Metal Ion Coordination Polymer-Capped pH-Triggered Drug Release

Article pubs.acs.org/journal/abseba

Metal Ion Coordination Polymer-Capped pH-Triggered Drug Release System on Titania Nanotubes for Enhancing Self-antibacterial Capability of Ti Implants Tingting Wang,† Xiangmei Liu,† Yizhou Zhu,† Z. D. Cui,‡ X. J. Yang,‡ Haobo Pan,§ K.W. K. Yeung,∥ and Shuilin Wu*,†,‡ †

Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Ministry of Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, School of Materials Science & Engineering, Hubei University, Wuhan 430062, China ‡ School of Materials Science & Engineering, Tianjin University, Tianjin 300072, China § Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China ∥ Department of Orthopaedics & Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China S Supporting Information *

ABSTRACT: The current work reports a novel hybrid system with a highly efficient, bioresponsive, and controlled release of antibacterial activity via the metal ion coordination polymer on titania nanotubes (TNTs). These hybrid systems exhibited a self-defense behavior that is triggered by the change of the ambient environment acidity due to bacterial infection with Gram-positive bacteria Staphylococcus aureus (S. aureus) and Gram-negative bacteria Escherichia coli (E. coli). The antibacterial agents, including antibiotics and nanosilver particles, can be loaded into TNTs and then sealed with coordination polymers (CPs) through the attachment of metallic ions such as Zn2+ or Ag+. The zinc and silver ions work as intermediate coordination bonds, and they are sensitive to the change in H+. Because of the strong bonding of CPs, the amount of released antimicrobial agents is maintained at a nonsignificant level when pH is maintained at 7.4. However, the coordination bond of the capped CPs was triggered to open and release antibacterial agents from TNTs once the environment becomes acidic. The release rate gradually increased as the pH value further decreased. Subsequently, the antibacterial efficiency of the hybrid system is accelerated as the local microenvironment becomes more acidic during bacterial infection. In addition, the metal ions that are used for intermediate bond bridging are also favorable for specific biological functions. For example, Zn2+ can promote the proliferation of osteoblastic cells, while Ag+ can further enhance the antibacterial capability. In conclusion, this smart surface coating system not only demonstrates excellent self-antibacterial properties and biocompatibility but also formulates a controllable delivery system for the long-lasting treatment of biomaterial-related bacterial infections. KEYWORDS: antibacterial, pH sensitivity, nanotubes, implants, drug delivery

1. INTRODUCTION

$50,000 per patient has to be paid to treat these infections. Furthermore, the current therapy for these infections involves administering drugs orally or intravenously to distribute drugs throughout the entire body, which is significantly more than what is needed for the infection site. Furthermore, overuse of drugs can possibly reduce natural immunity and also induce drug resistance.5 Local drug delivery can minimize these problems by reducing the unnecessary side effects by locally releasing proper amounts of drugs that are needed to achieve

With the development of biomaterials and medical science, many biomedical implants have emerged (e.g., hip replacements, dental implants, etc.) that require subsequent drug therapy regiments to aid in recovery.1 Because of the exceptional mechanical properties, titanium-based metals have been wildly used for repairing or replacing damaged hard tissues such as bones and teeth.2 However, these metallic implants are vulnerable to bacterial infections due to the ease of formation of highly structured microbial biofilms on the surface,3 which often induce the failure of orthopedic implant surgeries. According to the statistics,4 the reinfection rate after the revision surgery reaches 14%. Therefore, an average of © XXXX American Chemical Society

Received: February 13, 2017 Accepted: March 20, 2017

A

DOI: 10.1021/acsbiomaterials.7b00103 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

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ACS Biomaterials Science & Engineering Scheme 1. Schematical Illustration of the Preparation of the Metal Ion-Coordination Polymer Capa

Step 1: amination between −OH on the surface of Ti and APTES. Step 2: complex reaction between -NH2 of APTES and Zn2+. Step 3: complex reaction between Zn2+ and BIX.

a

the same effect.6 The common strategy is to develop a local drug delivery system on the surface of metallic implants to control drug release.7 Compared with traditional systematic administration, the site-specific controlled release systems can offer many distinctive advantages by regulating the loading and release behaviors via thermal, pH, light, or magnetic stimuli.8 In general, these smart surface systems are often composed of two types of materials. The first are bioactive inorganic materials such as hydroxyapatite (HA), calcium carbonate, and bioglass. The second are soft materials such as hydrogels, polymeric films, and micelles that are sensitive to internal or external stimuli.9 As we know, the local bacterial infection on the implantation site can reduce the local pH from neutral to 6.0 or lower due to the formation of a large amount of H+.10 Accordingly, the pH-responsive drug loading systems can smartly adjust the amount of drugs that are released into the site-specific place with a low number of side effects. Currently, pH-sensitive linkers, supramolecular nanovalves, acid-decomposable dots, polyelectrolytes, etc. have been widely used to control the pH-responsive release of drugs from the pore channels of nanocontainers.11 For example, cyclodextrin-based polyseudorotaxanes were adopted to regulate the release behaviors of guest molecules from nanocontainers in a pHcontrolled manner. 12 Through acidic dissolution, ZnO quantum dot lids on mesoporous silica nanoparticles (MSNs) can be employed to control the drug release in intracellular compartments.13 It has been reported that some metallic ions can be coordinated with some organics via coordination bonds.14 Moreover, TNTs were produced on Ti via anodic oxidation in fluoride electrolytes in 1999.15 Because of their excellent biocompatibility, large specific surface area, and tubular structure, TNTs have been widely used in various biomedical applications, especially in drug delivery systems. Furthermore, the pore size of TNTs can be regulated by changing the anodization voltage and other parameters.16 Furthermore, research has also reported on the strategy for controlling drug release from TNTs based on the surface functionalization of nanotubes.17−22 This approach was never

used on porous silica particles and then was successfully translated into TNTs by using polymers and monolayers owing to the excellent biocompability and stability for surface modification. In order to solve the problem that long drug release cannot be realized only by surface functionalization, many other strategies were used on top of the surface of TNTs to reduce the opening of nanopores, such as using the plasma polymer coating reported by Griesser et al. in 2008.23 Poly(lactic-co-glycolic acid) (PLGA) was introduced by dipcoating for controlling drug release and improving bone integration of TNTs.24 However, long-term drug release is not satisfied in critical situations such as osteomyelitis, bacterial infections, and so on, where high concentrations of drug are immediately required. So the concept of a simulated drug delivery system with external triggers based on TNTs is reported. Silane coupling agents were introduced as crosslinkers and filled with magnetic nanoparticles which can achieve magnetic- and photocatalytic-guided release of drugs.25 An application of local ultrasonic external field was reported by Aw et al. for triggering drug release.26 Song et al. report a voltagesensitive drug delivery system based on TNTs grafted with octadecylphosphonic acid attached to an enzyme of horseradish peroxidase.27 TNTs hold an electrical field trigger drug release, which was reported by Sirivisoot.28 Above all, to our knowledge researchers have not reported pH-responsive TNTs. Thus, here, we design an intelligent drug loading and release system on Ti implants that is based on the pH response of CPs on TNTs. The CPs can be prepared by 1,4-bis (imidazol-1ylmethyl) benzene (BIX) and metallic ions, such as Zn2+ or Ag+, where the metallic ions act as a coordination bond between TNTs and BIX. In a biological environment, the cleavage of this bond can be triggered by H+ and thus can be used as a switch to control the connection of BIX and TNTs under different pH values. The process is schematically illustrated in Scheme 1. Briefly, TNTs are first formed via anodic oxidation, and then, TNTs are functionalized via grafting 3-aminopropyltriethoxysilane (APTES) with amino groups. These samples are referred to as amino-functionalized TNTs (TNTs-NH2). After the amination by APTES, ibuprofen B


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ACS Biomaterials Science & Engineering

NH2−Van, the corresponding sample was named as TNTs-NH2− Van@Ag-BIX. 2.5. Drug Release. Four groups of samples were immersed in 100 mL of PBS (pH 7.4, 6.4, 5.4, and 4.0). At certain time intervals, 5 mL of the release solution was measured using a spectrophotometer at an absorbance of 223 nm (Ibu)/283 nm (Van) to determine the release content of the drugs. Then, the same volume of fresh PBS was added to the release system. 2.6. Antibacterial Tests. The Gram-positive bacteria S. aureus and Gram-negative bacteria E. coli that were used in antibacterial tests were purchased from the Culture Collection of the Tongji Hospital Wuhan. The samples were placed in LB agar plates that were seeded with two types of bacteria and incubated at 37 °C for a given time (S. aureus for 24 h and E. coli for 12 h). Then, the LB agar plates were photographed and analyzed using an imaging software system to identify the zone of inhibition (ZOI). To test the antibacterial ratio of the samples, different samples were placed into a 48-well plate, followed by the addition of bacterial suspension [105 colony forming unit (CFU) mL−1] into each well. Then, the samples were cultured in an incubator at 37 °C for a suitable time and measured at a wavelength of 600 nm using a microplate reader (Molecular Devices, SpectraMax i3). To evaluate the antibacterial activity of release solutions, TNTs-NH2− Ag(0.02 M)@Zn-BIX was selected as a representative. After 1, 3, 7, and 14 days of immersion at different pH levels, a 30 μL release solution was removed and added to each well of the 96-well plate with a 150 μL bacterial solution. The mixed solutions were incubated at 37 °C in an incubator for a given time (S. aureus for 24 h and E. coli for 12 h). The antibacterial ratio could be evaluated via optical density (OD) at 600 nm using a microplate reader. In order to evaluate the influence of samples on Gram-positive bacteria S. aureus and Gram-negative bacteria E. coli, the SEM method was also introduced. Samples were first placed in a 48-well plate, followed by the addition of bacterial suspension [105 colony forming unit (CFU) mL−1] into each well. Then, the samples were cultured in an incubator at 37 °C for a suitable time (S. aureus for 24 h and E. coli for 12 h). After the incubation, the bacterial suspension was removed, and 500 μL of 2.5% glutaraldehyde solution was added to each well for bacteria fixed in extractor hoods for 2 h. Before dehydrating the bacteria, these samples were immersed in 500 μL of PBS 3 times every 1 min. The dehydratiion of the samples was performed using different concentrations of ethanol solutions. After removing PBS, samples were immersed into 500 μL of ethyl alcohol of different concentrations of 30%, 50%, 70%, 90%, and 100% for 15 min. After dehydrating, ethyl alcohol was removed. Those samples were dried at room temperature. The bacterial morphologies were examined by SEM. 2.7. Cell Viability and Proliferation. The 3-[4,5-dimethylthiazol2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay was utilized to determine the MC3T3-E1 (Tongji hospital, Wuhan) viability on the surface of the samples. In total, 350 μL of a mouse MC3T3-E1 suspension (cell density of 1 × 105 mL−1) was added to each well of a 48-well plate. The wells with a cell suspension were divided into 8 groups with samples at the bottom and cultured at 37 °C in a humidified atmosphere of 5% CO2 for 1, 3, and 7 days. After removing the culture media, 350 μL of an MTT (0.5 mg mL−1) solution was dissolved in sterilized neutral PBS and then incubated in a 5% CO2 incubator for 4 h. After the incubation, the medium was removed, and 350 μL of dimethyl sulfoxide (DMSO) was added to the well, followed by the incubation of a color reaction for 15 min in an incubator. Then, the samples were removed, and the cultured medium was measured using a microplate reader at the wavelengths of 490 and 570 nm. 2.8. Alkaline Phosphatase (ALP) Activity. The alkaline phosphatase (ALP) assay was used to determine the osteogenic differentiation on the samples after culturing for 3, 7, and 14 days. After the incubation, the medium was removed, and 500 μL of Triton X-100 (1%) was added to each well for cell lysis. Stain reactions were performed in 48-well plates following the instructions in the ALP assay kit. After shaking for 5 min, the 48-well plates with the samples were incubated in a water bath at a temperature of 37 °C for 1 h. Then, 30 μL of supernatant was tested by the AKP ELISA kit at a wavelength of 520 nm using a microplate reader.

(Ibu), vancomycin (Van), and silver nitrate can be harnessed into TNTs through immersion in the corresponding solvents for a given time. These samples are referred to as TNTs-NH2− Ibu, TNTs-NH2−Van, TNTs-NH2−Ag (0.02 M), and TNTsNH2−Ag (0.01 M), respectively. Then, the drug-loaded samples are capped by the CPs through the gradual addition of BIX and Zn2+/Ag+ into the solution. The corresponding samples are named TNTs-NH2−Ibu@Zn-BIX, TNTs-NH2− Van@Zn-BIX, TNTs-NH2−Ag(0.02 M)@Zn-BIX, TNTsNH2−Ag(0.01 M)@Zn-BIX, and TNTs-NH2−Van@Ag-BIX, respectively. We determined that the @M(Zn/Ag)-BIX hybrid system is very sensitive to pH according to the release profiles and can be applied as a universal bioplatform for loading and releasing drugs/inorganic nanoparticles, thus avoiding the overuse of drugs and the resulting side effects. Furthermore, the selected metallic ions, i.e., @M(Zn/Ag), could be employed to achieve specific biofunctions.

2. EXPERIMENTAL PROCEDURES 2.1. Material Preparation. Commercial pure Ti plates (99.6%, supplied by Baosteel Group Corp, Shanghai, China) with a thickness of 0.25 mm and a diameter of 6 mm were used as the starting materials. These plates were mechanically polished with SiC sandpaper with different grit sizes and washed with ethanol and deionized water using an ultrasonic cleaner. The oven-dried plates were chemically etched by a solution composed of HF, HNO3, and H2O. Anodization was performed at 60 °C in NH4F that was dissolved in ethylene glycol (EG) at a voltage of 30 V. The procedure is described in detail elsewhere.29 Then, the products were washed with ethyl alcohol and deionized (DI) water. 2.2. Surface Amination. The samples were aminated in a solution of 1% (v/v) APTES (99.0%, Sinopharm Chemical Reagent Corp). The solution was refluxed for 12 h at 80 °C and cooled to room temperature. Then, the products were thoroughly washed with acetone, ethyl alcohol, and deionized water, successively.30 The resulting products were placed into a vacuum oven to remove the remaining solvent in the TNTs arrays. These samples are referred to as amino-functionalized TNTs (TNTs-NH2). 2.3. Drug Loading. The TNTs-NH2 samples were immersed in a solvent with 50 mg mL−1 of Ibu or Van (Zhengzhou Sainuokang Chemical Products Corp. Ltd. China) for 48 h and then removed and carefully washed to remove surface-adsorbed drugs. The samples were named TNTs-NH2−Ibu/Van. To load Ag nanoparticles, the TNT samples were immersed into the AgNO3 (0.02 M/0.01 M) solution for 2 days and then exposed to ultraviolet light for 1 h. After that, the samples were functionalized with APTES to avoid the complex reaction between amidogen and Ag+. The samples were accordingly named as TNTs-NH2−Ag(0.02 M)/TNTs-NH2−Ag(0.01 M). 2.4. Coordination Polymer. The typical process of complex reaction between CPs and metallic ions is depicted as follows. First, 52.8 mL of ethanol with 0.01 M Zn(NO3)2·6H2O solution and 24 mL of ethanol with 0.017 M BIX solution were prepared. Then, the TNTsNH2−Ibu sample was placed into 200 mL of ethanol solution as the complexation reaction solvent. After that, 17.6 mL of Zn(NO3)2·6H2O solution and 8 mL of BIX solution were added into the 200 mL of ethanol solution, and then stirred quickly at room temperature for 5 min. This procedure would be repeated 2 times. This procedure can slow down the complexation reaction to make the even distribution of coordination polymer on TNTs. Finally, these samples were thoroughly washed with ethanol and dried in an oven at room temperature for further use. These samples were referred to as NTsNH2−Ibu@Zn-BIX. The same process was employed for TNTsNH2−Van and TNTs-NH2−Ag(0.02 M)/TNTs-NH2−Ag(0.01 M). The corresponding samples were named TNTs-NH2−Van@Zn-BIX, TNTs-NH2−Ag(0.02 M)@Zn-BIX, and TNTs-NH2−Ag(0.01 M)@ Zn-BIX, respectively. When 0.01 M AgNO3 took the place of 0.01 M Zn(NO3)2·6H2O in the above reaction using the sample of TNTsC


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Figure 1. Synthesis and characterization of the metal ion responsive coordination polymer/titania nanotube system. (a) A schematic illustration of the procedure of preparation of titania nanotubes (TNTs), modification of TNTs with APTES to form TNTs-NH2, loading drugs (Ibu/Van/Ag) to form TNTs-NH2−Ibu, TNTs-NH2−Van, TNTs-NH2−Ag(0.02 M), and TNTs-NH2−Ag(0.01 M), and then further coating with BIX to produce the @M(Zn/Ag)-BIX hybrid system. Scanning electron microscopy images of the synthesized samples and the morphology of samples after release for 400 h at different pH values of 6.4, 5.4, and 4.0. (b) Transmission electron microscopy images of TNTs-NH2−Ag(0.02 M). (c) XPS spectra of TNTs-NH2−Ibu@Zn and TNTs-NH2−Ibu@Zn-BIX. (d) FTIR spectra of TNTs, TNTs-NH2, Ibu, TNTs-NH2−Ibu, and TNTs-NH2−Ibu@ZnBIX. 2.9. Cell Morphology. To evaluate the adhesion and spreading behavior of osteoblasts on the samples, MC3T3-E1 with a cell density of 5 × 104 mL−1 was seeded in each well of a 48-well-plate with presterilized specimens inside. After 8 h of incubation in a humidified atmosphere of 5% CO2 at 37 °C, the samples were removed and rinsed with PBS (37 °C) 3 times. These samples were immersed into PBS with a 4% formaldehyde solution for 10 min, then washed with PBS 3 times, and subsequently immersed in FITC (YiSen, Shanghai) for 30 min in the dark at room temperature. Before staining the cell nucleus, these samples were washed with PBS 3 times. The staining of the samples was performed using DAPI (YiSen, Shanghai) for 30 s in the dark at room temperature, followed by rinsing with PBS 3 times. An inverted fluorescence microscope (IFM, Olympus, IX73) was employed to examine the cell morphologies.

introduced to bond with a large amount of hydroxide radicals on the surface of TNTs shown by step 1 in Scheme 1. It can be seen that amino functionalization does not influence the shape and size of TNTs (Figure 1a) during the amination process. Compared with untreated TNTs, energy disperse spectroscopy (EDS) detected strong signals from Si and N after amination (inset in Figure 1a) due to the bonding of APTES with the titanium substrate. In comparison with the untreated samples, the pH-metric titration curve obtained from the aminofunctionalized samples at 80 °C showed two successive pH changes (Figure S2, Supporting Information), indicating two different acid−base reactions on the surface of titanium. The first reaction is characterized by a pKa of approximately 9.6. The value is directly correlated with the protonation of free amine groups and can be determined from eq 1 (and Figure S2, Supporting Information). The second reaction has a pKa of approximately 6.7 and is attributed to the protonation of zwitterion-like species TiO− on the substrate (Figure S2, Supporting Information). The characterization by both EDS and pH-metric titration confirms the successful amino functionalization of TNTs. After loading drugs or Ag nanoparticles using a given process, these TNTs were sealed with CPs through a connection with amino groups by Zn2+ as an intermediate coordination bond shown by step 2 and step 3

3. RESULTS AND DISCUSSION 3.1. Characterization of Modified TNTs. Figure 1a shows the uniform and highly ordered TNTs that are formed on the Ti substrate. The typical tube size is in the range of 85−100 nm, and the length is approximately 2 μm, as characterized by transmission electron microscopy (TEM) (Figure S1a, Supporting Information). TNTs prepared by anodization have been already quite mature, and Szesz et al. reported that TNTs’ critical load is 135 ± 10 mN by the nanoscratch test. It has quite good wear resistance for an implant material.31 To provide a bonding group with metal ions, APTES was D


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Figure 2. Drug release behaviors. a) Ag+ release of TNTs-NH2−Ag@Zn-BIX. b) The S. aureus antibacterial ratio of the release solution. c) The E. coli antibacterial ratio of the release solution. d) Zn2+ release of TNTs-NH2−Ag@Zn-BIX at pH 7.4, 6.4, 5.4 and 4.0. All experiments were carried out in triplicate, (Error bars represent +/− SD n=3).

carbonyl stretching vibration signal of Ibu compared to that of pure Ibu indicated that Ibu was encapsulated into the TNTs by CPs indirectly. In the case of CP-covered samples, there is a new peak at 1525 cm−1 in the spectrum, which is related to the BIX ligands.36 These results indicated the successful coordination bonding between the BIX ligands and Zn2+ as well as the final coverage of CPs onto the TNTs-NH2−Ibu sample. Because of the broad-spectrum antibacterial property, silver nanoparticles are widely used as inorganic antimicrobial agents.37−39 In this work, to examine the drug-loading versatility of this surface system, silver nanoparticles were loaded in TNTs via an in situ reduction reaction of AgNO3 under irradiation of UV light. As shown in Figure 1b, compared with the untreated TNTs (Figure S1, Supporting Information), there were many nanoparticles inside the TNTs. The selected area electron diffraction (SEAD) image that is shown in Figure 1b indicated the successful loading of Ag nanoparticles in TNTs. Similar to Zn2+, in this work, Ag+ can also be used as an intermediate coordination bridge. After loading Van, the TNTsNH2−Van was covered with BIX via Ag+ bonding. The binding energy shift of Ag 3d confirms the change of the chemical valence of Ag, indicating the successful connection of BIX with -NH2 via Ag+ as intermediate coordination bonding (Figure S3, Supporting Information). 3.2. Drug Release Behaviors. The CPs can successfully block the drug release from TNTs in a neutral biological environment that is shown by the curve of TNTs-NH2−Ibu@ Zn-BIX in Figure S4a, Supporting Information, illustrating that the bonding force between TNTs and coordination polymer is strongly enough to keep complete enough at neutral biological environment. The rapid release can be found from the sample

in Scheme 1. As shown in Figure 1a, the surface was almost entirely covered by CPs, and EDS indicated the existence of Zn2+ in the coating. After immersion in PBS with different pH values for 400 h, the sealing zone was partially exposed, and lower pH results in a larger exposed area (Figure 1a). This reveals that with the decrease of the local pH value, the breakage of CPs becomes more serious. This suggests that the coordination bond is sensitive to H+ and that CP gatekeepers on TNTs are prone to erosion in an acidic environment. As shown in Figure 1c, the X-ray photoelectron spectroscopy (XPS) narrow scan reveals two coordination states in the Zn 2p region for all samples, and the binding energy of Zn 2p3/2 obtained from TNTs-NH2−Ibu@Zn is 1021.5 eV. However, the value detected from TNTs-NH2−Ibu@Zn-BIX is 1022.2 eV and slightly shifts to a higher binding energy, indicating a different chemical environment of Zn in the latter, which further confirms the successful coordination bonding of Zn-BIX with APTES-modified TNTs. Fourier transform infrared spectroscopy (FTIR) was employed to further identify the surface modification processes of TNTs, such as amination, Ibu-loading, and subsequent BIX coverage through Zn2+ as an intermediate coordination bond. As shown in Figure 1d, the peak at 1655 cm−1 in the curve of TNTs-NH2 was attributed to the bending vibration of -NH2. Furthermore, the stretching vibration of the NH2 bond is also found at 1485 cm−1. After amination, a clear peak is seen at approximately 3400 cm−1, which contributes to the symmetric and asymmetric -NH stretch modes in APTES.32−35 Compared to TNTs-NH2, the spectrum of TNTs-NH2−Ibu displayed an additional peak at 1740 cm−1, which is assigned to the ester carbonyl stretching vibration and is in accordance with the characteristic spectrum of Ibu. The reduction of the ester E


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Figure 3. In vitro antibacterial activity. a) Photograph and diameters of the zones of inhibition (ZOIs) of test cements showing antibacterial activity of Staphylococcus aureus (S. aureus). b) Photograph and diameters of ZOIs of test cements showing antibacterial activity of Escherichia coli (E. coli). c) Diameters of ZOIs determined using an image software system. All experiments were carried out in triplicate, (Error bars represent +/− SD n=3). d) Antibacterial ratio against S. aureus and E. coli of the samples. All experiments were carried out in triplicate, (Error bars represent +/− SD n=3). e) SEM pattern of S. aureus and E. coli on the samples.

representative. As shown in Figure 2a, after the immersion at 37 °C for 22 days, the total release concentration of Ag+ from the neutral PBS was less than 1250 μg mL−1, which is significantly lower than the reported cytotoxic threshold of 1600 μg mL−1.40 As the pH decreased, the release rate significantly increased. After the immersion in PBS with different pH values of 6.4, 5.4, and 4.0, the corresponding releasing concentration of Ag+ was increased to 1750 μg mL−1, 2000 μg mL−1, and 2200 μg mL−1, respectively, indicating that the Zn2+-coordinated CPs on TNTs were pH-responsive. This was possibly caused by the following two factors. First, with a decrease of pH, the protonation of the -NH2 groups intensified, which partially cleaved the bonds between Zn 2+ and -NH 2 groups, consequently unfolding the CP cover. Second, with the increase of H+ concentration, the complete bond between Zn2+ and BIX was destroyed, inducing the release of Zn2+ from the hybrid system, as shown in Scheme 1. From Figure 2d, it could be seen that the cumulative release concentration of Zn2+ from the TNTs-NH2−Ag(0.02 M)@Zn-BIX sample that was immersed in neutral PBS for 22 days was approximately 200 μg

of TNT-Ibu without a CP covering at the same environment as shown by the curve of TNTs-Ibu in Figure S4a, Supporting Information. Furthermore, even at a different pH, the TNTsIbu sample exhibited a similar release trend (Figure S4b, Supporting Information). In order to evaluate the amount of loaded drugs in TNTs, TNTs-NH2−Ibu@Zn-BIX samples made by different batches were immersed in PBS at pH 4.0. When immersion time lasted for more than 400 h, the cumulative release concentrations from all groups were almost the same and kept constant, i.e., there were no more drugs released from TNTs, indicating that the initial loading dosage was almost the same (Figure S5, Supporting Information). When choosing the groups of TNTs-NH2−Ibu@Zn-BIX, TNTs-NH2−Ag(0.02 M)@Zn-BIX, TNTs-NH2−Ag(0.01 M) @Zn-BIX, and TNTs-NH2−Van@Ag-BIX for the releasing tests, the same tendency could be seen. So almost the same amount of antibacterial agents had been initially loaded into TNTs for different groups. To understand the release behavior of antibacterial agents from this smart hybrid system, the TNTs-NH2−Ag(0.02 M)@Zn-BIX group was selected as a F


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Figure 4. Cytocompatibility of the samples. a) Cell viability of the cultured MC3T3-E1 pre-osteoblasts. The absorbance was detected at the wavelengths of 490 nm and 570 nm. All experiments were carried out in triplicate, (Error bars represent +/− SD n=3). b) ALP activities of MCM3T3-E1 pre-osteoblasts that were cultured for 3, 7 and 14 days. The absorbance was detected at a wavelength of 520 nm. All experiments were carried out in triplicate, (Error bars represent +/− SD n=3). c) Fluorescence images of MCM3T3-E1 that were cultured on the samples. The green color indicates cell filament, and the blue color indicates cell nuclei.

mL−1. Under the same conditions, the corresponding release amount in PBS with a pH value of 6.4, 5.4, and 4.0 was approximately 600 μg mL−1, 900 μg mL−1, and 930 μg mL−1, respectively. These groups exhibited different antibacterial ratios due to the different amounts of Ag+ that is released from the hybrid system and the broad-spectrum antibacterial property of Ag+. As shown in Figure 2b and c, after the 1 day immersion, the antibacterial ratios of neutral PBS against S. aureus and E. coli were 5% and 17.5%, respectively. However, acidic PBS solutions showed a much higher efficacy. For example, PBS with a pH of 4.0 exhibited 27.5% and 30% antibacterial ratios against S. aureus and E. coli due to the highest amount of Ag+ released from the samples. When the immersion time was increased, the antibacterial ratio was also increased. After 14 days of immersion, the antibacterial ratio of PBS with a pH of 4.0 against S. aureus could reach 50%. In addition to Ag nanoparticles, other drugs, such as micromolecular Ibu and macromolecular Van, could also be loaded through this pH-responsive hybrid system. As shown in Figure S6a (Supporting Information), in a neutral biological environment, the TNTs-NH2−Ibu@Zn-BIX hybrid system could release less than 25 μg mL−1 Ibu after immersion for 400 h. As PBS gradually became acidic, the concentration of released Ibu from the TNTs-NH2−Ibu@Zn-BIX hybrid system increased. After 400 h of immersion in PBS with pH of 6.4, 5.4 and 4.0, the corresponding release amounts of Ibu were 150 μg

mL−1, 235.5 μg mL−1, and 260 μg mL−1, respectively (Figure S6a, Supporting Information). A similar release trend is also observed when this hybrid system is loaded with Van (Figure S6b, Supporting Information). When the intermediate coordination bridge of Zn2+ in this system is substituted with Ag+, similar release behaviors are observed, as shown in Figure S7, Supporting Information. This indicates that the CP gatekeeper with Ag+ as the coordination bond on TNTs also has a good pH-responsive behavior. This suggests that the metallic ions-responsive CPs could act as gatekeepers through the bridge bond of Zn2+, Ag+, or even other metal ions. In addition, these metallic ions could also fulfill some specific biological functions. For example, Zn2+ is a trace element in the human body and is required for cell growth at an appropriate dose.41 Some amounts of Ag+ can perform antibacterial functions via the release-killing42 and contactkilling43,44 capabilities of the broad antibacterial spectrum.45 These results demonstrate that the @M(Zn/Ag)-BIX hybrid system is pH-responsive. Therefore, this can reduce the release of antibacterial agents in initial neutral biological environments while accelerating the leaching ratio as pH is decreased. This suggests that this antimicrobial agent loading system can be used to resist local bacterial infection over time. Thus, the local acidic environment caused by bacterial infection triggers the in situ release of antibacterial agents by the breakage of CPs on G


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antibacterial mechanism of Ag nanoparticles had two aspects. First, Ag+ that is released from Ag nanoparticles may disturb the normal physical function of transmembrane proteins. Second, the released Ag+ may create accumulated electrons and disturb the transfer of complex I (consisting of the motifs for binding NADH, FMN, and tetranuclear FeS cluster) into oxygen to form O2 and H2O2, inducing oxidative damage and leakage of the bacterial membrane. 3.4. Cytocompatibility. The MC3T3-E1 viability on the samples measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5diphenyl tetrazolium bromide) is shown in Figure 4a. Noticeably, no significant inhibition of cell proliferation is exhibited on the samples in the early stage (3 days), possibly resulting from the small amount of drugs that are released from the surface system. However, during the middle stage (7 days), cell proliferation on modified TNTs samples is significantly reduced, which contributed to the drugs (Van/Ag/Zn2+) being released from the surface system. Furthermore, during the long stage (18 days), according to the release curves in neutral PBS, the drug release reached a balance after 8 days of immersion. A small amount of the drugs (Van/Ag/Zn2+) was released, resulting in an enhanced cell proliferation on Van/Ag/Zn2+loaded samples. When the samples were loaded with drugs (Van/Ag) without @Zn/Ag-BIX, a much lower cell viability was presented compared with the samples without drugs as the control. This phenomenon revealed that the drugs (Van/Ag) resulted in a lower cell viability and were slightly toxic if overdosed.50,51 Furthermore, the @Zn-BIX system did not favor cell proliferation after culturing for 7 days. When the culturing time was increased to 18 days, the @Zn-BIX system exhibited an increased cell viability. This was ascribed to the fact that Zn2+ can reduce cell proliferation at an early stage, while a certain concentration of Zn2+ seemed to stimulate cell proliferation. ALP activity is an important factor in the expression of bone mineral formation and osteoblastic differentiation on biomaterials in vitro.52 As shown in Figure 4b, the @Zn-BIX system exhibited a much higher ALP expression compared with that of the samples without @Zn-BIX at all stages. This phenomenon illustrates that the @Zn-BIX system can stimulate cell proliferation, as discussed in Figure 4a, and favor osteogenetic differentiation.53 Zn2+ cannot effect the activation of ALP directly. Instead, it is used to stimulate cell metabolism. However, when the intermediate coordination bond Zn2+ is replaced with Ag+, specific ALP activities of the @Ag-BIX system were much lower than those of the @Zn-BIX system. It was further proved that Zn2+ can promote bone formation ability.54 To observe the mitosis phase cells in the above-mentioned samples, the fluorescence images of osteoblasts were examined after culturing for 8 h. As shown in Figure 4c, weaker stress fibers were formed by F-actin in the TNTs-NH2−Van sample compared with those in TNTs modified by Ti, indicating that the Van drug actually had some toxicity.30 However, the amount of mitosis phase cells was clearly increased in the @ZnBIX system. This suggested that the @Zn-BIX system enhanced biocompatibility and improved bone formation ability, which is consistent with the results shown in Figure 4a and b. Furthermore, the CPs can successfully block the release of drugs from TNTs at a neutral biological environment, which decreases the toxic effects due to the overdose of drugs.

TNTs, which avoids toxic side effects caused by systemic injection. 3.3. In Vitro Antibacterial Activity. Figure 3 shows the antibacterial results of the samples against S. aureus and E. coli. As shown in Figure 3a, there is a clear ZOI against S. aureus around the samples of TNTs-NH2−Van (Figure 3a, 3#), while no ZOI against E. coli is found around the same group (Figure 3b, 3#), which indicates that Van is only effective against the Gram-positive bacteria S. aureus.46 When the TNTs-NH2−Van samples were sealed by CPs through the coordination bond of Zn2+, the corresponding ZOI decreased to 2 mm (Figure 3a, 4#). This indicates that CPs can block the Van release from TNTs, thus avoiding the excess dose of drugs being spread to the body. When loading Ag nanoparticles with the original AgNO3 concentration of 0.02 and 0.01 M instead of Van, the corresponding ZOI against S. aureus decreases to less than 1.5 mm (Figure 3a, 6#) and 1 mm (Figure 3a, 7#), indicating the weaker diffusion and antibacterial ability of Ag+ against S. aureus compared to those of the Van drug. It is clearly observed that a larger ZOI appears against E. coli, i.e., 3.5 mm (Figure 3b, 6#) and 2.7 mm (Figure 3b, 7#), compared with the one against S. aureus, indicating that Ag+ possesses a better inhibitory ability against E. coli than against S. aureus. In addition, the higher initial Ag+ concentration leads to a larger ZOI. When using Ag+ as the intermediate complex bond between CPs and -NH2 groups on the substrate, the corresponding sample of TNTsNH2−Van@Ag-BIX exhibits an excellent antibacterial efficacy against both S. aureus and E. coli, as shown in Figure 3b (sample 5#), with a corresponding ZOI of 4.5 mm and 1.9 mm, respectively, which was ascribed to the synthetic effect of released Van and Ag+.47 As shown in Figure 3d, the antibacterial ratio of TNTs-NH2−Van against S. aureus was more than 99%, but no E. coli was killed. The result is consistent with the conclusions drawn from Figure 3a and b: the Van drug was ineffective against E. coli. However, TNTsNH2−Van@Zn-BIX has an antibacterial ratio that is greater than 99%. This suggests that the released Zn2+ from the @ZnBIX system exhibits high antibacterial efficacy toward E. coli.48 In addition, when Ag nanoparticles were introduced into the system (Figure 1b), the samples displayed an effective antibacterial ability of greater than 90% against both S. aureus and E. coli. Interestingly, the TNTs-NH2−Van@Ag-BIX group also had significant antibacterial efficacy of over 99% against both bacteria. This indicates that the @Ag-BIX system can act not only as an intermediate bonding bridge but also as an efficient antibacterial agent. To investigate the antibacterial properties of this hybrid system more directly, the morphologies of bacteria on samples were examined using field-emission scanning electron microscopy (FE-SEM) (Figure 3e). Live S. aureus and E. coli bacteria can be seen on Ti. However, S. aureus and E. coli bacteria showed some shape change when present on the TNTs-NH2− Van@Zn-BIX sample, illustrating that Zn2+ had some inhibitory ability against both S. aureus and E. coli bacteria,43,49 which is consistent with the result in Figure 3d. In the case of the TNTsNH2−Ag(0.02 M)@Zn-BIX samples, two types of bacteria presented an irregular morphology (indicated by the red arrow), confirming the broad-spectrum antibacterial property of Ag nanoparticles.48 In addition, compared to TNTs-NH2− Van@Zn-BIX, a severe membrane disruption is observed on the surface of TNTs-NH2−Van@Ag-BIX with an irregular surface. This further illustrates that Ag nanoparticles have a much better antibacterial ability. It has been reported that the H


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4. CONCLUSIONS The drug-loading versatility of this surface system is perfect. It can load an Ibu micromolecule, Van macromolecule, and Ag nanoparticles into one surface system, making the materials widely used. A bacteria-triggered antimicrobial agent release structure is successfully fabricated on Ti. The coordination bond between the CPs and TNTs by the Zn2+ metal ion possesses a pH-responsive ability and stimulates bone growth. Furthermore, when Zn2+ is substituted with Ag+, the samples introduce a broad-spectrum antibacterial property even when they are only loaded with a narrow spectrum antibiotic Van drug. In addition, the samples retain the pH-responsive ability. Bacteria-triggered antimicrobial agent releasing materials have a potential use in bone implant materials because of their high cell proliferation and osteogenic potential. In implants, this material may improve the success rate against infection and result in fewer side effects.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsbiomaterials.7b00103. TEM and SEAD of TNTs; titration curves; XPS spectra; drug release behavior of the samples; and Van release behavior (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] or [email protected]. ORCID

Shuilin Wu: 0000-0002-1270-1870 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was jointly supported by the National Natural Science Foundation of China, Nos. 51422102 and 81271715, and the National Key Research and Development Program of China No. 2016YFC1100600 (subproject 2016YFC1100604), as well as Shenzhen Peacock Program (1108110035863317).

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REFERENCES

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Metal Ion Coordination Polymer-Capped pH-Triggered Drug Release

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