Advertisement

​Intervertebral fusion surgery poses a uniquely challenging situation in the spinal medical device market. Ultimately, it is the only place in the body where physicians aim to hold apart two bones (the vertebral bodies) and then induce them to fuse together. To do this, we use an intervertebral fusion device to hold the bones apart and place a biologic material within the device to stimulate the fusion process. Another challenge to the intervertebral disc space is that the device used to hold the bones apart is actually located within the fusion bed, and therefore can either help or hinder the fusion process, depending on the material and surface topography of the device.

Currently, there are three different materials that dominate the intervertebral fusion market; allograft (cadaveric bone), titanium, or polyetheretherketone (PEEK), which is a type of plastic.  PEEK devices used in conjunction with a very powerful biologic material known as BMP-2 (marketed as Infuse by Medtronic) has dominated the spinal fusion medical device market over the past decade, especially in the lumbar spine. It was assumed that PEEK was an inert spacer that merely acted as a carrier for the BMP-2. However, recent research has shown that PEEK is not inert, but rather creates a toxic environment for bone forming cells called osteoblasts.1 Additionally, BMP-2 has come under intense scrutiny over the past several years because of its higher complication rate compared to other bone grafts and bone graft substitutes.2, 3  Portions of the spinal surgical community have responded by beginning to search for a safe and effective alternative to using PEEK and BMP-2.

Titan Spine is a privately-held spinal device company that produces titanium interbody fusion devices that feature a subtractive roughened surface to enhance and promote cellular activity that allows the devices to dynamically participate in the fusion process. We have borrowed a body of literature from the dental industry that has turned to a similar subtractive surface to enhance healing of implanted screws within the jawbone.  In spinal surgery, the roughened surface not only enhances early fixation to the vertebral endplates, but also helps regulate the autocrine and paracrine cell signaling factors that lead to bone formation.4

Titan’s proprietary roughened surface actually encompasses several different layers. The macro surface that feels grossly rough to the touch is the anti-expulsion surface that initially binds the implant to the endplate upon insertion. The next layer is a micro surface (along the order of 10-6m, or one millionth of a meter) which is where osteoblastic (bone producing) cells like to reside. The most important layer is the nano-textured layer (10-9m, or one billionth of a meter). These nano-scaled textures bind to stem cell membranes through receptor proteins known as alpha2-beta 1 integrins. This binding upregulates the activation of mRNA (messenger RNA) within the cells leading to the production of bone forming proteins5. The cells produce many factors including natural BMP-2, which upregulates osteoblastic activity, other proteins that turn off osteoclastic (bone eating cells) activity, and still others that encourage production of vascular channels (angiogenesis.)4 These three factors collectively lead to net production of bone.

In order to further optimize our surface for patient healing, Titan Spine has been conducting research for the past five years to identify new and improved ways of manufacturing our surface to maximize the nano-textured features. In October of 2014, we received the first FDA clearance for a nano-textured orthopedic device, and are currently building out the manufacturing capabilities of applying this next-generation surface (nanoLOCK) to our portfolio of products. By the end of this year all our implants will feature the new nanoLOCK surface.

One question that repeatedly comes up is why did a type of plastic become so popular in the U.S. medical device industry for interbody fusion devices? A lot of the acceptance of PEEK has been centered on a concept known as modulus of elasticity (MOE). Modulus refers to an inherent property of a material to bounce back after a strain has been applied to it.  However, MOE is often confused with stiffness since both properties are measured in Pascals. The stiffness of an intervertebral device, however, is much more related to the device’s design than its material, and since all intervertebral devices are far stiffer than a vertebral body, it is not really clinically relevant. Yet, it is often quoted that the MOE of PEEK is between that of cancellous bone and cortical bone, so therefore it would be a better match with the vertebral bodies. Our industry continues to propagate the misconception that subsidence (sinking of the device in to the vertebral body) and failed fusions are due to MOE mismatches, even though there is no evidence for this in the literature. And they conveniently leave out the fact that a vertebral body is not comprised of cortical bone!6, 7

Even if the industry’s concept of MOE was accurate, it doesn’t address early bone healing. At the start of healing, biomechanical forces do not come into play. Bone will remodel due to biomechanical stress in compression, but this is a late-stage phenomenon. The initial healing phase is dominated by the endogenous recruitment of reparative cells, which is a biochemical process. This is the reason why the dental industry, and now Titan Spine, has sought to affect cellular healing by innovating and developing nano-textured titanium surfaces.

Some companies in the spine industry have responded to Titan’s research on roughened titanium surfaces by layering Titanium Plasma Spray (TPS) on top of their plastic intervertebral devices. Using the fallacious concept of MOE, they have stated in their marketing literature that this presents the best of both worlds – namely the superior osteointegration properties of titanium with the superior MOE of PEEK. Even if this combination proved true, and there is no research supporting it, it presents a very risky situation for the patient. TPS does not covalently bind to PEEK, and instead there is only a press fit (fastening as a result of being pushed together) of the titanium onto the PEEK surface, leaving increased risk for TPS particles to come off during insertion in to the intervertebral space. Histological evidence of particulate created during insertion of TPS coated implants is documented in the literature.8, 9, 10  This can have serious consequences for patients since the inflammatory response caused by metal debris may lead to implant loosening and device failure.11

Also, these TPS devices still have the problematic basis of PEEK, which, as stated earlier, has demonstrated to be not inert, but rather locally toxic to osteoblasts. In fact, cellular studies comparing our surface to PEEK found that our nano-textured surface was anti-inflammatory, whereas PEEK was markedly inflammatory and led to necrosis (premature cell death) of osteoblasts.1 This data was presented at three national and international medical meetings, won the prestigious Whitecloud award for best paper at the 21st International Meeting on Advanced Spine Techniques (IMAST) in 2014, and was published in a recent issue of SPINE. Collectively, our research represents a significant evolution in the understanding of cellular behavior during the bone healing and fusion process and how cells react to a particular material and topography.

It is our belief that the spinal medical device market should strive to understand and improve the cellular response to applied materials especially in the challenging intervertebral fusion market.  PEEK does not provide for the biochemical cellular reactions so critical to early bone healing. While changing the current status quo will be costly, the promise of quicker healing and more robust fusions for patients certainly would make it a worthwhile venture.

References
1R. Olivares-Navarrete, S. L. Hyzy, P. J. Slosar, J. M. Schneider, Z. Schwartz and B. D. Boyan, "Implant materials generate different peri-implant inflammatory factors: PEEK promotes fibrosis and micro-textured titanium promotes osteogenic factors," Spine, p. In Press, 2015.
2K. S. Cahill, J. H. Chi, A. Day and E. B. Claus, "Prevalence, complications, and hospital charges associated with use of bone-morphogenic-proteins in spinal fusion procedures," JAMA, vol. 302, no. 1, pp. 58-66, 2009.
3E. J. Carragee, E. L. Hurwitz and B. K. Weiner, "A critical review of recombinant human bone morphogenic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned," Spine J., vol. 11, no. 6, pp. 471-491, 2011.
4R. Olivares-Navarrete, S. L. Hyzy, R. A. Gittens, J. M. Schneider, D. A. Haithcock, P. F. Ullrich, P. J. Slosar, Z. Schwartz and B. D. Boyan, "Rough titanium alloys regulate osteoblast production of angiogenic factors," Spine J., vol. 13, no. 11, pp. 1563-1570, 2013.
5R. A. Gittens, R. Olivares-Navarrete, Z. Schwartz and B. D. Boyan, "Implant osseointegration and the role of microroughness and nanostructures: Lessons for spine implants," Acta Biomaterialia, vol. 10, pp. 3363-71, 2014.
6L. Mosekilde, "Vertebral structure and strength in vivo and in vitro," Calcif Tissue Int, vol. 53, pp. S121-S126, 1993.
7M. J. Silva, C. Wang, T. M. Keaveny and W. C. Hayes, "Direct and computed tomography thickness measurements of the human, lumbar vertebral shell and endplate," Bone, vol. 15, no. 4, pp. 409-414, 1994.
8M. Franchi, B. Bacchelli, D. Martini, V. De Pasquale, E. Orsini, V. Ottani, M. Fini, G. Giavaresi, R. Giardino and A. Ruggeri, "Early detachment of titanium particles from various different surfaces of endosseous dental implants," Biomaterials, vol. 25, no. 12, pp. 2239-2246, 2004.
9D. Martini, M. Fini, M. Franchi, V. De Pasquale, B. Bacchelli, M. Gamberini, A. Tinti, P. Taddei, G. Giavaresi, V. Ottani, M. Raspanti, S. Guizzardi and A. Ruggeri, "Detachment of titanium and fluorohydroxyapatite particles in unloaded endosseous implants," Biomaterials, vol. 24, no. 7, pp. 1309-1316, 2003.
10S. Vercaigne, J. G. C. Wolke, I. Naert and J. A. Jansen, "Histomorphometrical and mechanical evaluation of titanium plasma-spray-coated implants placed in the cortical bone of goats," J Biomed Mater Res, vol. 41, no. 1, pp. 41-8, 1998.
11Orthopedic and Rehabilitation Devices Advisory Panel, "Metal-on-Metal Hip Implant Systems," in FDA Executive Summary Memoriandum, Gaithersburg, 2012.

 

Entries Open: Establish your company as a technology leader. For 50 years, the R&D 100 Awards, widely recognized as the “Oscars of Invention,” have showcased products of technological significance. Learn more.

Advertisement
Advertisement