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The Journal of Bone and Joint Surgery (American). 2007;89:2092-2101. doi:10.2106/JBJS.G.00631 © 2007 The Journal of Bone and Joint Surgery, Inc. What's New in Orthopaedic Research
1 Hospital for Special Surgery, 310 East 71st Street, Unit 7D, New York, NY
10021. E-mail address:
gulottal{at}hss.edu
Specialty Update has been developed in collaboration with the Council
of Musculoskeletal Specialty Societies (COMSS) of the American Academy of
Orthopaedic Surgeons.
The field of orthopaedic research continues to evolve from one dominated by biomechanical approaches to one in which biologic factors are playing an ever-increasing role. Molecular therapies, such as the use of bone morphogenetic protein (BMP) to augment bone-healing and spinal fusion, and cellular therapies, such as the use of autologous chondrocyte implantation for the treatment of cartilage defects, are examples of how translational biologic research has improved patient care. As this field continues to progress, it is important for the clinician to remain up-to-date with the science behind these therapies. This article will review the most recent developments in the field of orthopaedic research. The sources for the majority of the studies in this report are the 2007 annual meetings of the American Academy of Orthopaedic Surgeons (AAOS) and the Orthopaedic Research Society (ORS). Interesting papers from the 2006 and 2007 issues of The Journal of Bone and Joint Surgery and the Journal of Orthopaedic Research have also been summarized and, when appropriate, references outside the traditional orthopaedic literature have been highlighted. Special attention will be paid to recent advances in our understanding of the mechanisms of tissue degeneration and the application of this knowledge to the development of molecula and cellular therapies for tissue repair. Novel developments in tendon and ligament biology, cartilage and osteoarthritis, bioengineered meniscal and cartilage scaffolds, fracture-healing, total joint replacement, and spine surgery will also be discussed. The goal of the present report is to provide the clinician with a foundation to understand the most current advances in orthopaedic research and to identify interesting studies that may serve as the groundwork for the therapies of tomorrow.
Tendinopathy Two theories regarding the inciting events that lead to tendinopathy were revisited at the 2007 Annual Meeting of the Orthopaedic Research Society. The debate involves whether mechanical overstimulation or mechanical understimulation is the best model to replicate the pathophysiology of tendinopathy in the laboratory. Using their well-established rat treadmill overuse model, Dr. Louis Soslowsky and colleagues at the University of Pennsylvania presented new data regarding the ability of rest to reverse the tendinopathy changes seen in the supraspinatus tendon. During overuse, the geneexpression profile was consistent with cartilage-like genes and immunohistochemical analysis showed an increase in injury-associated extracellular matrix proteins such as biglycan and collagen III. After as little as two weeks of rest, the gene-expression profile returned to one that was consistent with a normal tendon; however, immunohistochemical analysis revealed that collagen I failed to reach preinjury levels even after eight weeks of rest. Taken together, it appears that rest following overuse injuries can initiate the reversal of tendinopathy at the gene-expression level, but the biochemical composition of the tendon may take longer than anticipated to fully return to normal. The counter theory, that mechanical understimulation initiates the pathophysiologic process of tendinopathy, was further substantiated by Dr. Steven Arnoczky and colleagues at Michigan State University. Those investigators previously showed that stress-deprived rat tail tendons have an upregulation of (matrix metalloproteinase) MMP-131. At the 2007 meeting of the ORS, they reported that stress deprivation can also induce tenocyte apoptosis. With use of the same rat tail tendon system, they showed that stress-deprived samples had increased caspase-3 mRNA expression as well as more ssDNA detection on fluorescent microscopy, both consistent with apoptosis. The findings of increased MMP expression and tenocyte apoptosis are consistent with studies on human tendinopathy tissues and further suggest that stress deprivation may be the more physiologically accurate way to study this process in vitro. Regardless of the inciting event, the nonoperative treatment options for tendinopathy are limited to activity modification, physical therapy, and corticosteroid injections. Wei et al. helped to define the deleterious effects of corticosteroid injections on the surrounding normal tendons in a rat rotator cuff model2. They found that the ratio of collagen III (present in injured tendons) to collagen I (present in normal tendons) was 4.5 times higher in the group that was not injured but that received corticosteroid injection as compared with sham controls. Scutt et al. also found that dexamethasone reduced both cell number and collagen synthesis in tenocyte cultures in a concentration-dependent manner3. This was accomplished both through direct effects on tenocyte proliferation and collagen accumulation and also through modulation of the recruitment of tendon progenitor cells. Those studies suggest that corticosteroid injections may have detrimental effects on the ability of the tendon to heal on its own and may serve to caution clinicians against its indiscriminate use in patients. Furthermore, those studies emphasize the need to discover more specific therapeutic targets to block or reverse the process of tendinopathy. Three studies from Dr. George Murrell's group identified the free radical nitric oxide as a central mediator in tendinopathy. However, it is unclear whether its presence participates in the degenerative process or if it engages in a reparative effort. With use of a rat overuse model, those investigators showed that all three forms of nitric oxide synthase (which produces nitric oxide)—inducible, endothelial, and neuronal—were upregulated in tendons of the overuse rats4. In a subsequent study, they examined the role of c-Jun N-terminal kinase (JNK) activation and MMP-1 regulation in the presence of oxidative stress5. First, they found that both JNK and MMP-1 were upregulated in torn human supraspinatus tendons harvested during surgery. They then determined that the same upregulation is observed in human tenocytes that have been subjected to oxidative stress in vitro, whereas the inhibition of JNK prevented stress-induced MMP-1 expression. However, there is also evidence that nitric oxide and nitric oxide synthase may actually be beneficial for tendon-healing. In a previous study, the same group showed that nitric oxide and adenovirus-mediated inducible nitric oxide synthase expression was able to enhance collagen synthesis in tenocytes in vitro6. While the role of nitric oxide in tendinopathy is still not completely understood, it appears to be a participant in the process of tendinopathy and warrants further study.
Therapies to improve tendon-to-bone healing continue to attract much interest in the orthopaedic research community. In the past year alone, several studies investigated the usefulness of various therapies to improve tendon-to-bone healing. These therapies include the application of bone marrow-derived mesenchymal stem cells to the healing interface to help to regenerate a native insertion site7, the addition of demineralized bone matrix or BMP-2 to a calcium phosphate cement in order to induce bone growth into the scar-tissue interface8, the systemic administration of the experimental inflammatory bowel medication pentadecapeptide BPC 157 to decrease inflammation and subsequent scar-tissue formation9, manipulation of the profibrotic cytokine TGF-  1 and the antifibrotic
cytokine TGF-3 to also limit scar formation, the systemic administration
of bisphosphonates to neutralize the osteoclasts that form at the healing
interface10, and
the engineering of tissues that recreate the fibrocartilage interface through
gene therapy. While those studies all demonstrated encouraging results in
small animal models in terms of histology and biomechanics, it is unclear at
this time which of these will become clinically useful adjuvants in the
future. Therapies that improve tendon-to-bone healing may be far from clinical use, but a study by Galatz et al. demonstrated a clinically relevant variable that may be detrimental to healing11. With use of a rat rotator cuff repair model, they found that nicotine delivered through an osmotic pump resulted in a longer period of inflammation, less cellular proliferation, and less expression of type-I collagen as compared with a control group that received saline solution. While the mechanical properties in both groups increased over time, the maximum stress was significantly lower at ten days and the maximum force was significantly lower at twenty-eight days in the nicotine group. These findings suggest that perioperative smoking cessation may potentially improve the rate of healing following rotator cuff repair.
Two transcription factors that are involved in tendon development during embryogenesis are attracting much attention. Scleraxis is a basic helix-loop-helix transcription factor that is a marker for tenocyte differentiation and is present during tenocyte development. Shukunami et al. linked scleraxis expression with another tenocyte marker, the type-II transmembrane glycoprotein tenomodulin12. With use of a chick model, they showed that scleraxis and tenomodulin were simultaneously expressed in tissues that would eventually form tendons. Furthermore, retroviral expression of scleraxis in both cultured tenocytes and hind limb tissue in vivo resulted in overexpression of tenomodulin. Smad8 is a receptor-regulated transcription factor that is directly phosphorylated and activated by BMP type-I receptors, to which BMP-2 binds. Hoffmann et al. showed that the active unit of Smad8 was able to induce tenocyte differentiation when cotransfected into mouse mesenchymal stem cells with BMP-213. These cells did not form osteogenic or chondrogenic lineages that have been seen in previous studies with BMP-2, suggesting that the Smad8 pathway may be specific for tendon formation. These engineered cells were also able to induce tendon regeneration as demonstrated by double quantum filtered magnetic resonance imaging when implanted into a patellar tendon partial defect model. While the application of this knowledge is far from clinical use, these studies represent exciting breakthroughs in our understanding of tendon development and may one day lead to therapies that are capable of tendon regeneration. Because tendons heal with scar tissue that can weaken the repair and create adhesions, there has been an effort to manipulate the healing environment to minimize scarring and improve the strength of the repair. In a presentation at the 2007 meeting of the ORS, Ricchetti et al. reported that overexpression of the anti-inflammatory cytokine IL-10 by an adenoviral vector improved tendon-healing in a mouse patellar tendon defect model. Specifically, the maximum stress to failure and the percentage relaxation were greater in the Ad-IL-10-treated tendons than in controls that received saline solution. Thomopoulos et al. showed that a platelet-derived growth factor (PDGF-BB) linked to a heparin-fibrin sustained release delivery system was able to improve tendon range of motion and excursion in a dog tendon repair model. However, the tensile properties were not improved. These results could have been due to the growth factor itself or to the heparin portion of the delivery system.
Clinical studies have shown that patients who undergo anterior cruciate ligament reconstructive surgery have development of osteoarthritis at a higher rate than the general population. Several theories have been proposed to explain this finding. At the 2007 meeting of the ORS, Dr. Tom Andriacchi and colleagues from Stanford reported that twenty-one of twenty-four patients who underwent anterior cruciate ligament reconstruction had increased external rotation of the tibia in the involved leg as compared with the contralateral, uninjured leg throughout the stance phase of walking. This finding suggests that current anterior cruciate ligament reconstruction surgical techniques are not adequate to restore the kinematics of the knee in the internal-external rotation plane. It can be hypothesized that such altered kinematics can lead to abnormal stresses on the cartilage, which predispose to arthritis. Another study that was reported at the 2007 meeting of the ORS showed that patients who sustained an anterior cruciate ligament rupture had lower levels of the chondroprotective glycoprotein lubricin in the involved knee as compared with that in the contralateral, uninjured knee. Loss of this protein may make the cartilage susceptible to degradation, and its application may be chondroprotective in the acute postinjury phase. Along those lines, Green et al., in a canine model, showed that the creation of a bone bruise similar to that seen following anterior cruciate ligament injury resulted in increased levels of inflammatory mediators and matrix metalloproteinases proportionate to the size of the bruise on magnetic resonance imaging14. By restricting weight-bearing for four weeks after the injury, they found a decrease in the magnitude of the inflammatory response and subsequent cartilage degradation. The ability to primarily repair the anterior cruciate ligament following rupture should ensure the restoration of normal knee joint kinematics; however, previous attempts to do so have been disappointing. At the 2007 meeting of the ORS, Dr. Martha Murray presented an update of her experience with a collagen-platelet-rich plasma hydrogel (PRP hydrogel). The hydrogel allows for the formation of a bridging fibrin clot to form at the anterior cruciate ligament repair site, which can subsequently serve as a scaffold for healing. With use of a porcine anterior cruciate ligament transection model, the investigators found that anterior cruciate ligaments repaired with the PRP hydrogel had increased stiffness, yield load, and maximum load at four and six weeks as compared with anterior cruciate ligaments that had been repaired with sutures alone. However, even at nine weeks, the PRP hydrogel-augmented anterior cruciate ligaments were inferior to native, intact anterior cruciate ligaments. While these results are encouraging, longer time-points are needed to determine if the ultimate strength of the repaired anterior cruciate ligament can reach that of grafts.
Genetics and gene therapy have increasingly been used to understand and treat cartilage injury and abnormalities such as osteoarthritis. High-throughput gene-array studies have been performed by several investigators, producing a tremendous amount of data regarding the many genes that are upregulated or downregulated in osteoarthritis-affected cartilage when compared with normal-appearing age-matched controls. Integrating these findings and interpreting their importance will require a great deal of future research. One molecular pathway that is likely to be particularly important in understanding arthritis is Wnt signaling. First identified in Drosophila, at least nineteen Wnt ligands, twelve Frizzled (Frz) receptors, and several low-density lipoprotein receptor protein (LRP) coreceptors have now been described in mammals. The "canonical" Wnt signaling occurs through -catenin, which through an intracellular cascade finally translocates to
the nucleus and binds to lymphoid enhancer binding factor (LEF)/T-cell factor
(TCF) transcription factors, causing transcriptional activation of target
genes, including genes that control cell proliferation and survival.
Noncanonical pathways have also been described involving intracellular calcium
and activation of the calcium-sensitive enzymes as well as other pathways. Wnt
signaling has been shown to be critical for joint formation, and a recent
study showed that deleting Dikkopf-1, a regulatory molecule in the Wnt
pathway, prevented bone destruction in a mouse model of
arthritis15. Lane
et al. identified variations in the FrzB gene as a risk factor for
osteoarthritis, confirming the importance of the Wnt pathway in human
osteoarthritis16.
The analysis of single nucleotide polymorphisms (SNPs)—small, often
random mutations in genes—has revealed that variations in genes such as
asporin (ASPN) and growth and differentiation factor-5 (GDF-5), which are both
important for joint development and homeostasis, also predispose to
osteoarthritis16-19.
Asporin is a molecule that regulates the activity of transforming growth
factor-
Along these lines, TissueGene, a company in Gaithersburg, Maryland,
recently received Food and Drug Administration approval to enroll patients in
a phase-I trial to test the safety of their genetically engineered allogenic
chondrocyte product. At the 2007 meeting of the ORS, a representative from
TissueGene reported on the preclinical studies of their product, which is a
human chondrocyte cell line that was developed from tissue harvested from a
one-year-old child with polydactyly. The TissueGene product consists of a
mixture of unmodified harvested chondrocytes and chondrocytes that have been
genetically engineered to overexpress transforming growth factor-
Investigations in the area of matrix degeneration and mechanical injury
also continue to be important in the area of cartilage research. At the 2007
meeting of the ORS, the groups of Alan Grodzinsky, PhD, from the Massachusetts
Institute of Technology, and of C.C. Chen, PhD, from the Hospital for Special
Surgery, reported on the modulatory effects of mechanical load on the activity
of inflammatory mediators such as interleukin-1 (IL-1) and tumor necrosis
factor-
Biomaterials The clinical performance of highly crosslinked ultra-high molecular weight polyethylene (UHMWPE) (hereafter called highly crosslinked polyethylene) in hip and knee replacements after eight and five years of implantation, respectively, was outlined at the 2007 Annual Meeting of the AAOS. In a prospective, randomized study, Grimm et al. found that patients who had received a highly crosslinked polyethylene acetabular liner (Duration; Stryker Orthopaedics, Mahwah, New Jersey) had a significantly reduced wear rate and less evidence of osteolysis than did patients who had received a conventional liner. The Harris hip scores for both groups were statistically equivalent, suggesting that initial concerns about the oxidation of post-irradiation annealed polyethylene may be unfounded. Similarly, Prince et al. found no radiographic evidence of osteolytic lesions around total knee replacements implanted with highly cross-linked polyethylene. Of note, the implant that was used had a posterior cruciate ligamentretaining design with a deep-dish tibial plateau. The deep-dish feature allows for a wide area of contact between the femoral condyles and the tibial plateau, thereby reducing polyethylene stresses. Furthermore, as the implant is a cruciate-retaining device, the need for a post is avoided; thus, the potential for repetitive impingement and fracture of the post does not exist. The clinical findings of Prince and colleagues may therefore not readily translate to total knee replacement designs in which the stress distribution on the tibial component is less favorable.
Concern remains about the clinical implications of the reduced fracture
toughness associated with highly cross-linked polyethylene. Thus, new
techniques are being explored for enhancing the mechanical properties of
cross-linked polyethylene, the so-called second generation. X3 UHMWPE (Stryker
Orthopaedics), for example, is produced by subjecting polyethylene to a series
of three low doses of irradiation, each of which is followed by annealing. It
is believed that the sequential exposure to low levels of radiation enables
increased chain mobility when compared with a single high dose. Increased
chain mobility enables the free radicals to recombine more easily and
facilitates their more effective elimination. In a hip simulator study,
Dumbleton et al. found that the wear rate of X3 UHMWPE was 62% that of
Crossfire (a first-generation highly cross-linked
polyethylene)20.
Furthermore, the tensile modulus and wear particle size distribution of X3
were equivalent to that of conventional polyethylene. Other techniques used
for free radical stabilization include the post-irradiation impregnation of
UHMWPE with
The long-term survival of total joint replacements is dependent on the prevention of periprosthetic osteolysis. The current paradigm of osteolysis involves the activation of macrophages by particulate debris resulting from implant wear. This causes the release of pro-inflammatory cytokines that induce the activation and differentiation of osteoclasts, resulting in bone resorption and implant loosening. An understanding of the mechanisms by which these events occur can lead to therapies that can increase the survival of total joint implants and limit the need for revision procedures.
The ratio of receptor activator of nuclear factor Ramage et al. harvested tissue from the osteolytic lesions of nine patients undergoing revision surgery22. Immunohistochemical analysis of the tissue demonstrated that there was an intact RANKL/RANK/OPG system in the periprosthetic membrane that could regulate the focalized bone resorption seen in osteolysis. Granchi et al. showed that serum levels of RANKL correlated with the sum of the osteolytic areas seen radiographically around the femoral stems of patients (r = 0.38, p = 0.02)23. Therefore, detection of RANKL levels in the serum of patients may be predictive of the presence and extent of osteolysis. Collectively, these studies confirm that RANK signaling is a critical pathway in osteolysis and is emerging as the most logical target for therapeutics that prevent and treat osteolysis.
In addition to RANK-dependent differentiation of monocytes into
osteoclasts, there is new evidence that granulocyte-macrophage
colony-stimulating factor (GM-CSF) can also directly bind and activate nuclear
factor Another potential strategy for the prevention and treatment of osteolysis is to block the action of the osteoclast itself as this is the final common pathway. At the 2007 meeting of the ORS, McHugh et al. reported that mouse bone marrow cells grown in osteoclast-inducing conditions produced the osteoclast gene annexin VIII in abundance when grown on calvarial bone. Furthermore, they showed that annexin VIII is critical for the bone resorptive properties of osteoclasts as siRNA knockouts diminish this effect and that upregulation of the gene through stable transfection exaggerates it. The authors hypothesized that annexin VIII may play a role in the formation or fusion of the resorptive vesicles seen at the ruffled border of the osteoclasts. Inhibition of annexin VIII may prevent the ability of osteoclasts to resorb bone at the bone-implant interface.
Musculoskeletal tissues can exhibit complex mechanical behavior with characteristics such as anisotropy (with the mechanical properties depending on the direction of loading), inhomogeneity (with the properties depending on the location within tissue), and viscoelasticity (with the mechanical properties depending on the rate of loading). In the case of articular cartilage, for example, these characteristics are imparted by a collagenous framework and the complex interplay of water and proteoglycans in the hydrated gel-like matrix of the tissue. One goal of regenerative medicine is to mimic the properties of the native tissue by programming cells to produce and organize extracellular matrix components while seeded in a scaffold. The greatest control one can exert over the regenerative process is arguably in the design of the scaffold, which can be tailored to optimize cell response through physical, chemical, biological, and mechanical cues26. A loom designed to weave biodegradable yarns into porous textile-like structures with µm-scale resolution was developed in the laboratory of Dr. Fashid Guilak27. By controlling the three-dimensional orientation in terms of spacing, volume fraction, and type of weave, the investigators were able to control the anisotropic and depth-dependent properties of the constructs. With use of a polyglycolic yarn, a scaffold was designed with mechanical characteristics that mimicked that of articular cartilage, prior to cell-seeding. The ability to achieve such a mechanical response from a synthetic scaffold at time zero represents a new paradigm in efforts to engineer functional replacements for injured musculoskeletal tissue. The scaffold modulus of elasticity not only influences the ability of the scaffold to carry load but also can dramatically affect the behavior of the cells with which it is populated. Recently, it was suggested that stem cell lineage commitment can be triggered and maintained by controlling matrix elasticity. Engler et al. varied the level of crosslinking in polyacrylamide gels coated with collagen to produce matrices with a range of moduli28. Interestingly, the modulus of the scaffold influenced the differentiation of its implanted mesenchymal stem cells. Mesenchymal stem cells that were seeded on low-modulus gels intended to mimic brain tissue became neurogenic, mesenchymal stem cells that were seeded on stiffer gels designed to mimic muscle tissue became myogenic, and mesenchymal stem cells that were seeded on high-modulus gels designed to mimic cancellous bone became osteogenic. Of note, the scaffolds were not loaded during the experiment; rather, the inherent tendency of the cells to pull against the matrix and the transduction of the mechanical signal via non-muscle myosin II were deemed partly responsible for the lineage commitment. The laboratory of Dr. David Mooney also has used the microenvironment into which cells are seeded to modulate cellular activity, in this case, for the purpose of optimizing plasmid DNA delivery29. The efficiency of gene transfer is related to the rate of cellular proliferation, and RGD (arginine-glycineaspartate) peptides have been shown to regulate cell proliferation. By combining these two concepts, RGD peptides were covalently bound to crosslinked alginate hydrogels at a range of densities and distributions. The gene expression of seeded cells increased linearly with peptide density but decreased exponentially as a function of distance between peptide islands. That study emphasizes the power of controlling gene delivery, and hence cell response, through scaffold design.
There has been much interest in the lay press regarding the ability of xenograft scaffolds to regenerate tissue, and, at the 2007 meeting of the ORS, a workshop on xenografts was given. Currently, the clinical data behind the use of xenografts for orthopaedics are less than encouraging. Basic-science studies have shown that commercially available extracellular matrix scaffolds have biochemical compositions similar to that of tendons at time zero. However, the elastic moduli of these materials are an order of magnitude lower than that of tendon. This limits their ability to play a mechanical role in the augmentation of tendon repair30. Animal studies have shown that these materials are rapidly degraded and elicit a distinct host-tissue histologic response31. Two recent clinical studies questioned the safety and efficacy of a decellularized, multilayer, porcine small intestine submucosa (porcine SIS) graft for augmenting rotator cuff repairs. In the study by Iannotti et al., thirty patients with chronic two-tendon tears were randomized to be managed with either augmentation with porcine SIS or no augmentation32. The researchers ended their study prematurely because of a decreased healing rate in the augmentation group (four of fifteen) as compared with the control group (nine of fifteen). In a similar study, Walton et al. also abandoned their protocol when four of the nineteen patients who received the graft had development of severe inflammatory reactions within two to four weeks after surgery33. All four patients required reoperation for irrigation and débridement. The investigators then compared the remaining patients with matched historical controls and found no differences in healing. Recent studies have begun to elucidate factors that may prevent successful xenografting, particularly of porcine tissue to humans. Ide et al. recently reported that interspecies incompatibility of CD47 significantly contributes to the rejection of xenogeneic cells by macrophages, suggesting that genetic modification of porcine cells so that they can express human CD47 may be a possible solution34. The CD47 receptor recognizes signal regulatory protein (SIRP)alpha, a critical immune inhibitory receptor on macrophages, and this interaction prevents autophagocytosis. A gene-modification strategy was also used to delete alpha1,3-galactosyltransferase, significantly reducing xenoantigenicity by altering the cell surface carbohydrate structures of porcine cells35. Additionally, recent reports have described the successful treatment of diabetes and hemophilia in murine models through the use of fetal porcine pancreas or spleen, suggesting that the use of fetal tissue may be another means to improve the outcome of xenografts36,37.
The effectiveness of BMP-2 in the healing of difficult fractures continues to be evaluated clinically. Swiontkowski et al. evaluated 131 patients with type-IIIA or IIIB open tibial fractures who were randomized to receive either intramedullary fixation with routine soft-tissue management or intramedullary fixation with the application of a BMP-2 sponge at the time of definitive wound closure38. They found that the group that was treated with the BMP-2 sponge required fewer bone-grafting procedures and fewer secondary procedures of any nature and had a lower rate of infection as compared with the control group. In the study by Jones et al., thirty patients with tibial diaphyseal fractures with residual cortical defects (mean, 4 cm; range 1 to 7 cm) were randomized to receive either autogenous bone graft or allograft (cancellous bone chips) with a BMP-2 sponge for staged reconstruction of the tibial defect39. Ten of the fifteen patients in the autograft group and thirteen of the fifteen patients in the BMP-2/allograft group healed without further intervention. There were no significant differences between the groups in terms of Short Musculoskeletal Function Assessment (SMFA) scores. At the least, BMP-2 augmentation of difficult-to-heal fractures appears to be equivalent to the use of autograft and spares the patient the additional donor-site morbidity of autograft harvest. While recombinant BMPs are proving to be useful in clinical patient care, a more efficient delivery vehicle continues to be sought. At the 2007 meeting of the ORS, Hsu et al. reported that overexpression of the BMP-2 gene with use of lentiviral gene transfer in rats resulted in excellent in vivo bone formation. As the authors discussed, however, because of the very small but finite possibility of the generation of a wild-type virus through recombination, the safety concerns over the use of lentivirus remain to be settled. It is of interest that the BMPs have remained a favorite therapeutic gene for transfer, with half of the oral presentations in the Gene Therapy session at the ORS meeting relating to the transfer of BMP genes. Several studies at the 2007 meeting of the ORS outlined the role of parathyroid hormone (PTH) in the formation of bone and the stimulation of fracture-healing. Friedl et al. showed that periodic administration of PTH in rats was able to induce an increase in bone mass; however, the mechanism of that response depended on the age of the rat. Young rats (three months old) had an increase in the activity of the osteoblasts, whereas old rats (thirteen months old) had an increase in the number of osteoblasts in response to PTH stimuli. These bone-forming characteristics also were seen in animal models of fracture-healing. Androjna et al. created osteotomies in the fibulae of rats and then subjected them to a hind limb unloading protocol. Rats that received PTH at a dose of 80 µg/kg had healing of the osteotomy site with more callus and cortical bone volume and at a quicker rate in comparison with controls. While PTH appeared to augment healing in a simulated weightlessness model, Gardner et al. showed that mechanical stimulation and intermittent PTH administration act synergistically when used in combination as compared with when each is used alone. This implies that PTH in addition to a limited weight-bearing protocol may be a clinically useful adjuvant in the healing of difficult fractures. There is further evidence that HMG-CoA inhibitors, such as the cholesterol-lowering statin drugs, appear to play an anabolic role in bone formation. Two studies from Dr. Gregory Mundy's laboratory that were presented at the 2007 meeting of the ORS showed that lovastatin, delivered both transdermally and locally on nanobeads, was able to accelerate healing in a rat femoral fracture model. Wong et al. also showed that naringin, a flavonoid available in citrus fruits that also inhibits HMG-CoA, was able to increase osteoblast activity in terms of colorimetric tetrazolium (MTT) assay, total protein content assay, and alkaline phosphatase activity in vitro. While the effectiveness of HMG CoA inhibitors needs to be proven in larger animal models and eventually in human trials, these preliminary data present an intriguing new pathway by which bone heals. Clinical studies have shown that cigarette smoking slows fracture-healing. Since cigarette smoke contains >3000 chemicals, it is unknown which is responsible for this clinical finding. Specifically, it is unknown whether the use of nicotine substitutes during the healing period is safe. Previous animal studies investigating the role of nicotine have involved doses that would be toxic to or unachievable in the human smoker. Skott et al. showed that tobacco extract, but not nicotine, impaired the mechanical strength of fracture-healing in rats40. At the 2007 meeting of the ORS, that same group presented the results of a follow-up study that showed that doses of nicotine of as high as 12 mg/kg had no detrimental effect on the maximum torque, stiffness, and energy to failure of healing fractures in the rat. Clinical studies are needed to evaluate the effect of nicotine-replacement therapies on fracture and fusion healing before definitive recommendations can be made.
In recent years, spine surgery has been enjoying much of the same efforts to incorporate biological technologies and minimally invasive solutions as have the other subspecialties of orthopaedics. This year, several groups reported advances in the understanding of the molecular basis of spinal disease, provided potential means for genetic treatments of spine pathology, and added novel surgical solutions to advance fusion and non-fusion-based management strategies. We will review three broad areas of development: (1) the basis of degenerative disc disease and the potential for gene-based strategies for management, (2) motion preservation, and (3) fusion technologies.
Degenerative Disc Disease and Low Back Pain
Degenerative disc disease has also received a large amount of attention
from basic-science researchers, and our understanding of the role of bone
morphogenetic proteins (BMPs) in intervertebral disc health is broadening.
Studies presented at the 2007 meeting of the ORS showed that degenerated discs
have marked elevations of MMPs, and in vitro studies demonstrated the
induction of MMPs and degradative enzymes with inflammatory cytokines
(interleukin-1) that were blocked by cotreatment with BMP-7. BMP-7 was also
shown to protect cultured human intervertebral disc cells from TNF-
While these findings are exciting, there is still the question of how these
factors should be delivered to the disc space. The most straightforward method
would be direct delivery. Shortcomings of this approach include the potential
need for repetitive dosing for maximal effect as well as pain and the risk of
associated complications. Wallach and coauthors investigated the potential
sequelae of inaccurately placed intradiscal gene transfer in a rabbit model in
which transforming growth factor-beta-1 (TGF-
Motion-Preservation Technologies Other motion-sparing technologies include nucleus replacements and dynamic stabilization. Mechanical and wear assessments were reported for candidate nucleus-replacement devices by several groups of investigators at the 2007 meeting of the ORS, including PEEK (polyetheretherketone), hyaluron/gelatin hydrogels, NuCore (Spine Wave, Shelton, Connecticut) protein hydrogels, titanium mesh, and a textile composite. Although the devices are at different points in development, the authors collectively reported that all of the devices have characteristics that make them good candidates for clinical use. At the 2007 meeting of the ORS, Delamarter and coauthors reported an advance in dynamic stabilization that could be used to address the problem of pedicle screw loosening. Those investigators compared standard Dynesys pedicle screws (Zimmer Spine, Minneapolis, Minnesota) with screws modified by the addition of a hydroxyapatite coating. With use of a sheep model spanning one motion segment, they found that coated screws had higher torques required for retrieval at each time-point and that there was a significant difference at the ten-week time-point (p < 0.01), but by sixteen weeks the groups were not different. The authors concluded that coated screws may provide better early screw purchase clinically and that the sixteen-week performance was likely due to resorption of the hydroxyapatite coating.
Fusion Technologies Recent studies have shown that BMPs may improve fusion success rates in patients who are medically compromised. At the 2007 meeting of the ORS, Lu and coauthors reported successful results in a study of osteoporotic rat posterolateral intertransverse fusions augmented with rhBMP-7. They reported that BMP-7 improved the fusion rate but that it required a higher dose than that previously reported in the literature for wild-type animals. They concluded that BMP-7 overcame the negative effect of osteoporosis in the model. In another application representing a compromised fusion bed, Cunningham and coauthors also reported, at the 2007 meeting of the ORS, on a rat model for potential percutaneous anterior intervertebral body fusions. They used adenovirus to deliver genes of interest and implanted genetically modified rat bone marrow cells into two disc spaces of the lumbar spine. Significant increases in spine stiffness were reported for animals receiving chimeric BMP-2/BMP-7 heterodimers, and this stiffness correlated with fusion assessments made by palpation and radiographic end points, although the bone produced was anterior to the disc space. The investigators concluded that the technology has promise for the intended application but that further optimization is necessary. The currently approved anti-osteoporosis agent parathyroid hormone (PTH 1-34) was evaluated for its effectiveness in augmenting spinal fusions in animal models. At the ORS meeting, Abe and coauthors reported successful results in a rat posterolateral spine fusion model involving daily injections of saline solution or PTH (40 mcg/kg/day). They found that fusion rates improved from 83% to 100% and that several radiographic, histologic, and biochemical parameters were also improved with PTH treatment. PTH appears to have efficacy for augmenting spine fusion, consistent with its ability to improve fracture-healing and treat osteoporosis.
Each year, three Kappa Delta Awards and one Orthopaedic Research and Education Foundation (OREF) Clinical Research Award are given to the researchers who have achieved excellence in orthopaedic research. The 2007 awards highlight the current advances in the fields of cartilage degeneration and repair, magnetic resonance imaging of cartilage, tissue-engineering of tendons and ligaments, and the treatment of rotator cuff disease. Constance Chu, MD, received the Young Investigator Award for her translational research on the processing of fresh osteochondral allografts, the cytotoxity of radiofrequency ablation and bupivacaine on chondrocytes, and the development of a novel imaging technology (optical coherence tomography) that allows one to microscopically image cartilage through an arthroscope. In the Gene Therapy session at the ORS meeting, Dr. Chu's group also reported on the success of implanting human mesenchymal stem cells genetically modified by adeno-associated virus vectors into a cartilage defect in a porcine model48. This year's Elizabeth Winston Lanier Award went to Martha Gray, PhD, and colleagues for their work on delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) as a technique to noninvasively image the glycosaminoglycan concentration of articular cartilage as well as on its research and clinical applications. David L. Butler, PhD, and colleagues received the Ann Doner Vaughan Award for their work on improving tendon repair with use of a functional tissue-engineering paradigm. This paradigm includes the use of bioengineered gels consisting of sutures or posts, mesenchymal stem cells, and a type-I collagen sponge. The construct is then mechanically stimulated in a bioreactor to enhance the biomechanical properties to a degree comparable with a normal tendon. The OREF Clinical Research Award was given to Christian Gerber, MD, for his work on translating the basic-science understanding of rotator cuff disease and repair to patient care. In addition to his contribution to increasing our understanding of the anatomy and surgical repair of the rotator cuff, his research into the role of fatty degeneration of the muscle has made it clear that rotator cuff repair failures are a muscle-to-tendon-to-bone problem as opposed to an isolated tendon-to-bone problem.
NOTE: The authors thank Timothy Wright, PhD, and Joseph Lipman, MS, for their help in the preparation of this manuscript.
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Introduction
Tendon and Ligament
(TNF-
B ligand (RANKL)
to osteoprotegerin (OPG), a decoy receptor for RANKL, determines the rate at
which monocytes differentiate into osteoclasts. Support continues to build for
the central role of the RANK signaling pathway in osteolysis. Ren et al.
investigated the role of RANKL in a murine osteolysis model developed in RANK
knockout (RANK—/—)
mice