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Polydopamine Modified TiO2 Nanotube Arrays for Long-Term Controlled Elution of Bivalirudin and Improved Hemocompatibility Ying Yang,† Xiangyang Li,† Hua Qiu,† Ping Li,† Pengkai Qi,† Manfred F. Maitz,†,§ Tianxue You,† Ru Shen,† Zhilu Yang,*,† Wenjie Tian,*,‡ and Nan Huang*,† †
Key Laboratory of Advanced Technology for Materials of Education Ministry, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan 610031, China ‡ Sichuan Provincial People’s Hospital, Cardiology, Chengdu, Sichuan 610072, China § Max Bergmann Center of Biomaterials, Leibniz Institute of Polymer Research Dresden, Hohe Strasse 6, 01069 Dresden, Germany S Supporting Information *
ABSTRACT: Sustained and controllable release characteristics are pivotal factors for novel drug delivery technologies. TiO2 nanotube arrays prepared by self-ordering electrochemical anodization are attractive for the development of biomedical devices for local drug delivery applications. In this work, several layers of polydopamine (PDA) were deposited to functionalize TiO2 nanotube arrays. The anticoagulant drug bivalirudin (BVLD) was used as a model drug. PDA extended the release period of BVLD and maintained a sustained release kinetic. Depending on the number of PDA layers, the release characteristics of BVLD improved, as there was a reduced burst release (from 45% to 11%) and extended overall release period from 40 days to more than 300 days in the case of 5 layers. Besides, the BVLD loaded 5-layer PDA coating maintained the high bioactivity of BVLD and effectively reduced the thrombosis formation by inhibition of the adhesion and denaturation of fibrinogen, platelets, and other blood components. Both in vitro and ex vivo blood evaluation results demonstrated that this coating significantly improved the hemocompatibility. These results confirmed the capability of PDA fitted TiO2 nanotube systems to be applied for local drug delivery over an extended period with well retained bioactivity and predictable release kinetics. KEYWORDS: polydopamine, hemocompatibility, BVLD, long-term drug release, TiO2 nanotube technologies,6 self-assembly techniques,7 solvent-casting methods,8 and emulsion9 and extrusion methods.10 Among these existing routes for drug elution, electrochemical anodization provides an attractive platform to facilely achieve macro- and nanolevel geometric features from special metals. Since Zwilling and co-workers reported the self-ordered formation of TiO2 nanotubes (Ti NTs) by electrochemical anodization of titanium in 1999, it gained considerable attention due to the wellorganized geometric features and maintained outstanding biocompatibility of titanium.11,12 Besides the good biocompatibility of NTs, the open volume of the tubes makes them an excellent candidate for the development of local drug release applications.2 However, simple loading of the drugs into the tubes or in a network leads to an initial burst release and rapid exhaustion. The release kinetic can be controlled to some extent via adjusting the tube diameters or lengths during the anodization procedure, but there are still limitations for a
1. INTRODUCTION Systemic application of drugs is required for most biomedical implants during or after the implant procedures, such as dental implants, hip replacements, or vascular stents, with the aim to prevent infection, decrease inflammation, or control clotting. For the conventional drug delivery administration routes, including oral, inhalation, parenteral, and intravenous application, the drugs are distributed throughout the whole body and not specifically to the site of interest. However, in most cases, the drugs are only required at the target site. Thus, the development of more rational and efficient drug delivery strategies could help to address the inherent limitation of the current therapies.1 Local delivery of drugs from the implant surface possesses the advantages of reduced adverse effects and lower drug doses required for the same clinical efficacy compared to the systemic route.2 Long-term drug delivery systems can also help to improve patient comfort and compliance as well as improve existing pharmacotherapies.3,4 These systems are aimed at releasing desirable drugs continuously at a controllable rate over a period of weeks or months.5 To date, numerous strategies have been reported to design long-term drug delivery systems, including electrochemical and microelectromechanical © 2017 American Chemical Society
Special Issue: 10 Years of Polydopamine: Current Status and Future Directions Received: May 3, 2017 Accepted: August 16, 2017 Published: August 28, 2017 7649
DOI: 10.1021/acsami.7b06108 ACS Appl. Mater. Interfaces 2018, 10, 7649−7660
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ACS Applied Materials & Interfaces sustained drug release.13 Thus, sustained and controllable release characteristics become essential factors for advanced drug delivery technologies. During the recent decade, numerous studies have been devoted to explore suitable surface modifications, new structures, and release principles for fabricating ideal drug release systems based on NTs.14 Plasma polymerized allylamine coating was deposited onto NTs to obtain new properties and functionalities. This modification introduces amine groups, which allow further conjugation of target molecules. Further, this coating can decrease the pore diameter from 140 to 20 nm for further control of the release performance.15 Schmuki and co-workers have ingeniously designed an amphiphilic structure to obtain a controllable drug release system by introducing a hydrophobic cap onto the NTs.16 This hydrophobic cap prevents the undesirable nonspecific release of a hydrophilic drug into an aqueous solution; with the release of the cargo, it can be triggered by UV induced chain scission in the polymer. Losic and co-workers have explored two approaches to achieve sustained drug release by coating NTs with a biocompatible polymer and polymer micelles as drug nanocarriers. Both strategies indicated remarkably improved drug release characteristics, with decreased burst release (from 77% to ∼39%) and extended elution from 7 days to no less than 28 days.14 These results suggested that the NT based system can be applied for local drug release with an extended period. Even though the progress is encouraging, there is still an urgent need for the exploration of new strategies to achieve highly controllable and ultralong-term drug delivery systems. It has been over ten years since polydopamine came into focus in 200717 as a novel material, which brings global significance and arises extensive interest of scientific research. There are still rapidly increased studies focused on polydopamine and its derived materials around synthesis and promising applications in fields of environment, energy, and biomedicine.18,19 The primary advantage of polydopamine is that it can be facilely deposited onto virtually all kinds of materials with high binding strength.19−21 Polydopamine also provides secondary reactivity for constructing multifunctional coatings and further conjugating target molecules through simple chemistry.18−20 Moreover, owing to the durable stability, good biocompatibility, and controllable thickness, polydopamine coatings are excellent candidates for NTs surface modification. It can control the morphology of NTs and in addition also introduce reactive groups for drug conjugation to prevent the rapid release of hydrophilic drugs, thus extending drug elution duration.23 In this work, polydopamine coatings with different thicknesses were applied onto the NTs surface to get a longterm sustained and highly controllable release of bivalirudin (BVLD, 2180 Da, Figure S1). Unlike the conventional clinical anticoagulant heparin, BVLD is a direct thrombin inhibitor, which directly blocks thrombin without the need of the cofactor antithrombin III (ATIII), which may be exhausted at critically ill patients.24,25 There is also no risk for heparin-induced thrombocytopenia. BVLD has extremely high specificity and affinity for thrombin; it would not combine with red blood cells or other plasma proteins. The combination of BVLD with thrombin is essentially reversible.24 Besides, BVLD possesses a superior ability to inhibit clot(fibrin)-bound thrombin, while it also inhibits circulating thrombin and prevents thrombin mediated platelet aggregation and activation.25,26 BVLD has a short half-life and is much safer and more effective than heparin
for diabetic patients with acute coronary syndromes.24,25 Take these prominent characteristics into consideration, BVLD (hydrodynamic radius 30 days) drug release strategies including blood-contacting and orthopedic implants based on the favorable properties of NTs, like good biocompatibility, thermal and mechanical stability, hemocompatibility after loading of drugs (BVLD), hydroxyapatite formation, bone cell adhesion, differentiation, and proliferation. For short-term drug release scenarios, it can be used to suppress inflammation by loading anti-inflammatory drugs, and
for moderate term (1−2 weeks), to prevent bacterial infection. Thus, it is demonstrated that the application of multideposition of PDA onto NTs is a promising alternative to develop various localized drug delivery systems that possess the capability to overcome the limitations of systemic drug therapies.1
4. CONCLUSION In summary, we reported a facile strategy to obtain an advanced drug release system based on Ti NTs with extended drug release properties and significantly improved hemocompatibility. Multiple layers of polydopamine were applied onto Ti NTs to achieve a high loading capacity for BVLD and an ultralong elution period, reaching 537.0 ± 21.7 μg/cm2 and lasting for 300 days for 5 layers of PDA. The BVLD loaded to the PDA functionalized NTs maintained high bioactivity with remarkable ability to inhibit the adhesion and activation of fibrinogen, platelets, and other blood components. Both in vitro and ex vivo blood compatibility evaluations showed that BVLD5L@PDA significantly improves the hemocompatibility. This multideposition of PDA onto NTs has the flexibility to be applied for different purposes due to the controllable drug release with optimized concentration for a range of time scales.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.7b06108. Chemical structure of bivalirudin; XRD patterns of NTs before and after annealing at 450 °C; the top and typical cross-sectional image of NTs; the thickness of PDA coatings of different layers; MALDI-TOF MS spectrum of the PDA with tentative structures assigned to main peaks; UV−vis absorbance spectrum of BVLD solution; the thrombin activity adsorbed on the sample surface; table for the drug release characteristics of BVLD from flat Ti, NTs, and NTs with various PDA layers (n = 8); the APTT and TT results of the blood collected before 7658
DOI: 10.1021/acsami.7b06108 ACS Appl. Mater. Interfaces 2018, 10, 7649−7660
Forum Article
ACS Applied Materials & Interfaces
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and after the experiments from different specimens; the bioactivity evaluations of BVLD-5L@NTs after 300 days of elution (PDF)
AUTHOR INFORMATION
Corresponding Authors
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[email protected]. Tel: +86 28 87600625. Fax: +86 28 87607691. *E-mail:
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[email protected]. ORCID
Nan Huang: 0000-0003-2378-6889 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Project 31570957, 81501596, and Key Program 81330031), the Distinguished Young Scholars of Sichuan Province (Project 2016JQ0027), and the Fundamental Research Funds for the Central Universities (Project 2682015YXZT07).
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