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PEEK and stem cell-powered implants

Nikolaj Gadegaard and Matthew J Dalby
1 July, 2013  
A relatively young material among the plastics used for medical devices is polyetherether ketone (PEEK), which has had greatest success in the area of spinal implants
Nikolaj Gadegaard PhD
Reader in Biomedical Engineering
Matthew J Dalby PhD
Reader in Cell Engineering
University of Glasgow, Glasgow, UK
Considering the numerous alloys, ceramics and plastics used in everyday applications, perhaps surprisingly few have made it through to the clinical market and there are several reasons for this. The most dominating factor is the costs associated with achieving regulatory approval. Other factors relate to bio-incompatibility, chemical and mechanical properties as well as processing requirements. A relatively young material among the plastics used for medical devices is polyetherether ketone (PEEK). PEEK is a member of the polyarylether ketone (PAEK) family that was developed in the 1980s.
PEEK was made commercially available in 1999 by Invibio Ltd and has seen fewer than 15 years of clinical use, which for some orthopaedic implants (for example, hip implants) is shorter than their expected lifetime. The use of PEEK in the automotive and aerospace industry has seen a steady rise due to its unusual properties as compared to more traditional engineering plastics. Its strength-to-weight ratio, especially for fibre-reinforced materials, is a desirable mechanical advantage.
It has a high degree of chemical resistance to many organic solvents, including aromatic hydrocarbons. PEEK can be used at temperatures in excess of 300°C, which provides many advantages in those industries. On a biological scale, PEEK’s biocompatibility is largely related to the inert nature of the material in the body.
An important property for its use in orthopaedic devices is the ability to tune the elastic modulus from 3GPa to 18GPa by carbon fibre reinforcement, which brings the material close to that of cortical bone.(1) The match of mechanical properties between bone and PEEK means that stress shielding can be greatly reduced, which is an inherent and significant problem of current titanium alloy-based implants where the elastic modulus is nearly ten-times higher.
Tuning the material’s properties for application
The ability to modify the properties of the PEEK to tune its properties is a very attractive prospect. In Table 1, a list of different modifications of PEEK is given. The length of the PEEK polymer determines some of it physical properties, primarily its viscosity during injection moulding. For some applications, a low viscosity is necessary for the polymer to properly fill the tool. Although the elastic modulus of the native PEEK material is closer to that of cortical bone than titanium alloys, it can be brought even closer, or matched, by using carbon fibre reinforcement. Adding 30% carbon fibre to the polymer provides a good mechanical match.
The greatest success of PEEK in orthopaedic devices has been in the area of spinal implants. One of the major drivers behind this uptake is the inherent radio transparency of the polymer compared with metallic implants. Because of the surgical procedures near the spinal cord, it is vital for the surgeons to image both the implant and the spinal cord at the same time, which is not possible with metallic implants (Figure 1). Indeed, for spinal devices, the addition of a radio-opaque material such as barium sulphate (BaSO4) to the PEEK polymer enables the device manufacturers to tune the radio translucency of the devices so that they can be visualised on X-rays.
PEEK in orthopaedics
The first use of PEEK in the medical sector was for spinal implants. As described above, one of the main reasons is the ability to control the radio-opacity of the implant. This, combined with mechanical properties closer to that of bone, has resulted in PEEK being the dominating material for fusion cages and motion preservation of the spine. Within the first ten years of the introduction of PEEK, it has largely displaced bone grafts and metals as the main component of interbody fusion devices, comprising more than 65% of the market.(2)
 
Although there are some clear advantages from the use of PEEK in medical devices, there are still some hurdles to be addressed. Despite the possibility of matching the mechanical properties of cortical bone, the material itself is inert in the body and there is little response between the surrounding tissue and the implant. For skeletal applications, such as total joint replacement, this is a critical requirement that has been addressed by several approaches.
The first successful femoral stem to incorporate PEEK was the Epoch stem (Zimmer Inc). It has a CoCr core over which a PEEK sleeve is injection moulded. This combination provides an isoelastic performance-reducing stress shielding normally seen for pure metallic implants. The PEEK surface is covered with a titanium mesh to ensure bone integration with the implant. This serves two purposes: (i) it provides a surface to which bone cells can adhere, which is not possible on the PEEK surface; and (ii) it provides a roughened surface that enhances the integration with the ingrowing bone.
Smarter biomaterials
In 2002, Hench and Polak published their definition of first, second and third generation biomedical materials.(3)  First generation biomaterials were characterised as having minimal toxicity to the host tissue and thus largely being bio-inert. Interestingly, pure PEEK would fall in that category because of its inertness. First generation biomaterials still comprise the majority used in implants today. In the 1980s and 1990s, a flurry of new bioactive materials, such as bioactive glasses and synthetic hydroxyapatite (HA), were introduced. These materials provide an osteoconductive surface.(4)
This means that bone will grow on the surface as it regenerates at the defect; PEEK-HA is an example of such a biomaterial. Third generation biomaterials will be designed to stimulate specific cellular responses at the molecular level. The first materials were based on the release of small molecules, such as BMP-2, which directly regulated the formation of bone and provided osteoinduction.(4) However, its safety is currently being assessed and its clinical use uncertain for the future. 
Nanostructuring
When devices are made, the structure of the surface (topography) is influenced by the process, either inadvertently or deliberately, by roughening. Thus, from a fundamental point of view, there has been a longstanding interesting in determining the influence of such topographies on cell responses.
Although roughening is the most common way to control the surface topography, it has been reported that, although surfaces may share the same roughness average, the cellular response might be very different because that single descriptor does not provide a full description of the surface. Instead, we have taken a completely different approach using lithographic patterning technologies better known in the semiconductor industry. Specifically, we have used electron beam lithography to define highly specific and well-characterised nanopatterns in a range of different polymeric substrates.(5) In 2007, we discovered that a specific nanopattern could be used to directly control the fate of bone marrow mesenchymal stem cells.(6)
These nanopatterns consist of holes 120nm in diameter and 100nm deep, each separated by 300nm. If a substrate was prepared with a small amount of disorder, up to 50nm from its ideal position, we observed that bone marrow-derived stem cells were specifically driven down an osteogenic differentiation. This is illustrated in Figure 2, where cells cultured on the nanopatterned substrate showed a clear production of osteopontin (OPN) after three weeks in culture; this was not observed on the flat control.
This was corroborated by quantitative polymerase chain reaction, where bone-forming genes were upregulated. Indeed, if left for four weeks in vitro, bone minerals started forming on the substrate with no added chemical factors. This discovery is another example of a third-generation biomaterial where the material directly influences the cell behaviour at the molecular level. Here the advantage is that the cellular response is independent of the substrate materials and is indeed only driven by the surface topography.
PEEK processing
The materials demonstrating the stem cell effect are commonly thermoplastic polymers. This provides us with some interesting process opportunities. Today, a large number of PEEK-based implants are machined because of the inflexibility and large start-up costs for an injection moulding process. However, injection moulding holds a range of unique features that are likely to see the use of injection-moulded PEEK rise in the near future. These prominent features include the ability to include nanopatterning directly on the surface of the substrate during the injection moulding cycle, a feat not possible using traditional device machining.
Moreover, the injection moulding process also hold the clear advantage that a part with a complex surface geometry can be fabricated is a single step on a fully automatic platform. The use of injection moulding substrates with nanopatterns is well known from the optical storage media, where today’s Blu-Ray discs have feature densities very similar to our substrates. The resolution of the injection moulding process is impressive, and small features (approximately 5nm) can be replicated by this process.(7) For our samples, we have adapted the optical storage technology and can prepare PEEK substrates with a range of different surface patterns (Figure 3). 
Conclusions
There is no doubt that the use of PEEK will increase in the future. Being a ‘young’ material, its long-term performance is yet to be assessed. However, some of the traditional materials used in orthopaedic devices are now being withdrawn from the market, such as metal-on-metal implants, and may well be replaced by PEEK materials. It might also be expected that other joint devices, such as those for ankle, finger and shoulder, will see an uptake of PEEK.
This will partly be supported by the fact that PEEK can successfully be injection moulded into complex shapes in a fast and reproducible manner, with the ability to include surface topographical patterning. We are now seeing the development of true third generation biomaterials to provide cellular specificity at the biomolecular level, and it is very likely that this innovation will encompass materials with specific topographic patterns both at the micro- and nanometer scale. The challenges ahead for the realisation of these materials to surgeons and patients rest on providing patterned areas on non-planar samples.
References
  1. Kurtz SM. PEEK Biomaterials Handbook. 2012 Elsevier Inc ISBN: 978-1-4377-4463-7.
  2. Mendenhall S. Spinal industry update. Orthopaedic Network News 2010;21:3-6
  3. Hench LL, Polak JM. Third-generation biomedical materials. Science 2002;295:1014–17. 
  4. Albrektsson T, Johansson C. Osteoinduction, osteoconduction and osseointegration. Eur Spine J 2001;10:S96–S101.
  5. McMurray R, Dalgy M, Gadegaard N. Nanopatterned surfaces for biomedical applications. In Laskovski AN (ed) Biomedical Engineering, Trends in Materials Science. DOI: 10.5772/13453.
  6. Dalby MJ et al. The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder Nat Materials 2007;6:997–1003.
  7. Gadegaard N, Mosler S, Larsen NB. Biomimetic polymer nanostructures by injection molding. Macromol Mater Eng 2003;288:76–83.