SURGICAL SOLUTIONS, TECHNIQUES, AND TRENDS Osseointegration: Infection Solutions

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By Miki Fairley

Technological advances in prosthetic care have a long history. Archeologists have unearthed evidence of prosthetic treatment from nearly five millennia ago, according to "The History of Prosthetics," an online article by Mary Bellis. Fifth-century Dorian Greek historian Herodotus (also known as the "father of history") wrote one of the earliest known references to a prosthesis, according to Bellis, when he cited the story of a prisoner who escaped from chains by cutting off his foot, later replacing it with a wooden substitute. We now fast forward to the 21st century, which is seeing prosthetic research bursting forth and sprouting in many new directions-from neuroprosthetics, to osseointegration, to increasingly sophisticated computerized prostheses, to lighter, stronger, more comfortable and durable materials. Hefty funding from the Department of Defense (DoD) and the Department of Veterans Affairs (VA), is fueling research in the wake of military men and women suffering limb loss from the wars in Iraq and Afghanistan. Going hand-in-hand with prosthetic technology are advances in other rehabilitation specialties, including amputation surgical techniques. This article will focus on amputation-related surgery, updating advances in two aspects: osseointegration and an osteomyoplastic surgical technique thought to better prepare a residual limb for optimal prosthesis use and function.

Osseointegration: Infection Solutions

Figure 1: (a) Solid titanium abutment penetrating the residuum skin. (b) Surrounding skin. (c) Layer of pus between skin and abutment.
Figure 1: (a) Solid titanium abutment penetrating the residuum skin. (b) Surrounding skin. (c) Layer of pus between skin and abutment.

Osseointegration is a promising technique for providing function and quality of life for amputees while eliminating the pain and soft-tissue problems often associated with conventional socket-type prostheses. Amputees also report that osseointegrated prostheses provide less feeling of weight, easier donning and doffing, no perspiration, pain, and tissue breakdown from an external socket, no need to remake a socket, and more control over the prosthesis. Another significant advantage is "osseoperception"-the patient-reported feeling of heightened perception of the environment. For patients with a very short residual limb and high soft-tissue volume, osseointegration may be the best option, and, according to one expert, in some cases it may be the only option.

In osseointegration, a titanium rod is inserted directly into the bone. Bone cells then grow and integrate into the implant, providing an internal anchor for a prosthesis. "In true osseointegration, the living bone becomes fused with the oxide layer of the titanium, and this anchorage persists under normal conditions of loading-a true biohybrid approach," notes an article in the Journal of the American Academy of Orthopaedic Surgeons (JAAOS), September 2006.

Authors of this article include Roy K. Aaron, MD, along with seven others who are investigators at the Center for Restorative and Regenerative Medicine at the Providence VA Medical Center, and Brown University, Providence, Rhode Island. They describe three programs under way to advance the long-term goal of optimizing the human-prosthesis interface: (1) development of neural control interfaces, (2) improvement of leg-lengthening techniques, and (3) improvement of the soft-tissue seal around an osseointegration device.

Figure 2: Experimental porous titanium pylon 28 days after implantation in marrow canal of Wistar rat thigh.
Figure 2: Experimental porous titanium pylon 28 days after implantation in marrow canal of Wistar rat thigh.

Why is that last program so important?

At present, osseointegration has a downside-the risk of deep infection, which can lead to bone loss, loosening of the implant, and even a possible need to re-amputate the limb at a higher, less functional level. Since the rod or "abutment" protrudes through the skin, pathways can develop through the soft tissue. Thus external environmental contamination can enter to cause bone infection and titanium corrosion. Rigorous personal hygiene and the use of antibiotics can largely control the problem but do not totally eliminate it.

"Implants may be colonized by airborne, skin, and/or surgeon-related bacteria during surgery despite use of closely monitored surgical techniques," according to a report by Mark Pitkin, PhD, research associate professor of physical medicine and rehabilitation at Tufts University School of Medicine, and other researchers in a report published in the July/August 2006 issue of the VA's Journal of Rehabilitation Research & Development (JRRD) . "After successful attachment of the biomaterial surface, bacteria multiply and form a biofilm' community, which makes them much more resistant to antibiotic therapy and host immunity." Although bacteria on the surface of the biofilm may be killed by antibiotics, the bacteria underneath are still "alive and kicking." Roy Bloebaum, PhD, in the article, "Osseointegration: In the Wave of the Future?," in the September 2006 issue of The O&P EDGE says, "It's like just moving off the weeds, rather than killing the roots. So you have to keep this biofilm from forming." Tough little creatures, those bacteria!

Battling the Beast

Various groups are marshaling their forces to find a solution. One solution is to close the door to the path. The Brown University-Providence VA team is researching the development of an environmental seal, eliminating contact between the bone and the environment. This seal may be developed by promoting dermal and epithelial growth into prosthetic surfaces. To achieve this goal, the team is studying both tissue engineering and biomaterials approaches.

Figure 3: Cross section of experimental porous titanium pylon 28 days after implantation. Image by electron scanning photomicrography (2000x, JEOL-USA, Inc, Peabody, MA). Note deep penetration of cells inside pores. 1=erythrocyte, 2=lymphoid cell, 3=fibroblast-like cell, 4=intercellular matrix on metal surface.
Figure 3: Cross section of experimental porous titanium pylon 28 days after implantation. Image by electron scanning photomicrography (2000x, JEOL-USA, Inc, Peabody, MA). Note deep penetration of cells inside pores. 1=erythrocyte, 2=lymphoid cell, 3=fibroblast-like cell, 4=intercellular matrix on metal surface.

Figure 4: Cross section at area of contact with skin of experimental porous titanium pylon 28 days after implantation. Electron scanning photomicrography (30x, JOEL-USA, Inc, Peabody, MA). 1=titanium particles, 2=penetration of cells and elements of intercellular matrix into pores.
Figure 4: Cross section at area of contact with skin of experimental porous titanium pylon 28 days after implantation. Electron scanning photomicrography (30x, JOEL-USA, Inc, Peabody, MA). 1=titanium particles, 2=penetration of cells and elements of intercellular matrix into pores.

To improve the soft-tissue interface with osseointegrated prostheses, the Brown-VA researchers are pursuing two lines of investigation: (1) determining the optimal surface chemistry and morphology of titanium for the attachment of epidermal keratinocytes and dermal fibroblasts; and (2) developing a finite element analysis model to understand the mechanics of the skin-prosthesis interface in order to improve device design. Better design can aid in the fight against infection as well as advance osseointegration in other areas.

To promote dermal and epithelial growth, one approach being considered is treating the surface of the titanium in various ways to provide a porous surface that might enhance cell adhesion. "Anodization of the titanium to produce a porous oxide, coating the surface with powder that could be sintered to different degrees of porosity, is one possibility," according to the authors of the JAAOS article. "Another is the use of various mechanical surface-roughening treatments. We have devised a novel method to rapidly produce thin films of titanium and its alloys, with which we can control the chemistry, grain size, and morphology of the metal surface."

Figure 5: Control solid titanium pylon 28 days after implantation. Image by electron scanning photomicrography (30x, JEOL-USA, Inc, Peabody, MA). Note smooth surface of metal and lack of cell adhesion.
Figure 5: Control solid titanium pylon 28 days after implantation. Image by electron scanning photomicrography (30x, JEOL-USA, Inc, Peabody, MA). Note smooth surface of metal and lack of cell adhesion.

Experiments are under way to determine the stability of these surfaces under in vitro physiologic conditions. Initial testing of these surfaces also is under way, and the researchers have set up quantitative fluorescent assays to measure cell number, cell adhesion, and cell morphology. "These approaches will facilitate rapid and quantitative screening of a large array of surface chemistries and morphologies to identify those that are optimal for cell attachment," according to the article.

To validate a finite element analysis model, the research team has begun mechanical testing of whole human skin to determine its viscoelastic and biomechanical properties. The data will be incorporated into a first-generation finite element analysis model to examine the unique load conditions present at the percutaneous portion of the osseointegration device. "This model will facilitate the design of a more effective percutaneous abutment that resists epidermal regression, infection, and device failure," the article says. [Editor's note: The full text of the JAAOS article can be accessed at  www.jaaos.org/cgi/content/full/14/10/S198 ]

Porous Pylon Strategy

Another team of researchers also is tackling the problem. The team, which includes Pitkin and researchers from the I.P. Pavlov State Medical University, St. Petersburg, Russia, is pursuing the development of a porous titanium pylon to protect against infection. In the July/August 2006 issue of the JRRD , the research team reported the results of an in vivo animal pilot study in which a porous titanium pylon was implanted in four rats. The JRRD article notes that strategies for reducing skin infection in direct skeletal attachment have included surface and shape modification of the percutaneous device, the addition of antimicrobials to the device surface, and chemical modifications to reduce bacterial attachment. However, the authors report, "Thus far these strategies have been unsuccessful."

The Tufts-Pavlov team found that a porous titanium implant offers definite promise.

"Instead of a porous flange around the solid core, we developed a concept of a totally porous implant allowing for skin ingrowth horizontally," Pitkin told The O&P EDGE as he discussed the JRRD report.

Figure 6: Tissues surrounding experimental porous titanium pylon 28 days after implantation. Image by light microscopy (600x, Van Gizon staining). 1=lymphoid infiltration, 2=fibrous connective tissue capsule surrounding pylon, 3=granulation.
Figure 6: Tissues surrounding experimental porous titanium pylon 28 days after implantation. Image by light microscopy (600x, Van Gizon staining). 1=lymphoid infiltration, 2=fibrous connective tissue capsule surrounding pylon, 3=granulation.

Figure 7: Tissues surrounding control solid titanium implant 28 days after implantation. Neutrophil infiltration (designated by "1") suggests formation of abscess. Image by light microscopy (600x, hematroxylineosin staining).
Figure 7: Tissues surrounding control solid titanium implant 28 days after implantation. Neutrophil infiltration (designated by "1") suggests formation of abscess. Image by light microscopy (600x, hematroxylineosin staining).

The JRRD article continues, "After implantation of the porous pylon, cells and fibers, including erythrocyte lymphoid cells and fibroblast-like cells penetrated the pores. Development of fibrous tissues around the porous implant is a necessary element of osseointegration. Therefore, based on the current study, we suggest that the development of fibrous tissues around the porous pylon can potentially further the integration of bone and skin with the prosthetic device."

However, while the preliminary results suggest the potential for development of a skin barrier inside the porous pylon, more studies on sustainability of such a barrier are required, the authors say. Future studies will explore these characteristics of cell-pylon interactions: cell adhesion, morphology, spreading, proliferation, and metabolism. The presence of blood cells suggests the possibility of blood vessel germination, "which is necessary for development of a sustainable skin barrier inside the porous pylon." Such a skin barrier would be a strong deterrent to infection. [Editor's note: The complete report can be accessed at: www.vard.org/jour/06/43/4/pdf/pitkin.pdf]

The animal kingdom may also provide infection solutions. For instance, the African clawed frog produces secretions containing magainin, an antibiotic that protects the frog from bacteria found in puddles and ponds. John Hibbs Jr., MD, a research team member from the University of Utah and the Salt Lake City VA Medical Center, is exploring the possibility of synthesizing the frog's bacteria-fighting subproteins, along with other avenues.

For more information on recent developments in osseointegration, see" Osseointegration: In the Wave of the Future? ," The O&P EDGE, September 2006. Part two of this article continues in "Ertl Procedure: A New Beginning."