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J Dent Res 87(8):751-756, 2008
© 2008 International and American Associations for Dental Research

RESEARCH REPORT
Biomaterials & Bioengineering

Ti Nano-nodular Structuring for Bone Integration and Regeneration

T. Ogawa1,*, L. Saruwatari1,2, K. Takeuchi1, H. Aita1, and N. Ohno2

1 Laboratory for Bone and Implant Sciences (LBIS), The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, Biomaterials and Hospital Dentistry, UCLA School of Dentistry, 10833 Le Conte Avenue (B3-081 CHS), Box 951668, Los Angeles, CA 90095-1668, USA; and
2 Department of Oral Anatomy, Aichi-Gakuin University, School of Dentistry, Nagoya, Japan

* corresponding author, togawa{at}dentistry.ucla.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Nanostructuring technology has been proven to create unique biological properties in various biomaterials. Here we present a discovered phenomenon of titanium nano-nodular self-assembly that occurs during physical vapor depositions of titanium (Ti) onto specifically conditioned micro-textured titanium surfaces, and test a hypothesis that the Ti nanostructure has the potential to enhance bone-titanium integration. The nanostructure creation effectively provided geometrical undercut and increased the surface area by up to 40% compared with the acid-etched surface with microtopography. Depending on the size control, the nano-nodules can be added without smearing the existing micro-texture, creating a nano-micro-hybrid architecture. Titanium implants with 560-nm nano-nodules produced 3.1 times greater strength of osseointegration than those with an acid-etched surface in a rat femur model. The discovered titanium nano-nodular self-structuring has been proven feasible on biocompatible materials other than titanium, offering new avenues for the development of implant surfaces and other implantable materials for better bone-generative and -regenerative potential.

KEY WORDS: nanotechnology • dental implant • nano-micro-hybrid • self-assembly • vapor deposition


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Nanostructuring technology has been proven to create unique physical, chemical, mechanical, and biological properties of various materials, and explores the next generation of micron-scale technologies in the fields of engineering, information technology, environmental sciences, and medicine (Wang, 2002; Hamley, 2003). There are two common strategies for creating nano-surface structures: "top-down" and "bottom-up" fabrications (Edler, 2004). Since the top-down approach, represented by submicron-level lithography (Kim et al., 2003), is to create nanostructures from macro-structures or a complex entity by subtractive processes, the size of the processed structure reaches physical limits, such as the resolution and wavelength of the cutting source. Moreover, this approach is time-consuming and not suitable for large-area processing or mass production. In contrast, the bottom-up approach assembles nanostructures from sub-nano levels, molecule by molecule or even atom by atom, as represented by atomic assembly with nano-level-resolution microscopy (Gebeshuber et al., 2005) and metal solidification (Millman et al., 2005). In the future, the "bottom-up" approach is expected to overcome the limitation of the top-down method by improving the processing scale, speed, and cost.

Another issue is that the current technologies have difficulties in creating a co-existence of microstructure and nanostructure, which gives additional properties of the new surface while maintaining the existing micro-structure. For instance, in bioengineering fields, it would be beneficial to increase the surface area and roughness of biomaterials without altering the existing micro-scale configuration, which may help enhance protein-biomaterial interaction without sacrificing the proven, favorable cell-biomaterial interaction.

Titanium is a proven biocompatible material that possesses the potential to promote bone generation around it, and is used extensively in orthopedic and dental implants (LeGeros and Craig, 1993; Brunski et al., 2000). Most titanium surfaces in the currently used dental implants are roughened at a micrometer scale. The surfaces manifest better osteogenic responses, as demonstrated by a promoted osteoblastic differentiation (Takeuchi et al., 2005), faster bone formation (Ogawa and Nishimura, 2003), and increased tissue-titanium mechanical interlocking (Ogawa et al., 2000). Surface structure at a nanometer level, providing an increased surface area and finer surface roughness, may yield better biological responses of osteogenic cells and tissue-titanium mechanical interlocking. Here we show a uniform nano-nodular structuring of a titanium surface and test a hypothesis that the newly created titanium nanostructure has the potential to enhance bone-titanium integration over the surface without the nanostructure.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Titanium Substrate Preparation
Surfaces of commercially pure titanium (a disc form of 20 mm in diameter and 1.5 mm in thickness), nickel and chromium, and titanium alloy (Ti 85.5%, Al 6.0%, Nb 7%), as well as chromium cobalt alloy (Co 63%, Cr 28%, Mo 5%), were prepared by either machining, sand-blasting (50 µm AlO2 particles for 1 min at a pressure of 3 kg/m), various acid-etching periods with 66% sulfuric acid (H2SO4), 10.6% HCl (hydrochloric acid), 3% hydrofluoric acid (HF), chromium etchant (5–10% HNO3, 1–5% H2SO4, 5–10% ceric sulfate), or a combination of these. Additionally, untreated or sand-blasted non-metal substrates—including polystyrene cell culture dishes, microscopic slide glasses, poly-lactic acid (PLA), collagen membranes (Ossix, Implant Innovations, Inc., Palm Beach, FL, USA), and silicon wafers—were prepared.

Titanium Deposition
Surfaces of the prepared substrates were deposited with either titanium, nickel, chromium, silicon, or silica by e-beam physical vapor deposition (EB-PVD) technology (SLONE e-beam evaporator, SLONE Technology Co., Santa Barbara, CA, USA). The deposition rate was 5 Å /sec for Ti, Ni, Cr, and SiO2, and 2 Å /sec for Si. The duration was set to create a theoretical deposition of 500-nm thickness, i.e., it was 16 min 40 sec for titanium deposition. For a study to control the sizes of nanostructures, other durations were applied for titanium deposition as needed.

Surface Characterization
Surface morphology of the substrates, before and after the deposition, was examined by scanning electron microscopy (SEM) (JSM-5900LV, JEOL Ltd., Tokyo, Japan) and atomic force microscopy (AFM) (SPM-9500J3, Shimadzu, Tokyo, Japan). The contact mode scanning was performed in an area of 5 µm x 5 µm, and the images were constructed with a custom vertical scale or fixed scale of 1.5 µm. The AFM data were analyzed by packaged software for topographical parameters of root mean-square roughness, peak-to-valley roughness, spatial inter-irregularities, and surface area. Further, by AFM topographical profiles, the diameter and peak-to-valley distance of the nano-nodules were measured.

Biomechanical Evaluation of Nano-nodular Implants for Osseointegration
We have used an established biomechanical push-in test in the rat model for this purpose. Animal surgery and biomechanical testing were carried out as described in the APPENDIX, according to a previously reported protocol (Ogawa et al., 2000). The University of California at Los Angeles (UCLA) Chancellor’s Animal Research Committee approved this protocol, and all experimentation was performed in accordance with the United States Department of Agriculture (USDA) guidelines for animal research.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Creation of Ti Nano-nodular Structure on Pre-micro-roughened Titanium Surfaces
Scanning electron micrographs (SEM) revealed unique nano-scale rounded, nodular structures created during the electron-beam physical vapor deposition (EB-PVD) of titanium (Fig. 1AGo). The Ti EB-PVD deposition was performed for 16 min 40 sec onto variously prepared Ti surfaces. Uniform nano-nodular structures were developed only on the textured surfaces by either sand-blasting or acid-etching with hydrochloric acid (HCl) and/or sulfuric acid (H2SO4) (panels highlighted in blue in Fig. 1AGo), but not on relatively smooth surfaces, including machined and hydrofluoric-acid (HF)-treated surfaces (panels in gray in Fig. 1AGo). With these conditions, the de novo nano-architectures masked the existing microstructure characterized by sharp peaks and deep valleys. The morphology, uniformity, and density of nano-nodules differed among differently prepared substrates. The nano-structures were more even in size and uniformity on the acid-etched substrates than on the sand-blasted substrates, in accordance with the uniform microtexture on the original substrates. The nano-structures, when optimally constructed as seen on the HF-H2SO4 - and HCl-H2SO4-treated surfaces, while being hemi-globular or dendritic, seemed to provide an increase of surface area and geographical undercut all over the surface.


Figure 1
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  		Figure 1. Nano-nodular self-assembly of titanium on variously pre-micro-roughened titanium surfaces. (A) Scanning electron microscopic (SEM) x10,000 images before and after electron-beam physical vapor deposition (EB-PVD) of titanium for 16 min 40 sec, with a deposition rate of 5 Å / sec onto various titanium surfaces. Images in gray indicate no or little nano-nodules created, while images highlighted in blue indicate dense, uniform, and consistent nano-nodules. Titanium substrates (disks of 20 mm in diameter) were prepared by the following: machining (Machined), hydrofluoric-acid-etching (HF), sand-blasting, hydrofluoric acid and sulfuric acid dual-etching (HF-H2SO4), sulfuric-acid-etching (H2SO4), and hydrochloric acid and sulfuric acid dual-etching (HCl-H2SO4). Bar = 2 µm and applies to all panels. (B) Atomic force micrographs of the various Ti substrates tested, showing various degrees of micro-roughness before titanium deposition (top images). The images are presented in a fixed vertical scale of 1.5 µm. Nano-structuring was unsuccessful in the first two substrates (A). Histograms show the results of quantitative roughness analysis for the substrates before Ti deposition: root mean-square roughness; peak-to-valley roughness; inter-irregularity space. Data are shown as mean ± standard deviation (n = 5). The blue bars indicate the substrates that resulted in nano-nodular creation, while the gray bars indicate the substrates that created few or no nano-nodules.

 
Pre-treatment Conditions Required for Nano-nodular Structuring
The AFM images in a fixed vertical scale of 1.5 µm revealed recognizable roughness only for the sand-blasted, HF-H2SO4-, H2SO4-, and HCl-H2SO4 -treated surfaces, all of which were related to the nano-nodular structuring during the Ti EB-PVD (top images in Fig. 1BGo). AFM quantitative measurements indicated that emergence of the nano-nodules was associated with substrate surface topography that was > 200 nm in the root mean-square roughness and > 400 nm in the peak-to-valley roughness (blue bars in histograms, Fig. 1BGo). Because the nano-nodules were formed on the substrates with a wide range of inter-irregular spaces, ranging from 800 nm to 1.8 µm, there seemed to be no requirement in the inter-irregular spaces for nano-nodular formation. However, it was found that inter-irregular spaces ranging from 1000 nm to 1.5 µm, such as on HF-H2SO4- and HCl-H2SO4-treated surfaces, helped develop well-isolated and -defined nano-nodules (Figs. 1A, 1BGo). The substrates with inter-irregular spaces smaller than 1.0 µm, such as on H2SO4 -treated surfaces, produced nodules fused with existing and neighboring architectures, while the substrates with inter-irregular spaces larger than 1.5 µm, such as the sand-blasted surface, resulted in poorly defined and irregular nodules.

Control of Ti Nano-nodular Size, Enhancement of Surface Morphology, and Creation of a Nano-micro-hybrid Structure
Ti deposition (EB-PVD) was undertaken on the HCl-H2SO4 acid-etched Ti surface with different deposition times and a fixed deposition rate of 5 Å/sec. When the deposition time was 3 min 20 sec, the development of under-100-nm nano-nodules was recognizable in SEM and AFM images (Figs. 2A, 2BGo); nano-structure profiling revealed the average diameter to be 84 nm (Figs. 2C, 2DGo). Increased deposition time increased the size of nano-nodules progressively, even to values greater than 1.0 µm in diameter, with an average diameter of 925 nm when deposition time was 33 min 20 sec (Figs. 2A–2DGo). The average size of the developed nano-nodules, ranging from 84 nm to 925 nm, was in linear correlation with the deposition time we tested (Fig. 2DGo).


Figure 2
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  		Figure 2. Size and height control of nano-nodular structure by adjustment of the deposition time and expanded surface areas by the nano-nodules. (A) Scanning electron microscopic images after Ti electron-beam physical vapor deposition (EB-PVD) onto the acid-etched titanium for various deposition times, showing the sizes of nano-nodules correlated with the deposition times. The nano-nodule outbreaks occurred in a time period as short as 3 min 20 sec. The deposition rate was fixed at 5 Å /sec. Images are at x10,000 magnification. Bar = 2 µm (all panels). (B) Atomic force micrographs of the Ti nano-structures created in panel A. (C) Nano-nodular structure AFM profiling. The diameter (arrow) and peak-to-valley distance (arrowhead) of the nano-nodules were measured manually, by side-by-side analysis of two-dimensional images and profiles of the titanium surfaces. The diameter (D) and peak-to-valley distance (E) of nano-nodules generated by different deposition times. Data are shown as mean ± standard deviation (n = 9). (F) Three-dimensional surface area of the nano-nodular surfaces measured in the field of 5 mm x 5 mm. Four different nano-surfaces created by different deposition times. Data are shown as mean ± standard deviation (n = 9).

 
The height of the nano-nodules, measured by the peak-to-valley distance of the nodules (Fig. 2CGo), also increased with an increase in the deposition time, although it seemed to reach a plateau between 400 and 500 nm (Fig. 2EGo). The three-dimensional surface area, when evaluated in the two-dimensional 5 µm x 5 µm area, increased with the nano-nodular structuring by up to 40% compared with the acid-etched microstructured surface, when deposition occurred for 8 min 20 sec (p < 0.01) (Fig. 2FGo). Interestingly, after the peak, the surface area did not increase with increasing deposition time.

The co-existence of the substrate microstructure, as represented by the sharp peaks and uniform inter-peak compartments of the original acid-etched surface, with the nano-nodules added at the flanks or tops of the peaks, or at the bottom of the valley, was seen when the deposition time was 8 min 20 sec or less (Fig. 2AGo), allowing a Ti nano-micro-hybrid surface structure to develop.

Generalization of Nano-nodular Structuring
To generalize the phenomenon of nano-nodular self-assembly, we first determined whether titanium nano-structuring could be accomplished on other types of metals, and then determined whether the nano-structuring could be accomplished between various heterogeneous metals. The titanium nano-structures were successfully created by EB-PVD deposition onto the sand-blasted and selected acid-etched Ni and Cr surfaces (Appendix 1). We also demonstrated the establishment of Ti nano-nodules on Ti alloy and CoCr alloy, well-known biocompatible alloys, only when the metal surfaces were properly micro-textured (Appendix 1). In addition, the formation of nano-structured Cr and Ni on variously micro-textured surfaces of various metals was demonstrated (Appendix 2), indicating that nano-nodule self-assembly is not restricted by the types of metallic substrates or depositing materials. Further, we determined whether the material subjected to nano-nodular self-assembly had to be metallic in composition. Ceramic (SiO2) and semiconductor (Si) materials were deposited on micro-textured metals and non-metals (Appendix 3). Both SiO2 and Si generated nano-nodules on metallic and non-metallic substrates, i.e., on pre-micro-textured polystyrene, Ti, and Si wafers.

Ti Nano-nodular Structuring on Non-metallic Surfaces
We next aimed to determine the possibility of creating Ti nano-nodules on non-metallic surfaces by applying the Ti EB-PVD deposition procedure to non-biomaterials, such as polystyrene and glass, and to biomaterials such as a collagen membrane and poly-lactic acid (PLA) (Fig. 3Go). Ti nano-nodules similar to those on the metallic surfaces were constructed on all of the non-metals tested (blue panels in Fig. 3Go), when they were pre-textured by being sand-blasted.


Figure 3
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  		Figure 3. Titanium nano-nodular assembly on non-metallic surfaces: polymer, glass, and biomaterials. Scanning electron micrographs showing the original non-metallic substrates and successful Ti nano-nodules created on the substrates (blue panels). Ti was deposited for 16 min 40 sec onto the original or sand-blasted surfaces of polystyrene, glass, collagen membrane, and poly-lactic acid (PLA), by electron-beam physical vapor deposition (EB-PVD). Images in gray represent unsuccessful nano-nodule assembly. Images are at x10,000 magnification. Bar = 2 µm (all panels).

 
Enhanced Osseointegration by Nano-nodular Structure
The strength of osseointegration was compared by means of a biomechanical push-in test between the HCl-H2SO4 acid-etched implants and nano-nodular structured implants created by Ti deposition for 16 min 40 sec. Since this deposition time yielded the most defined, nodular architecture (Fig. 2AGo), we selected this setting for in vivo testing for its osseointegration capacity. In this setting, the diameter of the nodular structure was 560 nm on average (Fig. 2DGo), and the surface area increased by 28% compared with the acid-etched surface (Fig. 2EGo). The push-in value at wk 2 of healing was 3.1 times greater for the nano-nodular structured implants than for the acid-etched implants (Fig. 4Go).


Figure 4
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  		Figure 4. Nano-nodular-enhanced bone-titanium integration evaluated by a biomechanical push-in test. Push-in values of the acid-etched and nano-nodular-structured implants at week 2 of healing are shown as the mean ± SD (n = 5). The diameter of the nano-nodules created for this in vivo testing was 560 nm. Statistically significant at *p < 0.001.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Herein, we introduce a titanium nano-nodular structuring technology based on the discovery of a self-assembly phenomenon of nano-nodules on specifically conditioned micro-roughened titanium surfaces. We found that only the substrates with the appropriate surface micro-dimensions gave rise to this unique phenomenon. The process is rapid and controllable for the size and height of the nodules, and has been demonstrated to be feasible in a wide range of material types. The created morphology is unique and may serve as a novel surface modification technology to improve surface/ interfacial mechanical, electrical, chemical, and biological properties. In fact, one of the potential applications has been proven in this study. The strength of osseointegration was increased over 3 times by the created nano-nodules compared with the implants with the acid-etched surface. Although further studies are needed, the development of undercuts and 28% expanded surface area by the nano-nodular architecture may have improved the bonding between titanium and tissue by providing larger and more intimate interlocking. In this study, we tested the implants with nano-nodules of approximately 560 nm in diameter. Optimization of nano-nodular size may result in more enhancement of osseointegration in future studies. Another advantage of this technology is the capability of a nano-structure residing within the existing microstructure to derive additional effects of nano-structures while preserving benefits from the existing microstructures. By controlling the duration of deposition, we succeeded in creating a hybrid structure of micro- and nano-architectures.

Currently, several nano-structuring technologies are under investigation for potential usefulness in implant surface modification. Nano-scale calcium phosphate or a calcium phosphate/protein composite can be developed by electrochemical deposition (Hu et al., 2007; Narayanan et al., 2008; Wang et al., 2008). Nano-tubular structural modification of titanium has been achieved by anodization (Yao and Webster, 2006). Hydroxyapatite nano-precipitation may be useful for titanium coating (Barrere et al., 2004). Other techniques are available for titanium nano-structuring, including sol-gel and hydrothermal techniques (Chen and Mao, 2006). There are also commercially available dental implant surfaces having nano-scale morphological features. Acid-etched microtopography with irregular, discrete, 20- to 40-nm hydroxyapatite particles has been reported to enhance the strength and direct bone bonding of osseointegration (Nishimura et al., 2007; Orsini et al., 2007). Another example is a hydrofluoric-acid-treated sand-blasted titanium surface that produces an approximately 100-nm structural modification of a titanium surface, which may be related to the enhanced osteoblastic differentiation occurring on the surface (Guo et al., 2007). Each of these technologies, including the present technology, has technical advantages and disadvantages, such as cost, time, reproducibility, and complexity of the procedure. More importantly, the shape, size, and chemistry of the nano-structure differ among the technologies. The present technology produces controllable, unique nodular structures of titanium that resulted in an overwhelming 3.1-times increase of osseointegration strength over the acid-etched surface, one of the microtextured surfaces used most in the current dental implant market. Understanding biological responses to various nano-surfaces at the cellular and molecular levels should be an immediate goal, which will help optimize factors in nano-structuring, specifically suitable to the enhancement of titanium osseointegration.

Last, titanium serves as a well-documented bone-conductive material, and the combination of a titanium nano-structure added to other biocompatible materials, such as collagen and PLA, as presented in this report, may be a strategic option to improve bone regeneration and engineering. Thus, we expect that this novel "bottom-up" approach of nano-structuring technology will be tested promptly for potential extensive applications, because of its simple and controllable traits, in the fields of dental and orthopedic implants, and other areas of regenerative medicine.


   ACKNOWLEDGMENTS
 
This study has been supported by JIADS, the Nissenken Institute, and the Kyushu-Oita Implant Institution. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 RR014529 from the National Center for Research Resources, National Institutes of Health.


   FOOTNOTES
 
A supplemental appendix to this article is published electronically only at http://jdr.iadrjournals.org/cgi/content/full/87/8/751/DC1.

Received July 26, 2007; Last revision February 27, 2008; Accepted March 3, 2008


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Barrere F, Snel MM, van Blitterswijk CA, de Groot K, Layrolle P (2004). Nano-scale study of the nucleation and growth of calcium phosphate coating on titanium implants. Biomaterials 25:2901–2910.[ISI][Medline]

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Guo J, Padilla RJ, Ambrose W, De Kok IJ, Cooper LF (2007). The effect of hydrofluoric acid treatment of TiO2 grit blasted titanium implants on adherent osteoblast gene expression in vitro and in vivo. Biomaterials 28:5418–5425.[ISI][Medline]

Hamley IW (2003). Nanotechnology with soft materials. Angew Chem Int Ed Engl 42:1692–1712.

Hu R, Lin CJ, Shi HY (2007). A novel ordered nano hydroxyapatite coating electrochemically deposited on titanium substrate. J Biomed Mater Res A 80:687–692.[Medline]

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Nishimura I, Huang Y, Butz F, Ogawa T, Lin A, Wang CJ (2007). Discrete deposition of hydroxyapatite nanoparticles on a titanium implant with predisposing substrate microtopography accelerated osseointegration. Nanotechnology 18:1–9.

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