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Specialty Update   |    
What's New in Orthopaedic Research
Suzanne A. Maher, PhD1; Chisa Hidaka, MD1; Matthew E. Cunningham, MD, PhD1; Scott A. Rodeo, MD1
1 The Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021
View Disclosures and Other Information
The authors did not receive grants or outside funding in support of their research for or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Specialty Update has been developed in collaboration with the Council of Musculoskeletal Specialty Societies (COMSS) of the American Academy of Orthopaedic Surgeons.

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Oct 01;88(10):2314-2321. doi: 10.2106/JBJS.F.00688
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To address the challenges of translating discoveries from the basic sciences into clinical therapeutics, the National Institutes of Health recently launched a new program of institutional Clinical and Translational Science Awards (http://nihroadmap.nih.gov/). Designed to foster environments that can efficiently translate laboratory findings into clinical therapies, the program aims to create educational environments specifically for the purposes of training a new generation of clinician-researcher interdisciplinary teams. In the orthopaedic sciences, funding to help combine expertise from surgeons, researchers in the life sciences, and engineers should lead to an acceleration in the already exciting advances that have been made in molecular medicine and regenerative medicine.
The most recent developments in the basic, translational, and applied sciences in orthopaedics are reviewed in this article. Based in part on information presented at the 2006 annual meetings of the American Academy of Orthopaedic Surgeons (AAOS) and the Orthopaedic Research Society (ORS), the significant advances made in understanding the mechanisms of tissue degradation and in applying this knowledge to the development of molecular therapies for tissue repair are outlined. Novel developments in total joint arthroplasty and recent progress in understanding the plasticity of stem cells and in applying this knowledge to the design of constructs to repair tissue are also described.
Several studies have begun to elucidate the mechanisms that underlie degenerative processes in soft tissues such as cartilage and tendon. These studies have improved our understanding of how factors such as mechanical stress, inflammatory factors, degradative enzymes, and genetics may converge, resulting in the clinical manifestations that are commonly encountered in overuse syndromes and/or osteoarthritis. They also provide important new insight into potential novel targets for therapeutic intervention.
Two recent studies demonstrated the critical importance of a relatively new family of matrix-degrading enzymes, the ADAMTS (a disintegrin and metalloprotease with thrombospondin-like repeat), in the pathogenesis of degenerative and inflammatory arthritides. First discovered in 1997, the AD-AMTS family of proteases includes approximately nineteen members, including aggrecanase-1 and 2, also known as AD-AMTS-4 and 5, respectively. Observations that the synovial fluid of arthritic patients contained aggrecan cleavage products whose sequence indicated specific enzyme cleavage by proteases other than the other known matrix metalloproteinases led to the initial discovery of the "aggrecanases." Subsequent studies revealed that these "aggrecanases" were in fact ADAMTS-4 and 5. Two studies from independent laboratories showed that, at least in mice, the deletion of ADAMTS-5 is specifically protective in experimental models of arthritis. Glasson et al.1 reported that mice lacking ADAMTS-5 (AD-AMTS-5-/-) had development of significantly less severe arthritis than genetically normal (wild-type) control mice or ADAMTS-4-/- mice. Arthritis was assessed by means of histomorphometry four or eight weeks after surgical transsection of the medial meniscotibial ligament. Prior to surgery, at the age of eighteen weeks, the ADAMTS-5-/- mice had no observable skeletal abnormalities, suggesting that development occurred normally and that the observed arthritis did not occur as the result of a developmental predisposition. Similar studies in ADAMTS-4-/- and ADAMTS-5-/- mice by Stanton et al.2 showed the protective effect of specifically deleting ADAMTS-5 in in vitro and in vivo models of inflammatory arthritis in which interleukin-1 (IL-1) was used to induce cartilage degradation. Those studies strongly supported the possibility that specific blockade of ADAMTS-5 may be effective for treating osteoarthritis and/or rheumatoid arthritis.
Some questions regarding the role of ADAMTS-4 and 5 in human arthritides remain, however. For example, the ADAMTS-5 protein has not been found in mouse cartilage, although the messenger ribonucleic acid (mRNA) of ADAMTS-5 as well as specific cleavage products produced by the enzyme are easily detected1. Furthermore, in human cartilage explants, ADAMTS-4 is the enzyme that is induced in chondrocytes stimulated by factors such as IL-1 or tumor necrosis factor (TNF), which are known to stimulate matrix degradation by chondrocytes (chondrolysis). In contrast, ADAMTS-5 is constitutively active. Despite these questions, it is clear that the ADAMTS family of matrix degradation enzymes will likely be important targets for therapeutic blockade in the treatment of arthritis.
Investigators studying tendon abnormalities have focused on the cellular and molecular mechanisms of tendon response to both stress deprivation and stress overload. These studies have implications for improving our understanding of the basic mechanism (or mechanisms) underlying tendon degeneration. Particular attention has been focused on the role of mechanical stress on the development of tendinopathy (simulating clinical overuse injuries). Investigators in the laboratory of Steve Arnoczky, DVM, at Michigan State University, are studying the response of tendon cells to strain and their interaction with the pericellular matrix. This group recently reported upregulation of integrin a1 and a2 expression following stress deprivation in rat tail tendon3. Integrins are cell-surface receptors that mediate cell-matrix interactions. The changes in integrin expression were accompanied by loss of contact between tendon cells and their pericellular matrix. These findings shed further light on the mechanisms by which tendon cells sense strain in their microenvironment and how tendon cells interact with and regulate the surrounding matrix. Tendon explants that were subjected to excessive levels of cyclic loading (up to 18 MPa) released increased levels of collagenase and the inflammatory mediator prostaglandin E2 (PGE2)4. However, the role of inflammation in the development of tendinosis is unclear as inflammatory cells are rarely seen in biopsy specimens of degenerative human tendon. There is evidence that mechanical loading can even have an anti-inflammatory effect on cells cultured under "inflammatory conditions" (such as in the presence of the inflammatory cytokine IL-1)5. Additional studies are required to elucidate the complex interactions between mechanical load and cellular responses.
Although explant models allow precise control of loading conditions, improved understanding of tendon overuse injury will come from animal models that replicate the typical microstructural changes seen in tendinosis. A rat model has been developed to apply repetitive, controlled loading of the patellar tendon in vivo, resulting in a significant loss of mechanical properties (tendon modulus and failure stress) and histological changes consistent with tendinosis6. Models such as this one will be useful for examining the cellular repair responses to subfailure matrix damage. In a rat model of overuse injury of the supraspinatus tendon that was used to study microstructural and biomechanical changes that occur secondary to overuse, there was increased expression of genes that are highly expressed in cartilage in these animals, including type-II collagen and aggrecan7. Increased accumulation of type-III collagen protein also occurred in this overuse model. Those findings were supported by data from biopsies of degenerative Achilles tendon specimens that showed increased levels of aggrecan and biglycan, indicating that there is increased compression or shear stress in the abnormal tendon8.
Advances in understanding the molecular mechanisms of tissue degradation have contributed to new attempts to develop targeted therapeutics aimed at eliciting a reparative response from within musculoskeletal tissues. A burgeoning technology in the area of molecular medicine is the use of antisense ribonucleic acid (RNA) strategies for therapeutic gene silencing. In the past decade, RNA has been shown to have functions far beyond its role in providing a template for protein transcription. Specifically, RNAs have been shown to inhibit or modify gene expression and immunological reactions through their interactions with deoxyribonucleic acid (DNA) or other RNAs or through their ability to act as autocatalytic enzymes (ribozymes). The use of RNA to silence specific genes has been used to address many disease processes, including cancer and inflammation. One RNA product is clinically available for the treatment of retinitis, and others are in development. A recent study showed the effectiveness of this strategy in suppressing inflammation in a rodent model of rheumatoid arthritis. In addition to being a treatment strategy, the use of RNA for gene silencing is rapidly becoming established as a powerful tool for drug discovery.
A number of RNA-based strategies, including strategies involving oligodeoxynucleotides, RNA interference, and ribozymes, are currently used for gene silencing. The oligodeoxynucleotides are "antisense" DNAs that are the mirror-image sequence of RNAs that encode proteins, or "sense RNAs." Because of Watson-Crick binding, antisense oligodeoxynucleotides are able to bind specifically to their "sense" targets, forming double stranded DNA-RNA complexes that prevent association with ribosomes, and, therefore, protein translation, through steric effects. RNA interference (RNAi) occurs when double stranded RNAs (dsRNAs) are processed in the cells by specific exonuclease enzymes known as Dicers within a complex called the RNA-induced silencing complex (RISC) that cleave dsRNAs into 21-to-24-nucleotide single stranded RNA (ssRNA) molecules known as small interfering RNAs (siRNAs). The siRNAs, in turn, can bind target normal messenger RNAs encoding specific genes of interest, inhibiting normal protein translation. This type of gene silencing can be accomplished either by delivering dsRNAs or 21-to-24-mer siRNAs that mimic those produced by Dicer/RISC cleavage. Finally, ribozymes are RNAs that have both a complementary component that can recognize and bind to specific mRNA targets and an autocatalytic component that, on target binding, can cleave the target RNAs into fragments that are not functional.
As with many other molecular medicine strategies, delivery of the nucleic acids to the target tissue remains a difficult challenge in the development of these strategies for clinical use. The oligodeoxynucleotides and dsRNAs require modifications to facilitate entry across the cell membrane as well as survival in the in vivo milieu that normally favors rapid degradation of free nucleic acids. As opposed to oligodeoxynucleotides and dsRNAs, siRNAs and ribozymes can be introduced to and expressed in target cells through gene transfer with use of currently available vectors such as a retrovirus or adenovirus. The specificity of gene targeting is another area of concern when RNA antisense strategies are employed.
Despite these technical challenges, RNA-mediated gene silencing is a promising area for molecular therapy and drug discovery. In a recent study, Inoue et al.9 silenced the expression of tumor necrosis factor-a (TNF-a) in the joint by means of intra-articular injection of polyamine-conjugated siRNA followed by electroporation by means of application of an electric pulse generator on the skin around the knee joint in a collagen-induced model of arthritis in rats. A significant decrease in paw swelling was achieved in association with siRNA injection on days 3, 7, 13, and 16 after the induction of arthritis, although injections on days 7 and 10 alone were not effective. Decreased swelling correlated with improved histological scores. Reverse transcription polymerase chain reaction was used to confirm the ablation of TNF-a expression in the synovial tissue. Four different sequences of anti-TNF-a siRNA were compared. While all were effective, one particular sequence was most effective, underscoring the importance of sequence specificity when using this strategy.
Localized gene delivery clearly remains an important goal, whether for gene silencing or overexpression. To this end, Maloney et al.10 recently reported on an innovative method that results in the effective transfer and expression of genes in a particularly challenging tissue: articular cartilage. In that study, from the laboratory of Edward Schwarz, PhD, at the University of Rochester, ultraviolet (UV) light was used to activate the expression of marker genes (green fluorescent protein [GFP] or ß-galactosidase [LacZ]) in articular cartilage defects in rabbits with use of recombinant adeno-associated virus (rAAV)-mediated gene transfer. The use of ultraviolet light enhanced the level of rAAV transgene expression, which is often otherwise limited by the relative inefficiency of target cells to convert the single stranded AAV DNA into the double stranded form normally used by mammalian cells. Additionally, it ensured a very specific localization of gene expression that was limited to the area of ultraviolet light treatment. The study showed that the specific spectrum of ultraviolet light used (UV-A at fluencies of <6000 J/m2) did not induce DNA damage but resulted in a temporary induction of reactive oxygen species. Effective gene transfer with use of this method was shown in human chondrocytes and synovial fibroblasts in culture as well as in the superficial and middle zones of articular cartilage in rabbits. That study presented the intriguing possibility that rAAV vectors, in conjunction with ultraviolet light, could be used to silence or overexpress therapeutic genes within articular cartilage tissue with use of techniques that are highly compatible with clinical arthroscopic methods.
In summary, regardless of whether siRNA technology can be developed to be clinically applicable, it will clearly support the development of gene-based medicine. The ability to locally deliver genes and to silence candidate genes efficiently and specifically will enable researchers to identify novel gene targets for effective therapeutic intervention.

Scaffolds

Regenerative medicine has been described as being "at the interface of the medical implant industry and the biological revolution."11 For the orthopaedic sciences, regenerative medicine encompasses efforts to develop a tissue capable of withstanding physiological loads by controlling a combination of scaffold design features, cellular phenotype, and biological/mechanical stimulation.
The effect of material type, morphology, and biological factors on matrix generation within cell-seeded scaffolds continues to be a central research theme in musculoskeletal tissue engineering. Recent technological advances that enable components to be manufactured with controllable and well defined structural morphologies in the nanometer (10-9 m) range present a unique opportunity to optimize scaffolds for the purposes of tissue engineering at a scale that was previously unimaginable. As summarized in a symposium on "Nano-Technologies" held at the recent annual meeting of the ORS, geometric features such as fiber diameters and grain size, biological features such as the distribution and density of ligands incorporated within scaffolds, and scaffold mechanical characteristics are powerful modulators of cellular response. For example, by mimicking collagen fibril diameters (in the 60-nm range) in synthetic scaffolds, robust cellular adhesion and extracellular matrix generation of chondrocytes12 and preosteoblasts13 have been demonstrated. However, understanding cell-scaffold interactions is vital for optimizing in vivo scaffold performance. Recently, fluorescence resonance energy transfer imaging techniques were used to monitor the movement of adhesion peptides by preosteoblasts seeded onto alginate gels, and the data suggested that cellular proliferation and differentiation are regulated in part by the traction forces exerted by the cells on the adhesion ligands14.
The importance of the meniscus in the preservation of knee cartilage has been well established, and recent efforts have focused on developing novel biomaterials for the purposes of meniscal regeneration and repair. Tienen et al.15, for example, developed a biodegradable porous polymer implant made of polycaprolactone-polyurethane (PCLPU) that is geometrically similar to that of the native meniscus and serves as a scaffold to support meniscal tissue formation in vivo. Previous studies in their laboratory determined the optimal porosity and compression modulus. Although the implant supported the formation of fibrocartilaginous tissue, it did not prevent progressive articular cartilage degradation in a dog lateral meniscectomy model. Another group used a sheep model to evaluate a porous composite of polycaprolactone and hyaluronic acid as a meniscal scaffold16. This material supported neotissue formation and was well integrated with the joint capsule. However, giant cells accumulated throughout the implant. Alginate is another material that is being evaluated for meniscal tissue engineering. Meniscal fibrochondrocytes can be suspended in alginate and can produce glycosaminoglycan when cultured in vitro17. Improvements in material properties will require mechanical stimulation of the construct in vitro prior to implantation.

Stem Cells

The use of "stem-like" or progenitor cells with a large capacity for cellular proliferation as well as plasticity and multilineage differentiation continues to be a compelling area of research for regenerative medicine and tissue engineering. A great deal of controversy has surrounded research employing embryonic stem cells in the past several years, but the fervor over the issue is well deserved because of the tremendous potential of these special primordial cells to deliver tissue repair and healing where healing potential has been lost or impaired. Early efforts to assess and describe cell fates that are possible with human embryonic stem cells demonstrated that embryonic stem cells required differentiation queues and guidance toward a particular tissue lineage (e.g., bone, cartilage, muscle, etc.) to be utilized for medical applications. Furthermore, it has become apparent that the population of treated human embryonic stem cells cannot be assumed to be uniform with regard to their differentiation responsiveness to specific treatments.
This concept of responsive subpopulations has been addressed in several studies in which fluorescence activated cell sorting (FACS) has been employed to purify the subpopulation of interest. Barberi et al.18 reported mesenchymal differentiation of human embryonic stem cells with use of a co-culturing paradigm in tissue culture. They found that after forty days of co-culture of human embryonic stem cells on mouse-derived cells, approximately 5% of the human embryonic stem cells were positive for CD73 (an immunological mesenchymal marker) and could be efficiently separated from the rest of the nonresponsive population. Once separated, this mesenchymal subpopulation could be differentiated into cells with chondrocyte-like or osteoblast-like phenotypes. Although a great deal of progress has been made toward exploring the potential application of human embryonic stem cells, the true complexity of utilizing these cells for the purposes of repairing tissues is only emerging. Research on mouse embryonic stem cells from the laboratory of Eric Lander at the Whitehead Institute recently revealed critical aspects of the mechanism by which embryonic stem cells differentiate19. That study described two specific patterns of DNA modification—specifically, two different patterns of histone methylation—in which one pattern resulted in gene silencing and another resulted in a looser state of "protection" that allowed gene expression much more readily. In contrast to mature cells, where these patterns were discretely arranged, stem cells showed a "bivalent pattern" with both types of modifications overlapping. More important, this "bivalent pattern" occurred specifically at highly conserved sites within DNA, many of which encode for transcription factors that are important developmentally (so-called master genes). As such, that study suggested that in stem cells, but not in mature cells, master genes that determine the fate of a cell are in a "bivalent" state of being silenced and yet also poised for expression.
Stem cells have been discovered in several adult tissues, including adipose tissue, muscle, and bone marrow, and are thought to represent a dormant reservoir of cells that can be called on to repopulate or repair these tissues as needed while avoiding the ethical issues of utilizing human embryonic stem cells. Bone marrow-derived stem cells, also referred to as bone marrow mesenchymal cells or marrow stromal cells, have received a great deal of attention because of their ability to offer regenerative potential for multiple different tissues, including bone, blood, heart, kidney, fat, inner ear, and skin. The ability of murine bone marrow stem cells to differentiate down a skeletal muscle phenotype pathway via signaling through the canonical Wnt/beta-catenin pathway and to differentiate toward a cardiac muscle pathway via signaling through the noncanonical Wnt/Ca2+ pathway was demonstrated by Bedada et al.20. Those authors also found that treatments with fibroblast growth factor-2 or hepatocyte growth factor led to cell pheno-type changes consistent with the adoption of neuron-like or hepatocyte-like differentiation states, respectively.
Minguell et al.21 attempted to better explain the cellular mechanisms underpinning the multipotentiality of human bone marrow mesenchymal stem cells by examining the nature of uncommitted precursors. They found that human bone marrow mesenchymal stem cells, when placed in culture, could be divided grossly into two groups, uncommitted and committed, as determined by their morphology and division rate. Uncommitted human bone marrow mesenchymal stem cells were spindly and divided slowly, whereas committed cells showed more abundant cytoplasm and faster division rates (6% compared with 27% in S or G2/M, respectively). Both cell populations stained positively with markers for mesenchymal phenotypes (alpha-smooth muscle actin, beta actin, vimentin), as well as osteoblastic phenotypes (Cbfa1 and Msx-2) and chondrocytic phenotypes (Sox-9). Differences appeared in the cellular localization of the markers; specifically, undifferentiated cells had Msx-2 and Sox-9 in the nucleus only, whereas committed cells had these factors both in the nucleus and in the cytoplasm. It was suggested that the altered localization of the factors allowed their activation in the cytoplasm, resulting in further progress toward a differentiated pheno-type. Perhaps more dramatically, the myogenic marker Myf-5 and neuronal markers NeuroD, beta III-tubulin, and NeuN were only detected in committed cells, whereas myogenic markers desmin and MyoD and neuronal marker nestin were detected in both cell populations. Collectively, these observations imply that the resting "uncommitted" human bone marrow mesenchymal stem cells express markers for each of the different potential tissue lineages, despite their being obtained from bone marrow, and that when they become "committed" and begin dividing, their phenotypes are altered to make them more receptive to differentiation signals.
Other issues related to bone marrow stem cells are the stability of the cells when placed in culture for expansion and the effect that the age of the donor has on the quality and character of the stem cells that are obtained. Mareschi et al.22 found that donors who were less than eighteen years old had marrow with a significantly increased population doubling (growth rate) as compared with donors who were more than eighteen years old (p < 0.05). However, the numbers of cellular passages possible, the immunological phenotypes, and the stability of telomeres with the cells from the two donor pools were similar. These findings indicate that bone marrow stem cells can be isolated from both pediatric and adult populations, stably expanded, and potentially utilized for therapeutic interventions.
Several studies that were presented at the annual meeting of the ORS demonstrated the existence of cells (specifically, cells in tendon and ligament) with multilineage differentiation potential. Traditionally, it has been assumed that differentiated cells in tendon and ligament have a stable phenotype. However, recent work has shown that cells from these tissues have the potential to change phenotype, depending on environmental factors. This would have important implications for ligament and tendon healing as well as for understanding the development of the structural and metabolic changes seen in tendon degeneration. Lee et al. reported that cells derived from synovial fluid in knees with anterior cruciate ligament injury can differentiate into osteoblasts, adipocytes, and chondrocytes23. Steinert et al. reported that cells derived from culture specimens of the anterior cruciate ligament obtained at the time of anterior cruciate ligament reconstructive surgery also have multilineage differentiation potential24. In that study, the investigators were careful to remove the synovial covering over the torn anterior cruciate ligament in order to obtain anterior cruciate ligament cells; nonetheless, the possibility remains that synovial-derived cells had infiltrated the torn anterior cruciate ligament after injury. De Mos et al. reported that cells derived from human tendon also have multilineage differentiation potential25, which may explain the findings of increased glycosaminoglycan deposition, calcifications, and lipid accumulation in degenerative tendon.
Investigators in the laboratory of Rocky Tuan, PhD, at the National Institutes of Health, examined the multipotentiality of meniscal fibrochondrocytes derived from different regions of the meniscus (the outer vascular area, the inner avascular area, and the horn attachment area)26. Those investigators reported that meniscal cells from all regions have a multilineage differentiation potential, with cells from the outer region of the meniscus having a greater differentiation range. The more limited differentiation range of cells from the inner, avascular area of the meniscus likely contributes to the poorer healing potential in this area. Additional support for the potential of stem cells to improve meniscal healing was provided by a study involving the injection of synovium-derived stem cells labeled with green fluorescent protein into the knees of wild-type rats that had a full-thickness defect in the meniscus27. The transplanted cells remained in the meniscal defect and promoted healing in comparison with untreated meniscal defects. Platelet-rich plasma is a rich source of autologous growth factors that stimulates DNA synthesis and extracellular matrix protein synthesis in meniscal cells and promotes healing in vivo in animal models.

Regenerative Medicine in the Clinical Setting

During a symposium on tissue engineering that was held at the combined Research Day of the ORS and AAOS, the preliminary results of a phase-II clinical trial for the treatment of long-bone fractures with allogenic stromal cells were presented by Matthew Jimenez, MD. The study group included six patients with atrophic tibial nonunions. Cells were isolated from patient aspirates and were expanded with use of patented processes (Tissue Repair Cells; Aastrom Biosciences, Ann Arbor, Michigan). The cells were suspended in an electrolyte solution, combined with human serum albumin, and mixed with demineralized corticocancellous allograft (Musculoskeletal Transplant Foundation, Edison, New Jersey). When treatment with these cells was used in combination with internal fixation, osseous healing was found in all six patients within six months. Although the study was not a randomized, prospective clinical trial and the number of patients was limited, the study nonetheless represented an important advance in the use of multipotential cells to heal nonunions.
Hernigou et al.28 percutaneously injected progenitor cells isolated from bone marrow aspirates into tibial nonunion sites and found healing (defined as definite radiographic evidence of fracture union and full weight-bearing without tenderness) in fifty-three of sixty patients within six months. Interestingly, the authors found a correlation between the number of transplanted cells and outcome; if the number of progenitor cells was <70,000, an adverse outcome was likely. Of note, the relationship between the volume of callus formed and the number of progenitors in the graft was not examined.
Although the advantages of using bone morphogenetic proteins (BMPs) for reconstructive orthopaedic surgery are well recognized, their usefulness in augmenting osseous healing of large critical-sized defects is less well established, in part because of their short half-life. An international team including the laboratory of Edward Schwarz, PhD, at the University of Rochester, found that BMP expression did not differ when the robust healing of autografts was compared with the slower healing of allografts in a mouse femoral graft model29. On the basis of gene expression profiling studies, it was found that allografts were deficient in factors known to regulate angiogenesis (such as vascular endothelial growth factor [VEGF]) and osteoclastic bone resorption (receptor activator of nuclear factor kappa-B ligand [RANKL]). When recombinant adeno-associated viruses encoding RANKL and VEGF were freeze-dried onto the cortical surface of allografts, local allograft healing, vascularization, remodeling, and osseous union were observed. Although in vivo transduction efficiency was low and the formation of new bone was not uniform on all allograft surfaces, the findings represent a new paradigm for simulating a beneficial autograft response in a processed allograft.
Several studies that were published in the past year focused on the outcome of total disc replacement. Most of the studies from the United States have been positive, with good to excellent clinical results at two years after single and multiple-level implantations. Improvements in surgical technique have been suggested, including augmentation of vertebral bone stock in osteoporotic patients by means of open vertebroplasty to prevent implant subsidence. These early positive clinical outcomes are encouraging, but the need for long-term follow-up to establish the overall success of and indications for total disc replacements was highlighted in a study by Putzier et al.30. In that retrospective study of sixty-three disc replacements that were performed in fifty-three patients with use of the Charité Artificial Disc (DePuy Spine, Raynham, Massachusetts), poor long-term clinical and radiographic outcomes were reported. Subjective patient assessment according to the criteria of Odom revealed a 54% rate of good or excellent results. No degenerative segments were noted adjacent to functional total disc replacements. However, after seventeen years of followup, segmental motion as assessed with use of flexion-extension radiographs revealed a 60% prevalence of spontaneous ankylosis, a high percentage for an implant intended to maintain range of motion.
Although the Charité Artificial Disc was approved for use in the United States in 2004, in a recent landmark decision, the Centers for Medicare and Medicaid Services issued a proposed national noncoverage determination for this lumbar artificial disc replacement. Few patients over the age of sixty-five years have been managed with the Charité disc technology in the United States, and the paucity of data appears to have contributed to the conclusion that the disc was not indicated for this population (www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=170). It is not clear what impact this decision will have on the development and clinical use of other lumbar disc replacement technologies.
Other motion-sparing spinal implants for degenerative disc disease include nucleus replacements and semirigid stabilization systems. Both of these interventions have been used and reported outside of the United States for many years, but their use and evaluation in the United States have only recently been initiated. Nucleus replacements, also referred to as partial disc replacements, are commonly performed through minimally invasive posterior approaches and involve annulotomy, evacuation of native nucleus pulposus, and implantation of a replacement nucleus. As reported by Bertagnoli et al.31, nucleus replacements have been made from polymethylmethacrylate, silicone, and stainless steel, but they currently are also being made from a variety of polymers, including hydrogels. The outcome of a worldwide multicenter trial of the prosthetic disc nucleus (PDN) device (Raymedica, Minneapolis, Minnesota) revealed that pain (as assessed with a visual analog scale) and disability (as measured with the Oswestry disability index) decreased dramatically postoperatively. However, the rate of complications, including implant extrusion, averaged 25%. Implant design and surgical techniques are being refined to reduce the complication rate. The other popular motion-sparing implant concept is dynamic stabilization, which attempts to limit segmental motion in a degenerative level to a "safe zone" that protects against further degeneration. This methodology relies on specific placement of pedicle screws so that they can be connected by flexible connectors such as braided polyester bands (Graf artificial ligament stabilization; SEM, Montrouge, France) or polyethylene terephthalate cord and polycarbonate urethane spacers (Dynesys; Centerpulse, Winterthur, Switzerland). These devices have been associated with successful results in short to intermediate-term follow-up studies, but adequately powered prospective studies are lacking. These interventions may offer a means to protect against the continued degeneration of a segment after microdiscectomy and may be an option to allow protected healing of a degenerative segment instead of resorting to fusion.
The concept of controlling the dynamic motion of total knee replacements through mating surface geometry design, so called guided knee kinematics, was embodied in a novel implant (Journey; Smith and Nephew, Memphis, Tennessee) that was unveiled at the 2006 annual meeting of the AAOS. Intended to recreate normal knee movement, the medial surface of the tibial plateau is concave to provide anteroposterior stability and to promote a medial pivot. The lateral tibial insert is slightly concave and is posteriorly sloped to promote natural femoral external rotation during knee flexion. The posterior condylar surface is extended to allow for an increased area of contact at higher angles of flexion. Furthermore, an anterior cam limits anterior translation during early knee flexion to replicate anterior cruciate ligament function. Fluoroscopic analysis of patients within one year after implantation demonstrated the screw-home motion of the total knee replacement. Another advance in the arena of knee arthroplasty was the development of a gender-specific knee implant. The Zimmer Gender Solutions Knee (Zimmer, Warsaw, Indiana) was designed on the basis of an analysis of 800 femora and patellae, which revealed that female patients had a narrower femoral width, a reduced anterior condylar height, and a tendency toward a more lateral patellar track. The implant was designed to reflect a sizing system based on specific differences in mediolateral and anteroposterior dimensions for male and female patients. 510(k) regulatory clearance for this implant is pending.
Earlier hip resurfacing implants were plagued with problems such as poor wear performance of the articulating surfaces and femoral neck fracture. The latter occurred as loads were carried by the metal cap and bypassed the trabeculae of the femoral head and neck, leading to bone resorption and eventual fracture due to stress-shielding. Through improved material characteristics (smaller, more uniform metal grain sizes), improved manufacturing geometric tolerances, and strict patient selection criteria, hip resurfacing with use of a metal-on-metal articulation is on the cusp of a revival32. This is in part because larger femoral heads can increase range of motion, increase stability, and require less osseous removal that might otherwise be necessary. Nonetheless, total hip resurfacing prostheses are considered investigational implants by the United States Food and Drug Administration and thus are not currently approved for widespread use.
The multidisciplinary approach to understanding the mechanisms of tissue degradation and the development of therapeutics for eliciting a reparative response is leading to the development of novel therapeutic strategies. Furthermore, exciting advances in the manufacture and characterization of scaffolds, combined with the emerging availability of multipotential stem cells, likely will lead to important advances in efforts to engineer replacement musculoskeletal tissues. At the same time, developments to enhance the kinematics and to reduce osseous resection needed for the implantation of traditional implants continue to be vital for improving implant performance in younger, more active patients.
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Riley GP, Corps AN, Robinson AH, Movin T, Costa ML, Hazleman BL. Increased expression of aggrecan and biglycan mRNA in achilles tendinopathy. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1090.  2006 
 
Inoue A, Takahashi KA, Mazda O, Terauchi R, Arai Y, Kishida T, Shin-Ya M, Asada H, Morihara T, Tonomura H, Ohashi S, Kajikawa Y, Kawahito Y, Imanishi J, Kawata M, Kubo T. Electro-transfer of small interfering RNA ameliorated arthritis in rats. Biochem Biophys Res Commun.2005;336: 903-8.336903  2005  [CrossRef]
 
Maloney MD, Goater JJ, Parsons R, Ito H, O'Keefe RJ, Rubery PT, Drissi MH, Schwarz EM. Safety and efficacy of ultraviolet-a light-activated gene transduction for gene therapy of articular cartilage defects. J Bone Joint Surg Am.2006; 88: 753-61.88753  2006  [PubMed][CrossRef]
 
Ahsan T, Nerem RM. Bioengineered tissues: the science, the technology, and the industry. Orthod Craniofac Res.2005;8: 134-40.8134  2005  [CrossRef]
 
Li WJ, Tuli R, Huang X, Laquerriere P, Tuan RS. Multilineage differentiation of human mesenchymal stem cells in a three-dimensional nanofibrous scaffold. Biomaterials.2005;26: 5158-66.265158  2005  [PubMed][CrossRef]
 
Chen VJ, Smith LA, Ma PX. Bone regeneration on computer-designed nanofibrous scaffolds. Biomaterials.2006;27: 3973-9.273973  2006  [PubMed][CrossRef]
 
Kong HJ, Liu J, Riddle K, Matsumoto T, Leach K, Mooney DJ. Non-viral gene delivery regulated by stiffness of cell adhesion substrates. Nat Mater.2005; 4: 460-4.4460  2005  [PubMed][CrossRef]
 
Tienen TG, Heijkants RG, de Groot JH, Pennings AJ, Schouten AJ, Veth RP, Buma P. Replacement of the knee meniscus by a porous polymer implant: a study in dogs. Am J Sports Med.2006;34: 64-71.3464  2006  [PubMed][CrossRef]
 
Chiari-Grisar C, Koller U, Dorotka R, Eder C, Plasenzotti R, Lang S, Ambrosio L, Tognana E, Kon E, Salter D, Nehrer, S. A tissue engineering approach to meniscus regeneration in a sheep model. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1030.  2006 
 
Mizuno K, Sekiya I, Muneta T. Enhancement of meniscal repair by injecting large amounts of synovium-derived mesenchymal stem cells into the joint. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #0028.  2006 
 
Barberi T, Willis LM, Socci ND, Studer L. Derivation of multipotent mesenchymal precursors from human embryonic stem cells. PLoS Med.2005;2: e161.2e161  2005  [PubMed][CrossRef]
 
Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell.2006;125: 315-26.125315  2006  [PubMed][CrossRef]
 
Bedada FB, Gunther S, Kubin T, Braun T. Differentiation versus plasticity: fixing the fate of undetermined adult stem cells. Cell Cycle.2006;5: 223-6.5223  2006  [PubMed][CrossRef]
 
Minguell JJ, Fierro FA, Epunan MJ, Erices AA, Sierralta WD. Nonstimulated human uncommitted mesenchymal stem cells express cell markers of mesenchymal and neural lineages. Stem Cells Dev.2005;14: 408-14.14408  2005  [CrossRef]
 
Mareschi K, Ferrero I, Rustichelli D, Aschero S, Gammaitoni L, Aglietta M, Madon E, Fagioli F. Expansion of mesenchymal stem cells isolated from pediatric and adult donor bone marrow. J Cell Biochem.2006;97: 744-54.97744  2006  [PubMed][CrossRef]
 
Lee SY, Miwa M, Sakai Y, Kuroda R, Matsumoto T, Kurosaka M. Mesenchymal stem cells can be obtained from human ACL injury-induced hemathrosis of the knee. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #0983.  2006 
 
Steinert AF, Karl N, Pilapil C, Noth U, Evans CH, Murray MM. Multilineage mesenchymal differentiation potential of cells migrating out of the anterior cruciate ligament. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1133.  2006 
 
De Mos M, Jahr H, Weinans H, Verhaar J, Van Osch G. A possible role for tendon cell differentiation in the development of tendinosis. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1108.  2006 
 
Mauck RL, Martinez-Diaz GJ, Yuan X, Tuan RS. Regional variation in meniscal fibrochondrocyte multi-lineage differentiation potential: implications for meniscus repair. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1039.  2006 
 
Mizuno H, Roy AK, Zaporojan V, Vacanti CA, Ueda M, Bonassar LJ. Biomechanical and biochemical characterization of composite tissue-engineered inter-vertebral discs. Biomaterials.2006;27: 362-70.27362  2006  [PubMed][CrossRef]
 
Hernigou P, Poignard A, Beaujean F, Rouard H. Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am.2005;87: 1430-7.871430  2005  [CrossRef]
 
Ito H, Koefoed M, Tiyapatanaputi P, Gromov K, Goater JJ, Carmouche J, Zhang X, Rubery PT, Rabinowitz J, Samulski RJ, Nakamura T, Soballe K, O'Keefe RJ, Boyce BF, Schwarz EM. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat Med.2005;11: 291-7.11291  2005  [PubMed][CrossRef]
 
Putzier M, Funk JF, Schneider SV, Gross C, Tohtz SW, Khodadadyan-Klostermann C, Perka C, Kandziora F. Charite total disc replacement—clinical and radiographical results after an average follow-up of 17 years. Eur Spine J.2006;15: 183-95.15183  2006  [PubMed][CrossRef]
 
Bertagnoli R, Karg A, Voigt S. Lumbar partial disc replacement. Orthop Clin North Am.2005;36: 341-7.36341  2005  [PubMed][CrossRef]
 
Schmalzried TP, Silva M, de la Rosa MA, Choi ES, Fowble VA. Optimizing patient selection and outcomes with total hip resurfacing. Clin Orthop Relat Res.2005;441: 200-4.441200  2005  [PubMed][CrossRef]
 

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References

Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, Flannery CR, Peluso D, Kanki K, Yang Z, Majumdar MK, Morris EA. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature.2005;434: 644-8.434644  2005  [PubMed][CrossRef]
 
Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, Little CB, Last K, Farmer PJ, Campbell IK, Fourie AM, Fosang AJ. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature.2005;434: 648-52.434648  2005  [PubMed][CrossRef]
 
Egerbacher M, Arnoczky SP, Gardner KL, Caballero O, Gartner JA. Stress-deprivation of tendons results in alterations in the integrin profile and pericellular matrix of tendon cells. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1100.  2006 
 
Devkota AC, Almekinders LC, Weinhold PS. Short term biochemical response of tendon explants to cyclical loading of variable magnitude. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #0039.  2006 
 
Deschner J, Rath B, Agarwal S. Sustained anti-inflammatory effects of tensile forces in rat fibrochondrocytes. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #0025.  2006 
 
Lee H, Wang VM, Laudier DM, Schaffler MB, Flatow EL. A novel in vivo model of tendon fatigue damage accumulation. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1058.  2006 
 
Archambault JM, Jelinsky SA, Lake SP, Saraf K, Hill A, Brown EL, Seeherman H, Wozney J, Soslowsky LJ. Rat supraspinatus tendon expresses cartilage markers with overuse. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #0035.  2006 
 
Riley GP, Corps AN, Robinson AH, Movin T, Costa ML, Hazleman BL. Increased expression of aggrecan and biglycan mRNA in achilles tendinopathy. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1090.  2006 
 
Inoue A, Takahashi KA, Mazda O, Terauchi R, Arai Y, Kishida T, Shin-Ya M, Asada H, Morihara T, Tonomura H, Ohashi S, Kajikawa Y, Kawahito Y, Imanishi J, Kawata M, Kubo T. Electro-transfer of small interfering RNA ameliorated arthritis in rats. Biochem Biophys Res Commun.2005;336: 903-8.336903  2005  [CrossRef]
 
Maloney MD, Goater JJ, Parsons R, Ito H, O'Keefe RJ, Rubery PT, Drissi MH, Schwarz EM. Safety and efficacy of ultraviolet-a light-activated gene transduction for gene therapy of articular cartilage defects. J Bone Joint Surg Am.2006; 88: 753-61.88753  2006  [PubMed][CrossRef]
 
Ahsan T, Nerem RM. Bioengineered tissues: the science, the technology, and the industry. Orthod Craniofac Res.2005;8: 134-40.8134  2005  [CrossRef]
 
Li WJ, Tuli R, Huang X, Laquerriere P, Tuan RS. Multilineage differentiation of human mesenchymal stem cells in a three-dimensional nanofibrous scaffold. Biomaterials.2005;26: 5158-66.265158  2005  [PubMed][CrossRef]
 
Chen VJ, Smith LA, Ma PX. Bone regeneration on computer-designed nanofibrous scaffolds. Biomaterials.2006;27: 3973-9.273973  2006  [PubMed][CrossRef]
 
Kong HJ, Liu J, Riddle K, Matsumoto T, Leach K, Mooney DJ. Non-viral gene delivery regulated by stiffness of cell adhesion substrates. Nat Mater.2005; 4: 460-4.4460  2005  [PubMed][CrossRef]
 
Tienen TG, Heijkants RG, de Groot JH, Pennings AJ, Schouten AJ, Veth RP, Buma P. Replacement of the knee meniscus by a porous polymer implant: a study in dogs. Am J Sports Med.2006;34: 64-71.3464  2006  [PubMed][CrossRef]
 
Chiari-Grisar C, Koller U, Dorotka R, Eder C, Plasenzotti R, Lang S, Ambrosio L, Tognana E, Kon E, Salter D, Nehrer, S. A tissue engineering approach to meniscus regeneration in a sheep model. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1030.  2006 
 
Mizuno K, Sekiya I, Muneta T. Enhancement of meniscal repair by injecting large amounts of synovium-derived mesenchymal stem cells into the joint. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #0028.  2006 
 
Barberi T, Willis LM, Socci ND, Studer L. Derivation of multipotent mesenchymal precursors from human embryonic stem cells. PLoS Med.2005;2: e161.2e161  2005  [PubMed][CrossRef]
 
Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell.2006;125: 315-26.125315  2006  [PubMed][CrossRef]
 
Bedada FB, Gunther S, Kubin T, Braun T. Differentiation versus plasticity: fixing the fate of undetermined adult stem cells. Cell Cycle.2006;5: 223-6.5223  2006  [PubMed][CrossRef]
 
Minguell JJ, Fierro FA, Epunan MJ, Erices AA, Sierralta WD. Nonstimulated human uncommitted mesenchymal stem cells express cell markers of mesenchymal and neural lineages. Stem Cells Dev.2005;14: 408-14.14408  2005  [CrossRef]
 
Mareschi K, Ferrero I, Rustichelli D, Aschero S, Gammaitoni L, Aglietta M, Madon E, Fagioli F. Expansion of mesenchymal stem cells isolated from pediatric and adult donor bone marrow. J Cell Biochem.2006;97: 744-54.97744  2006  [PubMed][CrossRef]
 
Lee SY, Miwa M, Sakai Y, Kuroda R, Matsumoto T, Kurosaka M. Mesenchymal stem cells can be obtained from human ACL injury-induced hemathrosis of the knee. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #0983.  2006 
 
Steinert AF, Karl N, Pilapil C, Noth U, Evans CH, Murray MM. Multilineage mesenchymal differentiation potential of cells migrating out of the anterior cruciate ligament. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1133.  2006 
 
De Mos M, Jahr H, Weinans H, Verhaar J, Van Osch G. A possible role for tendon cell differentiation in the development of tendinosis. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1108.  2006 
 
Mauck RL, Martinez-Diaz GJ, Yuan X, Tuan RS. Regional variation in meniscal fibrochondrocyte multi-lineage differentiation potential: implications for meniscus repair. In: Transactions of the 52nd Annual Meeting of the Orthopaedic Research Society; 2006Mar19-22. Chicago, IL. Paper #1039.  2006 
 
Mizuno H, Roy AK, Zaporojan V, Vacanti CA, Ueda M, Bonassar LJ. Biomechanical and biochemical characterization of composite tissue-engineered inter-vertebral discs. Biomaterials.2006;27: 362-70.27362  2006  [PubMed][CrossRef]
 
Hernigou P, Poignard A, Beaujean F, Rouard H. Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am.2005;87: 1430-7.871430  2005  [CrossRef]
 
Ito H, Koefoed M, Tiyapatanaputi P, Gromov K, Goater JJ, Carmouche J, Zhang X, Rubery PT, Rabinowitz J, Samulski RJ, Nakamura T, Soballe K, O'Keefe RJ, Boyce BF, Schwarz EM. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat Med.2005;11: 291-7.11291  2005  [PubMed][CrossRef]
 
Putzier M, Funk JF, Schneider SV, Gross C, Tohtz SW, Khodadadyan-Klostermann C, Perka C, Kandziora F. Charite total disc replacement—clinical and radiographical results after an average follow-up of 17 years. Eur Spine J.2006;15: 183-95.15183  2006  [PubMed][CrossRef]
 
Bertagnoli R, Karg A, Voigt S. Lumbar partial disc replacement. Orthop Clin North Am.2005;36: 341-7.36341  2005  [PubMed][CrossRef]
 
Schmalzried TP, Silva M, de la Rosa MA, Choi ES, Fowble VA. Optimizing patient selection and outcomes with total hip resurfacing. Clin Orthop Relat Res.2005;441: 200-4.441200  2005  [PubMed][CrossRef]
 
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These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
CME Activities Associated with This Article
Subspecialty CME | February 15, 2007
Quarterly CME | January 05, 2007
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Helmut D. Link
Posted on November 29, 2006
Comments on the Charite Total Disc Replacement
Waldemar Link GmbH & Co KG, Hamburg, GERMANY

To The Editor:

In the recent "What's New in Orthopaedic Research", under the section "Total Joint Arthroplasty", the authors of the review comment on the publication by Putzier et al. who reported results of the "Charite Total Disc Replacement - Clinical and Radiographical Results After An Average Follow- up of 17 years" in the European Spine Journal(1).

I write to inform your readers that this study was seen as highly controversal and, as such, produced a number of letters to the editor of the European Spine Journal, one of which was authored by me(2).

In Putzier's report(1), the Charite surgeons lacked a sufficient variety of implant sizes, had insufficient instrumentation, and, last but not least, had no previous experience in proper patient selection for this new implant, thus leading to critical views on their conclusions. To be fair, one has to consider the shortfalls and difficulties of a surgeon being in a position of a pioneer.

It might be of further interest that in the October edition of the European Spine Journal, a study on long term results of the Charite kinematics in vivo was published(3). The authors came to the conclusion that "The total disc prosthesis SB Charite III seems to be a promising implant for the treatment of severe discopathy at one level"(3).

The author(s) of this letter to the editor did not receive payment or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author(s) are affiliated or associated.

References:

1. Putzier M, Funk JF, Schneider SV Gross C, Tohtz SW, Khodadadyan-Klostermann C, Perka C, Kandziora F, Charite total disc replacement-clinical and radiographical results after an average follow-up of 17 years. Eur Spine J. 2006;15:183-95.

2. Link HD, Letter to the Editor referring to the article, "Charite total disc replacement-clinical and radiographical results after an average follow-up of 17 years. Eur Spine J. 2006;15.#4.

3. Ali ES, Lemaire JP, Pascal-Mousselard H, Carrier H, Skalli W. In vivo study of the kinematics in axial rotation of the lumbar spine after total intervertebral disc replacement: long-term results: a 10-14 years follow up evaluation. Eur Spine J. 2006;15:1501-1510.

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