Reproduced with permission of the ACerS Bulletin.
Reproduced with permission of the ACerS Bulletin.

Over the past several decades, biomaterials researchers have developed various mechanisms for enhancing the stability of the interface between an implant and the surrounding tissue [1]. Over a half century ago, Brånemark used a rabbit model to demonstrate fusion between titanium chambers and the surrounding bone such that separation of the implant and the bone could not be accomplished without fracture [1]. He coined the term ‘osseointegration’ to describe direct (i.e., cement-free) contact between a load-carrying implant and the surrounding bone. Osseointegration inhibits microbial movement across the implant-tissue interface; preventing microbial movement is particularly important for percutaneous implants (e.g., implants for artificial limb insertion) that are exposed to the environment. Such integration also enables rigid fixation and mechanical interlocking between the surface of the implant and the adjacent tissue. The exceptional osseointegration properties of titanium and titanium alloy are attributed to the titanium oxide surface, which spontaneously forms under atmospheric conditions. Over 800,000 patients between 1965 and 2001 received dental implants that depend on osseointegration for fixation of the implant to the surrounding tissue [1]. Osseointegration is also utilized in implants for craniofacial, orthopedic, oral, and ear–nose–throat applications, including use in percutaneous cochlear implants.

Surface treatments such as acid etching may be used to increase surface texture and improve biological functionality (e.g., enhance bone formation) of dental and orthopedic implants. For example, partial sintering of metal spheres may be used to create pores on an implant surface for bone ingrowth. A variety of treatments have been developed to create roughness on surfaces for implant applications, such as grit blasting, grinding, acid etching, machining, laser texturing, physical vapor deposition, titanium plasma spraying, chemical vapor deposition, and sandblasting.

Since nanostructured surfaces exhibit larger surface areas than microstructured surfaces, they may enable better implant-tissue mechanical interlocking. In addition, an environment containing nanoscale topographical features can provide informational cues for cells. Nanoporous structures may serve as depots for pharmacologic agents or other biologically relevant molecules on the implant surface.

For example, Harmankaya et al. used evaporation-induced self-assembly to create mesoporous titanium oxide films on titanium implants with screw shapes as well as other materials [2]. Alendronate and raloxifene, two drugs used for treatment of osteoporosis, were adsorbed on the surfaces of these mesoporous films. It should be noted that alendronate and raloxifene suppress osteoclasts via different mechanisms; alendronate inhibits bone resorption by osteoclasts and raloxifene selectively modulates estrogen receptors. An in vitrostudy involving a quartz crystal microbalance showed that alendronate adsorption was thirty times higher on porous titanium oxide films than on hydrophilic non-porous surfaces. Raloxifene absorption was three times higher on porous methylated titanium oxide films than on methylated non-porous surfaces. The quartz crystal microbalance study also indicated that both alendronate and raloxifene adsorbed to the mesopores as well as exhibited sustained release patterns. The drug-loaded implants were implanted in the proximal metaphysis of the tibia in Sprague–Dawley rats. Twenty-eight days after implantation, the rats were sacrificed and the periimplant tissue was examined via transmission electron microscopy, histology, and quantitative polymerase chain reaction studies. The alendronate-loaded implants and raloxifene-loaded implants were shown in removal torque testing to provide significantly better bone-to-implant anchorage than controls. Energy-dispersive X-ray spectroscopy indicated that mineral containing calcium and phosphorus precipitated inside the mesopores; the mineral precipitation process was attributed to raloxifene. The alendronate coating was associated with higher bone density beyond the surface. The mesoporous coating was not altered by grinding and cutting activities, which suggests that it possesses stability against mechanical loading.

Several researchers have examined the effect of surface topography on cell attachment and cell differentiation. For example, Takeuchi et al. demonstrated 2.5–3 times higher elastic modulus values and 3–3.5 times higher hardness values for acid-etched titanium [3]. In a study involving rat bone marrow-derived osteoblastic cells, acid-etched titanium was associated with accelerated collagen synthesis and upregulated bone-related gene expression [3]. Kieswetter et al. showed that MG 63 osteoblast-like cells produced greater amounts of prostaglandin E2 and transforming growth factor β1 on rough titanium surfaces than on smooth surfaces [4].

Researchers have developed materials with small-scale features that exhibit precise and reproducible geometries. For example, Jayaraman et al. showed that grooved titanium surfaces were associated with higher attachment rates, higher proliferation rates, and more intense osteonectin expression by osteoblast-like primary cells than sandblasted and acid-etched surfaces [5]. Zinger et al. demonstrated that titanium surfaces with sub-micrometer features were associated with enhanced transforming growth factor β1 production and differentiation [6]. Prostaglandin E2 production was shown to be dependent on the dimensions of the micrometer-scale cavities on titanium surfaces; titanium surfaces with 100 μm cavities were noted to facilitate attachment and growth of MG 63 osteoblast-like cells [6].

The use of anodization for implant surface modification has also been investigated. For example, Frandsen et al. grew a titanium oxide coating on a zirconium oxide knee component using sputtering; this coating was subsequently converted to a titanium oxide nanotube coating using anodization [7]. MC3T3-E1 murine osteoblast cells were shown to exhibit better integration and adhesion on the nanotube surface than on the uncoated surface. Bauer et al. showed improved adhesion and spreading of mesenchymal stem cells on aligned arrays of zirconium oxide and titanium oxide nanotubes with 15–30 nm diameters [8].

A rapid prototyping approach known as two photon polymerization has been used to prepare surfaces with small scale features that may be appropriate for orthopedic and dental applications. For example, Miller et al. prepared a porous scaffold out of a zirconium oxide hybrid material using two photon polymerization [9]. The scaffold, shown in the figure, contains 100 micrometer diameter cylinders. Excellent cylinder-to-cylinder uniformity within one layer of a multilayer tissue engineering scaffold was observed using microcomputed tomography [9]. Witting et al. created microscale and nanoscale features (e.g., posts and rods) with titanium oxide coatings using a hybrid process involving two photon polymerization and atomic layer deposition; SaOs-2 osteosarcoma cells exhibited three-dimensional growth on surfaces that contained posts and rods [10].

The orthopedic and dental implant market is increasing every year because of the growing number of older individuals. Materials with controlled microscale and nanoscale features, including many of the features mentioned above and others yet to be developed, may enhance the quality of life for individuals who require orthopedic and dental implants.

Further reading

[1] R. Brånemark et al. J. Rehabil. Res. Dev., 38 (2001), p. 175

[2] N. Harmankaya et al. Acta Biomater., 9 (2013), p. 7064

[3] K. Takeuchi et al. J. Biomed. Mater. Res. A, 72 (2005), p. 296

[4] K. Kieswetter et al. J. Biomed. Mater. Res., 32 (1996), p. 55

[5] M. Jayaraman et al. Biomaterials, 25 (2004), p. 625

[6] O. Zinger et al. Biomaterials, 26 (2005), p. 1837

[7] C.J. Frandsen et al. Mater. Sci. Eng. C, 33 (2013), p. 2752

[8] S. Bauer et al. Integr. Biol., 1 (2009), p. 525

[9] P.R. Miller et al. Am. Ceram. Soc. Bull., 90 (2011), p. 24

[10] R. Wittig et al. J. Laser Appl., 24 (2012), p. 042011

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DOI: 10.1016/j.mattod.2013.06.007