Contemporary development of metallic implant materials is driven by the biocompatibility requirements and also by the need for improved mechanical performance of biomedical implants. Different paradigms govern this development for permanent and temporary (bioresorbable) implants. While materials for permanent implants, e.g. for bone or tooth replacement, obviously need to be as inert in bodily fluids as possible, those for temporary implants must degrade at a rate suitable for the targeted application.
Bioactive refers to a material which, upon being placed within the human body, interacts with the surrounding bone and, in some cases, even soft tissue.
Biodegradation is referred to as the material breakdown of chemicals by a physiological environment.
Bioinert refers to any material that, once placed within the human body, has a minimal interaction with its surrounding tissue.
Bioresorbable refers to a material that, upon placement within the human body, begins to dissolve or to be resorbed and slowly replaced by the advancing tissues (e.g., bone).
Fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework (stroma) for animal tissues, and plays a critical role in wound healing.
Hydroxylapatite, also called hydroxyapatite (HA), is a naturally occurring mineral form of calcium apatite and approximated by the formulation Ca10(PO4)6(OH)2. HA has been used as a coating on metallic alloys in orthopedic surgery.
Osteoblast is a mononucleate cell that is responsible for bone formation.
In a combined effort of our teams at Seoul National University and Monash University in Melbourne through a World Class University project on Hybrid Materials for Sustainability at Seoul National University, two archetypal alloy systems based on titanium and magnesium are investigated - an obvious choice for the two kinds of applications mentioned. Indeed, Ti forms a protective surface layer of titania and is considered to be bio-inert (thus being suitable for permanent implants), while Mg is extremely reactive and biodegradable.
Modifying the Surface Properties Through Refining the Bulk Structure?
Current research focuses on improving the biocompatibility and the mechanical performance of these systems through variations in alloy composition, microstructure and surface treatment. In the case of titanium, significant efforts go into enhancing the strength characteristics of commercial purity grades in order to avoid potential bio-toxicity of alloying elements, especially in dental implants.
In the case of magnesium alloys, a great challenge is the excessively high rate of their degradation, which is problematic both in terms of the durability of the implant and the high rate of hydrogen evolution during corrosion, e.g. in vascular stent applications.
To enhance the mechanical performance of implant materials through microstructure control, we apply a process known as equal channel angular pressing (ECAP), which is a viable processing route to grain refinement and property improvement. It turns out that the extreme grain refinement of the bulk of the metal down to nanoscale transpires to surface morphology (Fig. 1) that turns out to be conducive for enhanced adhesion and growth of living cells1. Indeed, proliferation of the preosteoblast cells on the surface of nanostructured Ti processed by ECAP was shown to be hugely enhanced, by a factor of about 20 1! The mechanism of this spectacular effect is yet to be unraveled.
Figure 1. Microstructure of commercial purity (Grade 2) titanium in the as-received (left) and ECAP processed (right) conditions. Note the stark difference in the surface topography of the two materials as revealed by atomic force microscopy.
Improved adhesion and accelerated rate of proliferation following ECAP processing of titanium was recently reported for osteoblast2 and fibroblast3 cells, as well. What is particularly important is that this excellent biocompatibility is combined with exceptional mechanical properties, the fatigue strength of the commercial purity titanium approaching the levels known only for Ti alloys, such as Ti-6Al-4V.
Figure 2. Enhanced growth of preosteoblast cells on nanostructured titanium (top) as compared to coarse-grained one (bottom). Note the morphology of the cells on nanostructured Ti indicating their better viability.
Direct Surface Modification
In addition to indirect surface modification via bulk microstructure refinement, our team also employs various direct surface modification techniques, including Micro-Arc Oxidation (MAO)4 , anodizing and coating with hydroxyapatite (HA)5. Bone cell growth on titanium designed for bone and dental implants is promoted by such techniques in a very efficient way. Bioactivity of titanium can be enhanced further by a combination of these coating techniques. For example, when HA was deposited on a MAO treated surface, bioactity was higher than in the case either surface treatment was used in isolation. In addition, coating layers can be utilized as a conduit for drug or growth factor delivery.
Towards Bioresorbable Magnesium Implants
The potential for using Mg alloys in bioresorbable vascular stents or bone implants has recently attracted a huge interest of researchers. Reducing the danger of inflammations and avoiding the need for repeat surgery by using temporary, biodegradable metallic implants and at the same time capitalizing on their good mechanical strength is, indeed, a very attractive possibility. It is small wonder many groups worldwide have rapidly moved into this area. Despite some problems with biotoxicity of certain alloying elements, structural Mg alloys have been used in biocompatibility tests, both in vitro and in vivo.
Clinical tests6 have demonstrated the viability of Mg alloys as stent implant materials. However, we believe that a thorough screening of Mg alloys with regard to their bio-corrosion and biocompatibility properties need to be conducted before the alloy selection is made and improving mechanical performance is attempted. We are currently engaged in such a screening study7. Recent results supported by the published work8 suggest, however, that in vivo tests are indispensable already at this stage, as biocompatibility of Mg alloys in vitro does not fully represent what happens in vivo.
Figure 3. SEM micrographs of surface-modified titanium implants: Morphology of MAO treated surface (top) , anodized surface (middle) and cross-sectional view of HA coating on Ti substrate (bottom).
Our work has demonstrated that bulk grain refinement techniques, such as equal-channel angular pressing, are potent tools to improve the fatigue strength and - at the same time - the bio-corrosion resistance of common structural Mg alloys9. We are exploring the ways to further improve the properties of Mg based alloys and make them fit for applications in bioresorbable implants.
However, bulk grain refinement may be insufficient to bring the bio-corrosion rate down to the levels required by the clinical needs. A natural way to contain corrosion of Mg and achieve controllable corrosion rates is by surface modification, particularly through smart coating design. For example, corrosion of Mg alloys is retarded markedly when a thin MgF2 layer is formed on the surface in a fluoridation process. Furthermore, when a bioactive material, such as hydroxyapatite, is deposited on top of the MgF2 layer, both the corrosion resistance and biocompatibility are enhanced significantly, as shown in Fig. 3
Figure 4 Coating layers of MgF2 and hydrohyapatite (HA) on Mg (top) and osteoblast cells attached on the surface of Mg coated with MgF2 and HA (bottom).
The field of biomedical implant material offers exciting and challenging opportunities for research at an interface between materials engineering and biomedical sciences. The interest in this research is fuelled by the high commercialization potential of innovations in this area. Important breakthroughs in research on nanostructured metallic materials for medical implants are therefore to be expected in near future.
1. Y. Estrin, C. Kasper, S. Diederichs and R, Lapovok, "Accelerated growth of preosteoblastic cells on ultrafine grained titanium", J. Biomed. Nater. Res. A 90A, 1239-1242 (2008).
2. R. Z. Valiev, I. P. Semenova, V. V. Latysh, H. Rack, T. C. Lowe, J. Petruzelka, L. Dluhos, D. Hrusak, J. Sochova, "Nanostructured Titanium for Biomedical Applications", Adv. Eng. Mater. 10, B15 - B17 (2009).
3. J.-W. Park, Y.-J. Kim, C. H. Park, D.-H. Lee, Y. G. Ko, J.-H. Jang and C.S. Lee, "Enhanced osteoblast response to an equal channel angular pressing-processed pure titanium substrate with microrough surface topography", Acta Biomat. doi: 10.1016/j.actabio.2009.04.038.
4. L.H Li., Y.M. Kong, H.W. Kim, Y.W. Kim, H.E. Kim, S.J. Heo and J.Y. Koak, "Improved Biological Performance of Ti Implants due to Surface Modification by Micro-arc Oxidation," Biomaterials 25 14. 2867-75 (2004).
5. S. H Lee, H.-E Kim and H. W. Kim, "Nano-Sized Hydroxyapatite Coatings on Ti Substrate with TiO2 Buffer Layer by E-beam Deposition," J. Am. Ceram. Soc. 90 1. 50-56 (2007).
6. R. Erbel et al. " Temporary scaffolding of coronorary arteries with bioabsorbable magnesium stents: a prospective, non-randomized multo-centre trial, Lancet 369, 1869-1875 (2007).
7. C. op't Hoog, N. Birbilis, M.-X. Zhang, Y. Estrin, "Surface grain size effects on the corrosion of magnesium", Key Eng. Mater 384, 229-240(2008).
8. Shaoxiang Zhang et al. "Research on an Mg-Zn alloy as a degradable biomaterial", Acta Biomater. DOI: 10.1016/j.actbio.2009.06.028.
9. H. Wang, Y. Estrin, Z. Zuberova, "Bio-corrosion of a magnesium alloy with different processing histories", Mater. Lett. 62, 2476-2479 (2008).
Copyright AZoNano.com, Professor Yuri Estrin (Monash University, Australia)
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