中国组织工程研究 ›› 2013, Vol. 17 ›› Issue (47): 8255-8262.doi: 10.3969/j.issn.2095-4344.2013.47.018
• 生物材料综述 biomaterial review • 上一篇 下一篇
二氧化钛纳米管的理论研究进展及临床实践
张杭州1，王 琳1，田 昂2，孙 羽1，白希壮1，薛向欣2
- 1中国医科大学附属第一医院运动医学科与关节外科，辽宁省沈阳市 110001；2东北大学材料与冶金学院，辽宁省沈阳市 110001
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修回日期:2013-08-19出版日期:2013-11-19发布日期:2013-11-19 -
通讯作者:白希壮，博士，博士生导师，主任医师，中国医科大学附属第一医院运动医学科与关节外科，辽宁省沈阳市 110001 zpmhh@sina.com -
作者简介:张杭州☆，男，1984年生，山东省淄博市人，汉族，中国医科大学在读博士，主要从事关节置换、膝关节运动损伤的相关研究。 zhanghz1000@sina.com -
基金资助:国家自然科学基金面上项目(81071449, L2010645)**
Research progress and clinical practice of TiO2 nanotubes
Zhang Hang-zhou1, Wang Lin1, Tian Ang2, Sun Yu1, Bai Xi-zhuang1, Xue Xiang-xin2
- 1Department of Sport Medicine and Joint Surgery, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China;2 School of Material and Metallurgy, Northeastern University, Shenyang 110001, Liaoning Province, China
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Revised:2013-08-19Online:2013-11-19Published:2013-11-19 -
Contact:Bai Xi-zhuang, Ph.D., Doctoral supervisor, Chief physician, Department of Sport Medicine and Joint Surgery, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China zpmhh@sina.com -
About author:Zhang Hang-zhou☆, Studying for doctorate, Department of Sport Medicine and Joint Surgery, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China zhanghz1000@sina.com -
Supported by:the National Natural Science Foundation of China (General Program), No. 81071449*, L2010645*
摘要：
背景：二氧化钛纳米管阵列电化学阳极氧化钛是目前应用前景较好的纳米材料之一。 目的：综述二氧化钛纳米管在临床应用方面的研究进展。 方法：以TiO2 nanotubes，Anodization，biomaterials为检索词，检索PubMed 数据库2000年1月至2013年6月中有关二氧化钛纳米管临床应用领域研究的文献。排除重复研究及陈旧研究，共保留47篇文献进行综述。 结果与结论：从检索到的47篇文献进行总结分析发现，二氧化钛纳米管能够促进包括人成骨细胞，间充质干细胞的黏附和增殖。体内实验证实，二氧化钛纳米管能够促进钛金属内植物在体内的骨整合。此外，二氧化钛纳米管还可作为载体负载其他药物如生长因子和抗生素以促进材料生物形容性及预防细菌黏附。结果说明，二氧化钛纳米管可促进材料的体内骨整合，具有良好的生物相容性。
中图分类号:
引用本文
张杭州，王 琳，田 昂，孙 羽，白希壮，薛向欣. 二氧化钛纳米管的理论研究进展及临床实践[J]. 中国组织工程研究, 2013, 17(47): 8255-8262.
Zhang Hang-zhou, Wang Lin, Tian Ang, Sun Yu, Bai Xi-zhuang, Xue Xiang-xin. Research progress and clinical practice of TiO2 nanotubes[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(47): 8255-8262.
General conditions of included data
TiO2 nanotubes are promising research subjects in the field of material at present. Drug can be delivered to the therapeutic region via nanomaterials effectively, which can overcome adverse distribution in the body, and avoid the defect of systemic medication (such as low efficiency, drug overdose, lack of choice and toxicity).
Totally new tissue culture scaffold can be obtained by changing materials’ appearance. Biologically, interface modification can simplify the complicated biological problems, and can be used as an essential manner for controlling cell behavior. Ti and its alloy surface receive interface modification using anodic oxidation, and TiO2 nanotubes coating can be prepared.
There were 24 literaturesconcerning implant-related infection[1-24], 23 literaturesaddressing mechanisms, biocompatibility and clinical application of TiO2 nanotube[25-47]. There were 6 literatures about effect of TiO2 nanotube on diminishing inflammation[26-28, 37, 45-46], 14 literatures on promoting effect of TiO2 nanotube on biocompatibility and osseointegration[30-33, 36-44, 47].
Characterization of research results of included data
Implant-related infection and strategy
Two thirds of implant-related infection was staphylococcus aureus infection[1-5, 9]. Bacterial biofilm is a property of most bacterial infection, especially staphylococci. Gilbert et al [18] confirmed that to kill bacteria in the bacterial biofilm needed a large dose of antibiotics, about > 1 000 times of killing the same kind of bacteria in cell suspension.
Another property of bacterial biofilm is to induce drug resistance of bacteria in bacterial biofilm. When drug concentration was low, and did not reach the minimal inhibitory concentration, pathogen easily had drug resistance, and increased the difficulty of treatment[19-21]. Poelstra and colleagues[22] found that the first 6 hours after the implant was implanted in the body was a key period to prevent infection. Six hours later, bacterial biofilm on the surface of the implant formed. Although aseptic processing was strictly performed and laminar flow operating room was used, the incidence of postoperative implant infection in patients undergoing joint replacement was 2%-4%[3-7].
What is more serious is that the incidence of implant infection after open fracture was 50%[20-21]. Differing from clinical common infection, the implant-related infection cannot be cured by common systemic application of antibiotics. The steel plate or artificial joint should be taken out of and surrounding tissues should be debrided and the operation should be operated again, which always brought huge pains on the soul and body and heavy economic burden. The patents have to take many risks such as long length of stay, complicated rebuilding, prosthesis failure, even death. High-concentration systemic application of antibiotics would cause adverse reactions all over the body, including low efficiency, prolonged duration, repeated hospitalization, drug overdose, lacks of selectivity and toxicity[16]. Moreover, the drug is hard to be transferred to the site of the infection[16]. Under an ideal condition, pharmacodynamic action should be added and adverse reactions all over the body should be reduced. At present, the curative effects of local application of antibiotics were better than that of systemic application of antibiotics[8, 22-23].
Local application of antibiotics could precisely control the dose of antibiotics in the implant, high effectively release antibiotics, avoid the adverse reactions of systemic application of antibiotics, and reduce the possibility of drug resistance of the bacteria. Administration of antibiotics all over the body had poor penetration ability for necrotic tissues, but elevation of drug dose would lead to toxic complications all over the body such as liver-kidney related toxicity[8, 22-23].
Local administration of antibiotics could increase local drug concentration and avoid adverse reactions of systemic medication, instead of systemic application of antibiotics. Local application of antibiotics in the prevention of infection has been selected in the clinic in the Department of Orthopedics, such as gentamicin bone cement. To overcome the defect of traditional strategy, local drug delivery has been a promising method. Local drug delivery system has been first used in antibiotics bone cement (PMMA) in 1980s by Buchholz et al [9].
The advantages of local drug delivery system comprised prevention of adverse reactions of systemic medication, and local high performance of antibiotics[24]. Nevertheless, the main shortcoming of antibiotic bone cement is that the implants have to been taken out twice. Antibiotic bone cement is not fit for cementless prosthesis (hip and knee joint prosthesis and implant steel plate). Another shortcoming of antibiotic bone cement is that when drug release concentration is low (lower than minimal inhibitory concentration), low-dose antibiotic release can lead to the production of drug-resistant bacteria. Kendall et al [19] found that bacteria could survive on the surface of antibiotic bone cement in vitro models. Anagnostakos et al [21] confirmed that pathogen was staphylococcus aureus and methicillin-resistant staphylococcus aureus in 18 patients suffering from antibiotic bone cement infection. Therefore, it should be careful whether antibiotic bone cement was extensively used in the prevention of prosthesis infection.
Development background and formation mechanism of TiO2
The development of nanotechnology provides a new drug delivery platform for local drug delivery in implant. The aperture and length of nanomaterial could be controlled. TiO2 nanotubes could be made by anodic oxidation[25] (Figure 1).
TiO2 nanotubes are promising research subjects in the field of material at present. Drug can be delivered to the therapeutic region via nanomaterials effectively, which can overcome adverse distribution in the body, and avoid the defect of systemic medication (such as low efficiency, drug overdose, lack of choice and toxicity).
TiO2 nanotubes not only elevated osseointegration of the metal, cell proliferation and differentiation, but also can be utilized as a drug carrier. TiO2 nanotubes provided many cell attachment points to contribute to cell adhesion and proliferation by deposition of numerous proteins (Figures 2, 3).
Totally new tissue culture scaffold can be obtained by changing materials’ appearance. Biologically, interface modification can simplify the complicated biological problems, and can be used as an essential manner for controlling cell behavior. Ti and its alloy surface receive interface modification using anodic oxidation, and TiO2 nanotubes coating can be prepared.
Studies demonstrated that this kind of nano-structured coating can induce a series of biological effects at cellular levels. During the research, that material would be first used in the study of cell adhesion, and gradually expanded on cell proliferation, migration and differentiation[26-35]. TiO2 nanotube coating can be employed for precise control in the adhered structure of interaction between cells and materials at nanometer scale, and provide a valuable theoretic guidance for designing and developing intelligent cell culture scaffold[26-35]. Gong et al [25] first successfully prepared TiO2 nanotube array in fluorhydric acid electrolyte system in 2001. Mean diameter, length and thickness of TiO2 nanotube were controlled by parameters of anodic oxidation (oxidation time, voltage, and F-concentration)[25]. In the same electrolyte system, inner diameter of nanotubes increased with increased pressure of oxidation, and thickness of nanotube wall reduced. Nanotube length increased with prolonged oxidation time and elevated oxidation pressure. In different electrolyte systems, F-concentration and its corrosion rate on TiO2 are important factors for nanotube length[25]. In the postprocessing of TiO2 nanotube array, annealing temperature could affect the appearance and microstructure of TiO2 nanotube coating. During annealing in the air, the coating has a thermal stability in a certain range. When annealing temperature was higher than 650 °C, the structure of nanotubes collapsed. Subsequently, numerous studies have focused on clinical application of TiO2 nanotube[36-47]. TiO2 nanotube contributed to biocompatibility[36-40, 42, 45-47]. Animal studies verified that TiO2 nanotube promoted osseointegration of the implant in swine models[41, 43-44].
Biocompatibility of TiO2 nanotube
TiO2 nanotubes promoted biocompatibility[36-40, 42, 45-47]. Biocompatibility of biomaterials is a core problem in the field of regenerative medicine and tissue engineering. The surface of the material is a ligament of implant inserted in the host. A totally new tissue culture scaffold was obtained by effectively changing materials’ appearance and chemical component. The surface appearance of the biomaterial directly affected the physical and chemical behaviors of the biomaterials in vivo and in vitro. Surface appearance of the material is a hot problem in the field of regenerative medicine and tissue engineering. Nanomedicine has been considered as a new field with giant potential. A whole new function of biomaterials can be found by changing the surface appearance of present materials. Ti metal and its alloy have been extensively applied in clinical medicine for over 50 years due to its excellent biocompatibility. Recent studies suggested that the alteration of the surface appearance of Ti metal (such as TiO2 nanotube) elevated its biocompatibility[36-40, 42, 45-47]. TiO2 nanotube biomaterials not only elevated biocompatibility of the materials, but also increased its therapeutic function, such as anti-infection ability. Some studies demonstrated that TiO2 nanotube surface is an effective platform of osteoblast growth and differentiation, and osteoblast viability was elevated by controlling nanotube appearance[40-45]. Cooper[30] pointed out that surface appearance of the implant influenced the osseointegration of the implant in vivo. The increase in surface appearance of the implant contributed to osteoblast viability and elevated osseointegration of the material[30]. The diameter of TiO2 nanotube varied from several nanometers to hundreds of nanometers. Different diameters of nanotubes had different effects on the functions of osteocytes and bone marrow stem cells. The main dispute is the effect of big nanotube diameter (50 nm–100 nm) on cells.
Some scholarsdiscovered that the size of TiO2 nanotube diameter affected osteoblastic adhesion, proliferation and differentiation[36-39]. Park et al [39] verified that 15 nm diameter facilitated integrin aggregation, and promoted cell adhesion and reduced apoptotic rate. When nanotube diameter was longer than 50 nm, osteoblastic adhesion and diffusion were suppressed, and cell viability was noticeably reduced, resulting in cell apoptosis[36-39]. However, numerous studies had an opposite conclusion and indicated that large-diameter (80 nm-100 nm) could not cause cell apoptosis, but promote the proliferation and differentiation of bone marrow stem cells. Khang et al [32] investigated the effects of surface appearance (subnanometer, nanometer and submicron) of the implant on cells and confirmed that surface characterization of subnanometer, nanometer and submicron could selectively activate integrin receptor and induce the differentiation of bone marrow mesenchymal stem cells into osteoblasts, and surface roughness of nano-Ti contributed to osteoblast differentiation. At subnanometer and submicron scales, they studied stem cell reactions such as integrin activation, cyclin, key open gene of osteoblast differentiation and osteoblast phenotype gene-produced effects. Compared with subnanometer surface, pure nano-Ti surface has perfect activated integrin. Jayaraman et al [33] found that surface appearance of the implant influenced osteoblast proliferation, differentiation and extracellular matrix protein expression. Nanometer structure promoted fibronectin expression, and contributed to osseointegration of implant and bone tissue.
Some scholars pointed out that TiO2 nanotubes accelerated osteoblastic adhesion and osseointegration[40-44]. The ability of accelerating osseointegration depends on the size of the diameter of TiO2 nanotubes. Nanotubes of big diameter showed better ability on bone formation compared with nanotubes of small diameter. The nanotubes of small diameter (about 30 nm) contributed to osteoblastic adhesion, but nanotubes of big diameter (70-100 nm) induced cell differentiation and resulted in an elevated activation of alkaline phosphatase.
Popat et al [45] performed histological analysis at 4 weeks after implantation in Lewis rats and found that TiO2 nanotubes promoted cell adhesion, cell viability, including alkaline phosphatase and calcium contents. Biocompatibility results demonstrated that TiO2 nanotubes could not induce chronic inflammation or fibrosis. von Wilmowsky et al [43] implanted TiO2 nanotubes into pig models for 3, 7, 14, 30 and 90 days, conducted histological examination, and found a significant high expression of type I collagen after implantation of TiO2 nanotubes at 7 and 14 days. Nanotubes of 30 nm diameter enhanced osteoblast function and affected bone formation and development. The study showed that TiO2 nanotubes contributed to cell adhesion and elevated cell viability and promoted osseointegration. Moreover, TiO2 nanotubes exhibited a good and stable structure, and were not destroyed by shearing force. Bjursten et al [44] confirmed that nanotubes excessively promoted osseointegration in vivo. Study contained nanometer group (80 nm in diameter and 2 μm in length) and micrometer group (2 μm). Using rabbit models, study verified that nanotubes facilitated osseointegration. The contact rate of bone tissue and material was greater in the nanometer group than that in the non-nanometer group. The contact rates of bone tissue and material were (78.3±33.3)% and (21.7±24.7)% in the nanometer group and the micrometer group, respectively. Stretch forces were (10.8±3.1) N and (1.2±2.7) N in the nanometer group and micrometer group, respectively. Studies confirmed a large amount of new bone formation on the surface of nanotubes. Calcium and phosphorus contents were obviously increased on the surface of nanometer structure compared with the micrometer group. These characteristics benefited for the application of biotype implant in clinic, such as biotype artificial hip knee joint prosthesis and intravascular stent.
Application of TiO2 nanotubes as drug carrier
At present, orthopedic implant only can be used for 10–15 years due to various reasons including infection and poor osseointegration. Recent study results demonstrated that TiO2 nanotube smear layer not only promoted osseointegration in implants, but also can be utilized as drug carriers such as antibiotics and bone morphogenetic protein. TiO2 nanotubes not only have good biocompatibility and contributed to ossification, but also can be used as a carrier to load other drugs such as growth factor and antibiotics. Peng et al [37] employed TiO2 nanotubes to carry drugs (protein, rapamycin and paclitaxel). In this study, the size of TiO2 nanotubes varied to elute albumin and common micromolecule drugs. Drugs on nanotubes eluted bioactivity and reduced cell proliferation in vitro. Nanotube height and diameter deeply affected dynamics of eluting. Small nanotube diameter and long nanotube height prolonged the time of drug release. Molecular weight of the drugs also affected the time of drug release. The release time of drugs with big molecules was longer than that of micromolecules. This study suggested that TiO2 nanotubes are promising smear layer of implants. A previous study demonstrated that TiO2 nanotubes are promising drug carrier of implants in the Department of Orthopedics[37]. Popat et al [45] loaded TiO2 nanotubes with various doses of gentamicin. TiO2 nanotubes were 80 nm in diameter and 400 nm in length, loaded with 200, 400 and 600 μg gentamicin. They studied release dynamics of these nanotubes and staphylococcus epidermidis adhering gentamicin. In addition, the study evaluated MC3T3-E1 effects on cell function by observing cytological behavior of MC3T3-E1 on these nanotubes. Study results indicated that TiO2 nanotubes carrying gentamicin not only contributed to osteocyte viability, but also significantly diminished the adhesion of staphylococcus epidermidis. Presently, TiO2 nanotubes carrying dexamethasone, penicillin and streptomycin reduced infection and inflammation. George et al [44] verified that TiO2 nanotubes carrying drugs (streptomycin, penicillin and dexamethasone) could promote osteoblast viability.
A recent study confirmed that TiO2 nanotubes had apparent inhibitory effects on glial cells[34]. A study successfully prepared hydroxyapatite/TiO2 nanotube complex smear layer by simulating body fluid soaking method[35], first investigated the biological behavior of glial cells on the surface of Ti nanotube array, and explored the effects of nanotubes of different diameters on survival rate and morphology of glial cells such as U87 cells and C6 cells. With increasing diameter of nanotubes, cell number and viability showed a decreased tendency on the surface of TiO2 nanotubes smear layer. Cell apoptosis would appear if the nanotube diameter exceeded critical size (50 nm in this experiment).
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Skeletal disease and trauma have great impacts on human’s health and quality of life. In particular, the skeletal disease impacted the quality of life and society greatly. In general, at least 10% medical cost was spent on the diseases related to bone every year (such as joint replacement and fracture fixation). With the social development, more and more biomaterials related to orthopedics have been used in clinic such as artificial joint, spinal fusion and bone clamp including internal fixation and external fixation. Every year, at least several millions of patients needed hip joint or knee replacement[1-2]. Although strict sterilization and aseptic procedures were performed, medical implant injection remains a main reason for failure[1-9].
This study sought to explore the clinical application of TiO2 nanotube array, especially the problems related to implant in the Department of Orthopedics, and discussed the advantages of TiO2 nanotube on decreasing inflammation and infection and elevating osseointegration. This study summarized the research progress of TiO2 nanotube on inflammation and infection decrease and biocompatibility and osseointegration increase.
Bacterial adhesion in implant mainly contained following pathways[10-17]: (1) pathogenic bacteria on the skin and pathogenic bacteria in surgical environment were adhered on the surface of the implant, inducing bacterial proliferation and infection. (2) Bacteria were extended on the surface of the implant through circulatory system and urinary system. Bacterial proliferation caused infection surrounding the implant. (3) Surrounding tissue infection resulted in bacterial invasion and implant-related infection. Implant-related infection is a severe complication after implantation in the Department of Orthopedics. Host infection has been defined as an unbalance of tissue and microorganism. Numerous studies demonstrated that the formation of bacterial biofilm on the surface of the metal is a direct inducement and basic characteristic of this kind of infection. Biofilm has a physical barrier can effectively prevent the killing effect of
immunocytes, antibodies and antibiotics against bacteria, finally leading to postoperative implant-related infection[10-17].
Surgical technology (aseptic technique and laminar flow operating room) in bone surgery and prosthetic design have a perfect improvement. Implant-related postoperative infection remains a giant challenge for doctors of the Department of Orthopedics. As for implant-related infection, bacterial adhesion is the first and important step. The procedure of bacterial adhesion is complicated, and bacterial adhesion was affected by environmental factor, bacterial property, the function, charge, hydrophobicity and roughness of material’s surface[10-17]. At present, preventive method for implant-related infection contains systemic and local application of antibiotics. TiO2 nanotube array prepared by anodic oxidation is the most attractive material at present.
Retrieval strategy
Retrieval database: The first author retrieved PubMed Database using computer. The key words were TiO2 nanotubes, anodization, and biomaterials. Search time was from January 2000 to June 2013.
Inclusion and exclusion criteria
Inclusion criteria: treatise and review addressing cytological experiments and animal experiments of TiO2 nanotube biocompatibility.
Exclusion criteria: unrelated literatures of TiO2 nanotube biocompatibility; old and repetitive literatures.
Data extraction
109 literatures were retrieved. A total of 62 literatures unrelated or weakly related to study objective were excluded, and 47 literatures were included. Four people independently got out the study content and discussed the problems. They focused on the information about the research progress of inflammation and infection decrease and osseointegration increase of TiO2 nanotube.
Evaluation of literature quality
A total 47 literatures were included[1-47]. The effects of TiO2 nanotube on reducing inflammation and infection and in elevating biocompatibility and osseointegration were summarized.
Anti-infection of the implant is always a difficulty in medical field. With rapid development of tissue engineering, the theory of promoting osseointegration by anti-infection of TiO2 nanotubes gradually formed. In vitro studies confirmed that TiO2 nanotubes promoted biocompatibility (including accelerating adhesion and proliferation of human osteoblasts and human mesenchymal stem cells. Animal in vivo studies (pig model) verified that TiO2 nanotubes facilitated osseointegration. TiO2 nanotubes not only have good biocompatibility and promote osseointegration, but also can be used as biological carrier to load other drugs such as growth factor and antibiotics. TiO2 nanotubes as biological carrier provides a new thinking and deserves further deep research. However, there is lack of the clinical application research of TiO2 nanotubes. Present study mainly focused on biocompatibility of TiO2 in vitro. No studies concerned drug-loaded TiO2 nanotubes such as osseointegration, causticity resistance of in vivo materials and ion blood drug level, which requires further investigation and development. TiO2 nanotubes are simple, have low cost, convenient establishment, and can be utilized as a drug carrier. TiO2 nanotubes are promising medical implant smear layer. Nanotube appearance was in primary stage of the study, but we can predict that novel orthopedic nanomaterial would facilitate the development of the science of orthopedic material.
1 此问题的已知信息：二氧化钛纳米管显著的优越性能逐渐成为目前一个最有吸引力的生物材料，在医学内植物研究中有着良好的前景。 2 文章增加的新信息：目前学者们正通过各种方式对假体材料进行改进与修饰，以求降低材料的感染率，并增强其与骨组织的整合能力。 3 临床应用的意义：随着假体材料的不断推陈出新，二氧化钛纳米管若能在临床应用中取得突破性进展，定将会在人工关节置换领域得到广泛应用。
文章特点：综述目前二氧化钛纳米管在临床相关研究的进展，结果显示二氧化钛纳米管在体内外的相关研究中显示出良好的生物相容性及骨整合能力。二氧化钛纳米管阵列由电化学阳极氧化技术制备。由于二氧化钛纳米管显著的优越性能逐渐成为目前一个最有吸引力的生物材料。文章将重点介绍作为局部药物载体的二氧化钛纳米管阵列的临床应用，特别是应用于骨科内植物。
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