In an EIS measurement, a small perturnating sinusoidal voltage E0 = Esin(2πf ) is applied to the tested system with frequency f. The response is analysed in terms of the resultant current density i0 = isin(2πf + Φ), where Φ represents phase angle, as schematically presented in Figure 5A. The spectrum of corresponding complex impedance Z*(f ) can be obtained by varying the signal frequency f. The impedance spectrum is presented in a plot of Nyquist (–Z'' as the Y-axis and Z' as the X-axis scanning from high f to low f ) (Figure 5A). Using an equvalent circuit (EC) to decribe the EIS, a paralled RC circuit leads to a semicircle in the Nyquist plot.



The diameter of the semicircle equals to the resistance Rt, and thus a larger diameter illustrates better anti-corrosion ability. The time constant is determined by the inverse of characteristic frequency f *. Accounting for the non-ideal electric behaviour, constant phase element (CPE) and Warburg diffusion impedance elements (W) are often introduced, resulting in a circle arc and a diffusion line, respectively (Figure 5A).


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Figure 5. Impedance spectra of iron sheets with or without polymer coatings. (A) Schematic diagram of EIS principles and typical Nyquist plots for the indicated equivalent circuit with solution



resistance Rs, parallel charge-transfer resistance Rt, and double layer capacitance Cdl. The ideal semicircle turns to a circle arc by inducing a constant phase angle element (CPE) with the demonstrated dispersion index n assigned as 0.8, and a diffusion tail at an angle of /4 to the Z' axis in the low frequency is presented by introducing a Warburg impedance. The scanning frequency f is decreased from left to right. f * denotes the characteristic frequency. (B) Nyquist plots for different samples respected to the indicated immersion times. On day 0, a part of Nyquist plots in the dashed box was enlarged successively for better visualization of the PLA-coated iron and bare iron plots. (C) Bode plots for different samples at the indicated immersion times.

EIS was applied to further determine the effect of the PLA coating on the corrosion resistance of iron. The Nyquist plots are shown in Figure 5B. The capacitance loop was an imperfect semicircle attributed to the frequency dispersion caused by surface inhomogeneity of the sample. The capacitance loop of the PLA-coated iron was larger than that of the bare iron but much smaller than that of the PMMA-coated iron on day 0. So, the resistance of the PMMA-coated iron was much greater than that of the PLAcoated iron, while the PLA coating could hardly protect the iron from corroding even at the early stage. The curves of the PMMA-coated iron and the PLA-coated iron presented a mixture of two arcs, where the arc at high frequency was thought to be caused by the polymer coating. The mixture arcs of two time constants were poorly separated, which implied that the electrolyte started to penetrate into the coatings during the electrochemical tests. In contrast, the bare iron presented a single capacitance loop corresponding to only one time constant. The Nyquist plots changed drastically after immersed in Hank’s solutions, and each curve exhibited an arc and a tail after 3 days and 28 days of immersion. The capacitance loop at high frequency of the PMMA-coated iron became smaller, indicating the decrease of the corrosion resistance of the coating. For the bare iron, the size of the capacitance loop at high frequency increased with immersion time and a part of another capacitance loop appeared at low frequency, implying the formation of a barrier layer on the surface.


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We also presented the results of EIS tests in Bode plots in Figure 5C. It is known that a material with a higher impedance at lower frequencies exhibits better corrosion resistance. The impedance at low frequency of the PLA-coated iron was lower than the PMMA-coated iron and higher than the bare iron on day 0, indicating a poorer protection of the PLA coating than the PMMA coating. The impedance at low frequency of the bare iron increased and that of the PMMA-coated iron decreased dramatically over immersion time. The frequency dependence of the real part Z' and the negative imaginary part -Z'' of the impedance, as well as of the real part Y' and imaginary part Y'' of the admittance all showed an increase of corrosion resistance of the bare iron and a decrease of corrosion resistance of the polymer-coated iron over degradation time (Figure S6). The value of phase angle at high frequency reflects also coating performance. When the resistance of the coating is high, the coating can be equivalent to a capacitive, and the phase angle would be near -90°; when the resistance of a coating is low, the coating can be equivalent to a resistance, and the phase angle would be near 0°.53-54 The phase angles of the PLA-coated iron at high frequencies were below 20° at the initial time, meaning that electrolytes might have permeated through the PLA coating and electrochemical reactions under the coating might occur. The appearance of two time constants of the PLA-coated iron and the PMMA-coated iron on day 0 also indicated a rapid permeation of electrolytes through the polymer coatings. For the bare iron, time constant changed from one to two after immersed in Hank’s solution and the values of the phase angles at high frequencies increased over immersion time, indicating the formation of a passive layer and the increase of the resistance of the passive layer over time. 3.7 Effects of pH and Lactate Concentration on Iron Corrosion. The degradation products of PLA were supposed to influence iron corrosion. We then tried to explore which product plays a more important role, hydrogen ions or lactate ions. Corrosion current density (icorr) was employed to quantify the corrosion rate of iron: a larger icorr indicated a higher corrosion rate. According to Figure 6A, the corrosion rate of iron increased significantly with pH decreasing from 8.5 to 3.0. Both cathodic and



anodic reactions were found to be accelerated, as seen from the potentiodynamic polarization curves in Figure S7(A). The corrosion potential (Ecorr) first decreased then increased with pH decreasing from 7.4 to 3.0, and the turning point of the increase of Ecorr upon decrease of pH happened at about pH 4.0.

Figure 6. Corrosion current density (icorr) and corrosion potential (Ecorr) of bare iron in Hank’s solution measured with an electrochemical workstation and calculated via Tafel curve fitting. (A) Change with solution pH's, which were adjusted by addition of lactic acid (LA) with the indicated concentrations; (B) Change with the indicated lactate concentrations at pH 7.4, which was fixed by further addition of NaOH. The shadow region in (B) covers roughly the experimental range of lactate concentrations in (A). The mark “**” denotes statistical significance (p < 0.01), “NS” denotes no significance. Comparison of (A) and (B) illustrates that the pH effect might be predominant over the lactate ion effect on accelerating iron corrosion of a PLA coating in the metal-polymer composite stent.

In contrast, the corrosion rate of iron did not significantly increase with the increase of lactate concentration, as shown in Figure 6B. The largest icorr of the Hank’s solution containing lactate ions (0.5 M) was still less than that of pH 6.5. The shadow in Figure 6B covers the range of lactate concentrations introduced in the electrolytes when adjusting the pH in Figure 6A; and there is no significant influence of the lactate ions on corrosion rate of iron in this range. So, the effect of lactate ions on the icorr in Figure 6A could be basically ignored. As a result, the effect of decrease of pH might be predominant over that of


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generation of the lactate ions on accelerating iron corrosion in the PLA-coated iron. Interestingly, the effect of lactate ions on iron corrosion might undergo different mechanisms in different concentration ranges. The anodic reaction was inhibited by lactate ions at low concentration (0.2 M) but facilitated at high concentration (0.5 M) as shown in Figure S7(B). This implied different interactions of lactate ions and iron surfaces at different lactate concentrations. 3.8 Effects of Ca/P on the Corrosion of Bare Iron and PLA-Coated Iron. The results of electrochemical tests implied that a barrier layer was formed on the surface of the bare iron in Hank’s solution. It is reasonable to speculate that some inorganic ions might deposit on the iron surface. The surface morphology and element composition of a bare iron sheet was observed and detected after 72 h of immersion in Hank’s solution (Figure 7A). In the uncorroded region, the EDS maps presented the occurrence of Ca (green) and P (yellow) elements. The iron surface under a PLA coating and the surface of the PLA coating adjacent to iron were observed by SEM along with an EDS analysis, with the results shown in Figure 7B. No Ca and P elements were detected on the surface of iron and the interior surface of the PLA coating; in particular, Cl element in the PLA coating was detectable with EDS-SEM, and the fractions of the main elements are summarized in Figure 7C. These results illustrated that the PLA coating might have a good permeability of Cl- yet a poor permeability of Ca2+ and PO43-, which was favorable for iron corrosion.



Figure 7. Element contents of the sample surfaces and effect of Ca/P on corrosion current density (icorr). (A) EDS-SEM images of bare iron. In the first row, the left is an SEM image, and the right is an overlay image of EDS of various elements. The second row is an amplification of the part in the dotted rectangle on the overlay EDS-SEM images. (B) EDS-SEM images of iron surface under a PLA coating and the interior side of the PLA coating adjacent to iron. (C) Element content measured by EDS, “-” means no noticed content of the elements. (D) Effect of Ca/P on bare iron, PMMAcoated iron and PLA-coated iron at different immersion time points. The samples of D-Ca/P groups were immersed and tested in Hank’s solution without Ca2+, H2PO4- and HPO42-.

The effects of calcium ions and phosphate ions were investigated further by comparing the corrosion behaviors in Hank’s solution and D-Ca/P Hank’s solution. The


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icorr values of bare iron, PMMA-coated iron and PLA-coated iron both in Hank’s solution and D-Ca/P Hank’s solution were measured. The bare iron in D-Ca/P Hank’s solution corroded much faster than in Hank’s solution, as shown in Figure 7D. Polarization curves in the D-Ca/P Hank’s solution presented a feature of active corrosion, while the shapes of the anodic branches indicated the formation of a passive film after immersed in Hank’s solution for 3 days and 14 days (Figure S8). For the PMMA-coated iron and PLA-coated iron, the differences between corrosion rates in the D-Ca/P Hank’s solution and Hank’s solution were much less than that of bare iron, especially at the early stage. The polarization curves of the PMMA-coated iron and PLA-coated iron in Hank’s solution and D-Ca/P Hank’s solution showed similar shapes at the corresponding immersion time (Figure S8). We then carried out a global test to estimate the Ca/P effect in each group, enlightened by the statistical analysis of global comparison in our previous cell studies on micropatterned surfaces.55-57 The fluctuation of raw data was eliminated by normalization, and all the relative icorr values of each group at different degradation time points were gathered as a set. The statistical analysis showed a very significant difference between the icorr in the Hank’s solution and the D-Ca/P Hank’s solution for bare iron (p = 1.1  10-5) but no significant difference for PLA-coated iron (p = 0.13) (Figure S9). The global comparison clearly reflected that the presence of calcium ions and phosphate ions played an important role in hindering the corrosion of bare iron. Thus, the alleviation of Ca/P layer formation by the PLA coating might be one of the main reasons for the acceleration of iron corrosion.

4. DISCUSSION In the Pourbaix diagram for Fe-H2O system calculated under biomimetic condition, the thermodynamic state of iron shifts to left with the decrease of pH, leading to a stronger thermodynamic driving force for both hydrogen evolution and oxygen reduction (Figure 1A). The electrochemical measurements (icorr versus pH) confirmed that oxygen-consuming corrosion of iron was significantly accelerated with the electrolytes changed from weak alkaline to weak acid and the hydrogen-ion-consuming



corrosion came to dominate in a significant acidic solution (Figure 2A). PLA can hydrolyze to produce a local acid environment, and thus it is reasonable that iron corrosion can be accelerated by a PLA coating. Besides, Ca/P deposition was proved to play an important role in hindering corrosion of bare iron in the biomimetic condition while the presence of a PLA coating could inhibit calcium ions and phosphate ions to reach the iron surface (Figure 7). Faster corrosion of the PLA-coated iron was verified by both the observation of the corrosion morphology (Figure 3F) and the results of the electrochemical measurements (Figure 4). 4.1 Modification of Pourbaix Diagram to Better Reflect the Critical pH for Hydrogen Evolution and to Estimate the Predominant Mechanism of Metal Corrosion (Oxygen Reduction or Hydrogen Evolution) in a Biomimetic Medium. When a metal is in contact with physiological environments, its corrosion in the aqueous environments of the body fluid involves the setting-up of electrochemical corrosion cells. In general, thermodynamics is an excellent starting point for many corrosion studies, and a corresponding fundamental tool is Pourbaix diagram. We calculated the Pourbaix diagram for Fe-H2O system at 37°C, with the results presented in Figure 1A. We have also made a modification of the hydrogen line by taking the hydrogen overpotential into account in the Pourbaix diagram in order to demonstrate the available pH range of hydrogen evolution more realistically and clearly. In fact, the overpotential for H+ discharge on iron surface was determined by Dr. Stern from Corrosion Laboratory, Massachusetts Institute of Technology (MIT) early in 1955.58-59 He investigated elegantly the electrochemical behavior of pure iron in his well-designed deaerated acid media and determined hydrogen overpotential about 200 mV at relatively low corrosion currency density. So the hydrogen line in the Pourbaix diagram in Figure 1(A) has been moved down 0.2 V for intuitive guidance of engineering use in our present study. The experimental data of corrosion potentials (Ecorr) at various pH's were added in the calculated Pourbaix diagram as an Ecorr-pH line, as presented in Figure S10 in Supporting Information. The Ecorr values here correspond to those in Figure 6A, which


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were obtained by processing potentiodynamic scanning tests of bare iron in Hank’s solution. The intersection points of experimental Ecorr-pH line and theoretical hydrogen lines gave two critical pH's, 6.7 for the hydrogen line based on the thermodynamic calculation and 4.8 for the modified hydrogen line taking the hydrogen overpotential into account. In theory, H+ cannot be reduced beyond the critical corrosion potential or over the critical pH.60 The experimentally measured icorr of bare iron in Hank’s solution of various pH's proved that oxygen reduction played an important role in the cathodic reactions when pH was higher than 4.5, while hydrogen evolution became the dominant cathodic reactions when pH was lower than 4.0 (Figure 2A). The change of the hydrogen gas volumes collected during iron corrosion also indicated a critical pH between pH 4.0 ~ 5.0 (Figure 2B). The modified Pourbaix diagram with introducing hydrogen overpotential, which gave a critical pH value of 4.8, could better interpret our experiment results. Hydrogen bubbles can cause serious problems for a metal stent potentially applied in clinic. During our corrosion tests of the PLA-coated iron in vitro and the MPS in vivo, hydrogen bubbles have never been observed.42 The PLA-coated iron was immersed in a weak alkaline medium (pH 7.4). Although PLA hydrolysis must lead to lowering the local pH, the OH- produced by oxygen reduction shall result in partial neutralization. Considering again the weak alkaline of the Hank’s solution and the quite slow degradation of PLA61, the very local microenvironment of the iron surface under a PLA coating might only be weakly acidic. The pH on the surface of iron substrate under a PLA coating was about 5.6 as we measured after 24 h immersion in Hank’s solution (Figure 3C & Figure S2). Even though the pH value may fluctuate with corrosion time, it might not deviate from 5.6 much as a lower pH results in a quicker neutralization of the H+ by the corrosion products due to a faster corrosion of iron. Allowing for the critical pH 4.8, hydrogen evolution might not dominate in the cathodic process of the PLA-coated iron around pH 5.6. The corrosion of the PLA-coated iron might be mainly triggered by oxygen reduction under the biomimetic condition.



4.2 PLA Coating Cannot Hinder Sufficient Penetration of Water and Dissolved Oxygen etc. onto the Iron Surface. Water and dissolved oxygen are essential for iron corrosion and particularly important for oxygen reduction. As iron corrosion often develops in the presence of water, dissolved oxygen and some inorganic ions such as Cl-, the anti-corrosive mechanism of a polymer coating might lie in that a coating can act as a barrier to hinder the penetration of electrolytes etc. to the metal surface.62-63 In our study, the introduction of a PLA coating was found to accelerate iron corrosion instead of to hinder it. To investigate the underlying mechanism, we tried to figure out the penetration of water and dissolved oxygen into PLA films in the demonstration experiments. We first examined water permeability of a PLA film. As a demonstration, an allochroic silica gel was used as a water indicator, which was sealed by a PLA film and immersed in water (Figure S11). If sufficient water penetrated the PLA film, the silica gel might change its color from blue to pink. The results indicated sufficient water penetrating through the PLA film about 20 μm thick within 3 days. So, the PLA coating with a thickness of 1.5 μm on the iron sheet could not act as a barrier of water penetration onto the iron surface after a few hours (Figure 3F). The dissolved oxygen permeability of the PLA film was also examined. We used a PLA film to separate aqueous solution of high O2 concentration from that of low O2 concentration (Figure S12). The concentration of dissolved oxygen in the low O2 solution increased over time and reached maximum at 10 h, manifesting a fast diffusion of dissolved O2 through the PLA film. Therefore, the PLA coating in the PLA-coated iron would not be a barrier of O2 diffusing onto iron surface during iron corrosion. In addition, chlorine element was detected in the PLA coating with a weight percent of 2.2% (Figure 7C), indicating that Cl- in the Hank’s solution had penetrated through the PLA coating and reached the iron surface. It has been known that chloridecontaining media facilitate iron and steel corrosion.64 It seems worthy to note that in principle a polymer coating must hinder iron corrosion at the early stage as schematically presented in Figure S13. But as the thickness of the PLA coating in our experiments was just about 1.5 μm, the


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corresponding early stage was quite short. The emergence of the second time constant in Bode plots (Figure 5C) illustrated that electrolytes had reached the interface of the PLA coating and iron substrate during the EIS measurement, which took about only 30 minutes. The results of icorr in Figure 4C indicated that the inhibition of the PLA coating on iron corrosion was limited even at the initial time. Hence, with sufficient water, dissolved oxygen and Cl- permeating through the PLA coating within a short time, the corrosion of the PLA-coated iron might not be retarded by the PLA coating during the corrosion process as long as a few weeks. 4.3 PLA Coating Can Accelerate Iron Corrosion by Decreasing the Interface pH and Alleviation of a Passive Layer. The results of corrosion morphology (Figure 3F) along with corrosion currency density icorr (Figure 4) showed faster corrosion in the presence of a PLA coating. The acceleration of iron corrosion by the PLA coating might be attributed to the probable effects of hydrogen ions, the effect of lactate/oligomers, and the physical barrier to alleviate the formation of passivation layer on the iron surface. In the perspective of the thermodynamic principle, corrosion of a PLA-coated iron shifts to left in the Pourbaix diagram with decrease of the local pH (Figure 1A). So, one can predict a stronger thermodynamic driving force for cathodic reactions (oxygen reduction and hydrogen evolution), which is in favor of iron corrosion. In light of electrochemical dynamics, the icorr of the bare iron was found to increase significantly from weak alkaline media to weak acidic media (Figure 6A), for instance, icorr at pH 6.5 and 5.5 were, respectively, about twice and seven times of that at pH 7.4. These results indicated that a slight decrease of pH in the biomimetic solution could lead to much faster corrosion of iron. In contrast, the icorr of bare iron increased slightly with the concentration of lactate ions increasing at a given pH (Figure 6B), revealing a much smaller influence of the lactate than pH on iron corrosion. Considering that the local pH of the iron surface under a PLA coating was about 5.6 (Figure 3C & Figure S2), the hydrogen ions produced in PLA hydrolysis may play a major role in accelerating iron corrosion. According to the principle of electrochemical corrosion, the corrosion rate of iron



in an oxygen-containing weak alkaline solution is mainly determined by the diffusion rate of oxygen to an effective cathode surface.65-66 For bare iron, a passive film might be formed on the metal surface. The appearance of another time constant in the Bode plots of bare iron after immersed in Hank’s solution confirmed the presence of a passivation layer (Figure 5C). Moreover, Ca and P elements were detected on the surface of bare iron (Figure 7A). Such an inorganic passive film acted as a barrier to oxygen diffusion, which in turn hindered the corrosion of bare iron. The corrosion of bare iron in Hank’s solution without calcium ions and phosphate ions was much faster than that in Hank’s solution (Figure 7D), which illustrated that the Ca/P deposition played an important role in the slow corrosion of bare iron in the biomimetic solution. For the PLA-coated iron, the PLA coating prevented the formation of a passivation layer, especially at the early stage. Neither Ca nor P element was detectable on the surface of iron under the PLA coating. Calcium ions and phosphate ions in Hank’s solution had less effect on the corrosion of PLA-coated iron than bare iron (Figure 7D). In absence of the passivation layer, oxygen could easily permeate a PLA coating, and oxygen reduction would be accelerated vigorously, which facilitated the corrosion of iron under the PLA coating. 4.4 Equivalent Circuit Models of Pure Iron and Polymer-Coated Iron under the Biomemmetic Condition over Time. For a comprehensive interpretation of the corrosion process, we fitted the impedance spectra with proper equivalent circuit (EC) and depicted the corresponding iron surface condition as shown in Figure 8A. The terms Rs, Rc, Rt denote solution resistance, coating resistance and charge transfer resistance, respectively. For bare iron, Rc represents the resistance of a passivation layer containing Ca/P. Gernerally speaking, larger Rc and Rt values mean better corrosion resistance. Considering the inhomogeneity of the iron surface and the shape of the impedance spectra, we used Qc and Qdl to replace the coating capacity and double layer capacity, respectively. Following the fasion of modern electrochemistry, Q denotes constant phase element (CPE), and W refers to Warburg impedance related to diffusion. We put forward circuit A to circuit E in Figure 8 to model the impedance spectra of bare iron, PMMA-coated iron and PLA-coated iron during biodegradation. The


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evolutions of EC of the three groups are shown at the bottom of Figure 8A. The Nyquist plots are well fitted in the assigned circuits (Figure S14), and the fitting data are shown in Tables S7-S9. For bare iron on day 0, there were only Rt and Qdl, which indicated that the electrolyte could reach the iron surface directly. So bare iron had the largest corrosion rate at the initial time, consistent with the icorr results. Rc appeared and increased dramatically over immersion time, implying that a passivation layer was formed in Hank’s solution and the layer became thicker and more compact with time. The increases of Rc and Rt mean that the presence of a passivation layer hindered iron corrosion. For the PLA-coated iron, Rc and Rt decreased during the immerison tests, which resulted in a gradual increase of the corrosion rate of iron. The impedance spectrum of the PLA-coated iron at the late stage was well fitted with circuit E, where Rc disappeared, indicating that the PLA coating could not protect iron from corrosion due to the polyester degradation. In contrast, while the Rc and Rt of the PMMA-coated iron also decreased with time, the evolution was much slower than that of the PLA-coated iron. The hydrolytical degradability of PLA made the evolution of the corrosion of PLA-coated iron distingushed from that of other polymer-coated iron.



Figure 8. (A) Electrical equivalent circuits along with the corresponding interfaces for the bare iron system and polymer-coated iron system, and the EC models fitting the three kinds of samples during biodegradation. (B) Schematic graph of the main mechanisms of accelerating iron corrosion by a PLA coating.


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In brief, PLA coating accelerates iron corrosion mainly by lowering the local pH at the interface between metal and polymer and by inhibiting the formation of a passivation layer containing Ca/P on the iron substrate, as schematically summarized in Figure 8B. As a composite material, PLA-coated iron has combined the excellent mechanical properties of the metal, iron, and the controllable degradation profiles of the polyester, PLA. Shedding light on the corrosion mechanism of PLA-coated iron is helpful for tuning corrosion rates of iron by regulating the coating composition. Our previous in vivo experiments42 have proved that an appropriate PLA coating could make iron stents totally corrode in 3-6 months and the corrosion rate was regulated by increasing the mass of PLA or adding low molecular weight PLA.

5. CONCLUSIONS A PLA coating dramatically accelerated iron corrosion instead of protecting it in the biomimetic condition. The modification of Pourbaix diagram (potential versus pH) was suggested by introducing hydrogen overpotential to better determine the critial pH of hydrogen evolution, and the experimental results confirmed that hydrogen evolution might not be the predominant corrosion mechanism of the PLA-coated iron under the plasma-mimetic condition. Taking also advantage of the slow release of hydrogen ions during PLA hydrolysis and the good permeability of oxygen through the polymer coating in the tissue-regenerating time scale, the acceleration of iron corrosion by the PLA coating might be achieved mainly by the enhancement of the oxygen reduction. The enhancement was driven mainly by two ways: a lower local pH adjacent to the iron surface owing to PLA hydrolysis and the alleviation of deposition of a passivated layer by the polymer coating. The combination of the two ways led to a complicated kinetic process of the corrosion of PLA-coated iron, which was described by a time-dependent model from equivalent circuit C to circuit D and finally to circuit E as put forward in this study.



The metal-polymer composite technique is an efficient strategy to combine the good mechanical properties of metallic materials and controllable degradation profiles of biodegradable polyester, which is particularly beneficial for the development of the next-generation coronary stents.

ASSOCIATED CONTENT Supporting Information Supporting information associated with this article can be found, in the online version, at doi: ***. Calculation of Pourbaix diagram for Fe-H2O system in physiological environment including main reactions related the corrosion of iron, general relations between potential and pH for each reaction, calculation of standard Gibbs free energy at 37°C, establishment of potential-pH relations for each reaction under physiological condition; Supplementary experiments including characterization of the degradation of the PLA coating on glass, more data about local pH measurements at the interface of PLA-coated iron sheets detected with pH tester pens with different detection ranges, characterization of the thickness of the polymer coatings and surface properties of the PLA film, monitoring open circuit potential, relationship between impedance/admittance and frequency, effects of pH and lactate concentrations on the potentiodynamic polarization curves, effects of calcium and phosphate ions on the potentiodynamic polarization curves, critical pH of cathodic reaction in Hank’s solution, demonstrating that a PLA coating cannot hinder sufficient penetration of water, demonstrating that a PLA coating cannot hinder sufficient penetration of oxygen, Nyquist plots and the corresponding parameters fitted by the indicated equivalent circuits. AUTHOR INFORMATION Corresponding Author


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*E-mail: [email protected] (JD Ding); phone: 0086 21 31243506. Declaration of interest It is declared that Deyuan Zhang is an employee of Lifetech Scientific Corporation. The other authors declare no conﬂict of interest.

ACKNOWLEDGEMENTS This work was financially supported by National Key R&D Program of China (grant No. 2016YFC1100300), National Science Foundation of China (grants No. 51533002 and 21604011), Science and Technology Commission of Shanghai Municipality (grant No. 17JC1400200). We thank Prof. Jin LI at Fudan University for the help of his group in our study of iron corrosion. Besides Prof. LI, our appreciation is also extended to Prof. Changjian LIN at Xiamen University for critical reading of the manuscript.



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Graphic for Table of Contents


Mechanism of Acceleration of Iron Corrosion by a Polylactide Coating

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