Over the last year, our understanding of the biological basis of orthopaedic pathology and its treatments has expanded. Particular attention continues to be directed toward the role of stem cells for tissue regeneration as well as the role of growth factors for healing augmentation. Substantial advances have also been made in our understanding of the response of stem cells to load, topography, and growth factors. While bench research is promising, recent clinical studies, specifically, those on the use of platelet-rich plasma (PRP), haven fallen short of expectations. The exact reasons for the disconnect between promising basic science research and discouraging clinical results is most likely multifactorial, and further research is needed to identify the various factors critical for success.
This article will review the most recent developments in the field of orthopaedic research. While this is a broad topic, attempts have been made to highlight studies that are approaching the translational stage, clinical studies evaluating the application of recent laboratory advances, and a few studies that represent interesting research pathways that are earlier in the discovery process. The goal of this review is to provide the practicing orthopaedic surgeon with a foundation to understand and apply the role of orthopaedic research in clinical practice.
Tendon and Ligament
Stem Cells, Growth Factors, and the Mechanical Environment
Much research has been focused on improving the reattachment of torn tendon to bone with stem cell therapy, specifically, discovering the signals required to stimulate stems cells to differentiate at the insertion site. Tendon-to-bone bioengineering is particularly challenged by the complex transition site that must allow for load transfer between two distinct tissues (tendon and bone).
Over the past year, several studies have examined how nanotopography and mechanical loading affect the differentiation of human tendon stem cells. Sharma and Snedeker combined both mechanical and molecular cues by culturing bone marrow stromal stem cells on a hydrogel matrix with a gradient of mechanical compliance as well as gradients of fibronectin and collagen type I1. Bone marrow stromal stem cells differentiated toward osteogenic precursors on the stiffer fibronectin substrates, whereas tenogenic precursors were formed on the compliant collagen substrate. Yin et al. further demonstrated that cells sense matrix topography and that this information affects gene expression and differentiation2. They seeded human tendon progenitor cells on aligned or randomly oriented nanofibers. The expression of tendon-specific genes was higher in cells growing on aligned nanofibers, whereas osteogenic precursors were formed on the randomly oriented nanofibers. Zhang et al. showed that low-level mechanical stretching at 4% strain directed tendon stem cells into tenocytes, whereas stretching at 8% strain directed stem cells into adipogenic, chondrogenic, and osteogenic lineages3. These studies demonstrate that the differentiation of pluripotent cells depends on the mechanical environment. This research has implications on the development of tissue-engineered scaffolds to improve healing.
Previous studies on rotator cuff healing have shown that mesenchymal stem cells alone may be insufficient to augment healing4. This has led most researchers to conclude that growth or differentiation factors are also required to direct cellular differentiation in vivo. Gulotta et al. found that scleraxis and membrane type-1 matrix metalloproteinase (MT1-MMP), two genes that are expressed during the development of the rotator cuff enthesis during embryogenesis, may augment rotator cuff healing when transduced into mesenchymal stem cells5,6. They found more cartilage deposition at the tendon-bone transition zone and increased mechanical strength of the repair at four weeks. The clinical implications of this technology are uncertain at this time.
Tendon Healing and Platelet-Rich Plasma
Platelet-rich plasma therapy has been introduced with the aim of enhancing tendon healing by increasing the concentration of growth factors. Laboratory studies have indicated that platelet-rich plasma influences the response to inflammation, as demonstrated by increased cell migration and angiogenesis. Considerable effort has begun to translate this promising treatment to patients7. However, while laboratory studies have suggested that this technique shows promise, clinical studies have yet to convincingly support the use of platelet-rich plasma for the treatment of tendinopathy and tendon repair.
Over the last year, several clinical studies have been published, with equivocal results. Castricini et al., in a randomized controlled trial of patients with rotator cuff tendon tears, demonstrated no significant difference between patients who were managed with rotator cuff repair and platelet-rich fibrin matrix (PRFM) and those who were managed with rotator cuff repair alone8. However, restoration of a normal-sized tendon footprint area and normal tendon signal intensity was more common in the platelet-rich fibrin matrix group9. In a randomized, double-blind, placebo-controlled trial, de Vos et al. reported that platelet-rich plasma, when injected into patients with chronic tendinopathy of the Achilles tendon, did not lead to improvement in terms of pain, function, satisfaction, or time to return to sports activity10. In a parallel double-blind, randomized, placebo-controlled trial conducted by the same group, patients were randomized to eccentric exercise therapy with either platelet-rich plasma or saline solution11. No difference in tendon structure was found between the platelet-rich plasma group and the control group at twenty-four weeks. Future studies must try to understand why the promise demonstrated in the laboratory has not translated to improved clinical results.
Fracture-Healing and Mechanical Loading
The mechanical micro-environment influences stem cell differentiation and gene expression. Mechanical stimulation was shown to influence the differentiation of multipotent mesenchymal stem cells. Sen et al. demonstrated that strain inhibited mesenchymal stem cell adipogenic differentiation and increased β-catenin, WISP1, and COX212. Huebsch et al. demonstrated the effect of the mechanical environment on mesenchymal stem cell differentiation in a three-dimensional environment13. Mesenchymal stem cells, when placed within hydrogels of varying rigidity, committed to osteogenesis predominantly at 11 to 30 kPa. Adhesive peptides within the hydrogel bound to integrin on the stem cell surface. Integrin-peptide binding peaked at 22 kPa, correlating with osteogenesis. This relationship was lost when a myosin inhibitor was added, suggesting that cell contractility, fundamentally controlled by myosin, was required to form crosslinks with the microenvironment and to eventually lead to osteogenic differentiation. The complex role of mechanical loading was demonstrated by Bai et al., who reported on the combined effects of mechanical stresses and biochemical stimuli14. The combined stimulation of shear stress and vascular endothelial growth factor (VEGF) resulted in more endothelial cell-oriented differentiation of mesenchymal stem cells than either VEGF or shear stress alone.
In the area of articular cartilage, research in the past year has continued to focus on understanding the fundamental mechanisms involved in the pathogenesis of osteoarthritis. There is an increased focus on trying to understand the very early signs of cartilage injury or degeneration so that interventions can be developed to stop the osteoarthritis process. Some of the key molecules thought to be involved in early osteoarthritis include hypoxia-inducible factor-2α (HIF-2α), which promotes chondrocyte apoptosis and drives the expression of matrix metalloproteinase-13 (MMP-13). The role of MMP-13 in osteoarthritis continues to be considered pivotal and is further evidenced by decreased experimentally induced osteoarthritis in MMP-13-deficient mice. Cartilage proteoglycan loss through activation of A Disintegrin and Metalloprotease with Thrombospondin Motifs-5 (ADAMTS-5) continues to be investigated as an initiator of osteoarthritis.
Various growth factors continued to be investigated as a treatment for early joint pain or osteoarthritis and for cartilage regeneration, and they were recently reviewed15. Osteogenic protein-1 (OP-1) (also known as bone morphogenetic protein-7 [BMP-7]) in combination with insulin-like growth factor-1 (IGF-1) appears to be the most promising growth factor combination for osteoarthritis treatment because they are synergistic and anabolic and their anti-catabolic actions are not diminished in aged or osteoarthritic cartilage. However, this combination of OP-1 and IGF-1 is not routinely clinically available. Biologic or regenerative therapies such as platelet-rich plasma, autologous conditioned serum (ACS), and bone marrow concentrate that deliver a milieu of growth factors are very popular and are of interest to clinicians because they are derived from the patient and can be administered readily to the patient. There are few Level-I studies investigating their use, but many such studies are presently being conducted to determine their clinical efficacy.
The use of stem cells to regenerate articular cartilage remains a topic of active investigation with clinical promise for application to all musculoskeletal tissues, but the focus has changed from the differentiation of stem cells into tissue-specific functional cells such as chondrocytes to the role of stem cells in immunomodulation and in regulation of the local environment16,17. Another paradigm shift in stem cell therapy is the investigation of methods such as novel biomaterials to recruit the body's own stem cells to the site of injury rather than implanting exogenous cells18. Coincident studies are aimed at understanding why and how stem cells “home” to sites of injury.
Progenitor stem cells have been identified in normal and osteoarthritic human articular cartilage with use of clonal expansion or cell surface markers to identify progenitor cells19,20. These studies have suggested that cartilage progenitor cells may be a superior cell source to mesenchymal stem cells because they do not proceed through terminal differentiation as evidenced by collagen type-X expression as mesenchymal stem cells do. Additional study is required to understand how to recruit these resident cartilage progenitor cells to the site of damage.
Future studies on the maintenance of articular cartilage and the prevention of osteoarthritis will continue to define methods to detect early, submacroscopic changes in cartilage that lead to the initiation of osteoarthritis. With respect to stem cells, when musculoskeletal tissues are injured and repair or regeneration is the goal, methods to enhance local stem cell recruitment to the site of injury and understanding how those stem cells behave and respond to the local environment will continue to be a major focus in the near future.
Biologic Markers of Early Osteoarthritis
The identification of sensitive and specific biomarkers for the detection of early osteoarthritis is being pursued through the use of serum and urine biochemical biomarkers as well as new methods of articular cartilage imaging. In a longitudinal study investigating serum and synovial fluid markers in patients who had sustained a cartilage injury, several synovial fluid markers were significantly increased and several were decreased21. Some biomarker concentrations were significantly higher in synovial fluid, including interleukin-1β, fetal aggrecan FA846, C-terminal crosslinked telopeptide type-I collagen (CTxI), N-terminal telopeptides of type-I collagen (NTx), osteocalcin, cartilage oligomeric matrix protein (COMP), and MMP-3. There were significant correlations between serum and synovial fluid concentrations for CTxI, NTx, osteocalcin, and MMP-3 but not for the other biomarkers tested. These in vivo results from patients with naturally occurring osteoarthritis mimic those found in in vitro studies involving the use of inflammatory molecules to mimic osteoarthritis. This suggests that in vitro studies can be used to model in vivo conditions to find which biomarkers are key regulators and potential targets for interventional therapies. These therapies can ideally be administered after an injury to prevent terminal disruption of the articular cartilage environment.
Imaging of Osteoarthritis
Clinically, radiographs are one of the most accepted means of diagnosing osteoarthritis, but the link between pain and radiographic osteoarthritis is poor. Understanding the pain that is associated with osteoarthritis is obviously critical for initiating treatment in patients. A report from the Osteoarthritis Initiative indicated that the rate of cartilage loss over time in the weight-bearing region of the medial femoral condyle was greater in painful knees than in nonpainful knees even when adjusting for radiographic disease stage22. This finding indicates that patients with pain alone, regardless of the radiographic osteoarthritis signature, should be thought of as having early osteoarthritis and that attempts should be made to stabilize the articular cartilage environment. These results also emphasize the need for imaging modalities that can detect earlier changes in damaged articular cartilage that are present prior to the onset of clinically detectable osteoarthritis.
In addition to radiographs, the other two clinically available methods of detailed cartilage imaging are magnetic resonance imaging (MRI) and computed tomography (CT). Mosher et al. performed a multicenter study of fifty patients with normal or mild, moderate, or severe osteoarthritis who were evaluated four times with magnetic resonance imaging23. Water-excited three-dimensional T1-weighted gradient-echo imaging, T1-ρ imaging, and T2 mapping of cartilage in the axial and coronal planes were performed for each examination. The results indicated that measurements of cartilage T2 and patellar T1-ρ with magnetic resonance imaging demonstrated moderate to excellent reproducibility, which supports the use of these biomarkers in preclinical and clinical trials of cartilage regeneration and osteoarthritis.
Several cartilage imaging techniques that provide higher-resolution images than routine MRI are at various stages of clinical investigation. They are aimed at the very early detection of posttraumatic cartilage injury, such as that which occurs at the time of anterior cruciate ligament (ACL) injury. The concept is that if signatures of cartilage damage could be detected exceptionally early, then early interventional therapies could be applied to prevent rather than to slow or diminish the degenerative process. One promising method is optical coherence tomography (OCT), which can be used transarthroscopically and is capable of quantitatively assessing surface topography, subsurface heterogeneity, and collagen orientation. These changes can be detected in articular cartilage with an intact surface prior to the development of macroscopic changes, and they correlate with quantitative MRI analyses24,25. Multiphoton microscopy also can detect three-dimensional structural changes similar to those seen with use of OCT, but it has the advantage of being capable of imaging down to the cellular level, which renders it the highest-resolution in vivo imaging modality26,27.
Clinical options for the treatment of damaged menisci in the U.S. are restricted to either suturing the torn ends of the tissue together or partial removal. However, because of concerns regarding the biomechanical consequences of even partial meniscectomy and as the number of surgical procedures for meniscal injuries climbs to 1 million per year in the U.S., the quest to find a suitable partial or complete meniscal replacement has become more pressing28. Active research in this field has been focused on two areas: (1) the development of non-cell-seeded scaffolds intended to replace a portion of the damaged meniscus and to encourage cell migration into the defect site and (2) the development of nondegradable synthetic menisci intended to replace the complete meniscus.
The Menaflex collagen meniscus implant (ReGen Biologics, Hackensack, New Jersey) is a resorbable collagen-based mesh composed primarily of type-I collagen and glycosaminoglycan. However, despite short-term follow-up studies (one to five years) suggesting the ability of Menaflex to encourage new tissue ingrowth at the site of implantation, U.S. Food and Drug Administration (FDA) approval for Menaflex was withdrawn in 2010, partly because of concerns over the 510(k) approval process that was used during the review. Recently, however, more definitive evidence has emerged, suggesting that implantation of this collagen mesh has the ability to reduce the risk of degenerative disease in the long term. Zaffagnini et al. reported on a prospective clinical trial in which thirty-six patients with acute or chronic meniscal injuries opted for either Menaflex implantation or partial meniscectomy29. Clinical evaluation showed significant improvement of all measured scores (lower visual analog scale [VAS] pain scores, higher objective IKDC [International Knee Documentation Committee] scores, higher Tegner index scores, and higher SF-36 [Short Form-36] scores) for the Menaflex group at five years postoperatively, and these differences were maintained to ten years. However, the study was not blinded or randomized and the number of patients was small.
Actifit (Orteq Bioengineering, London, United Kingdom), an acellular porous polyurethane-based scaffold, is also being used in Europe; FDA approval has not yet been obtained in the U.S. In a prospective, single-arm, multicenter, proof-of-principle study, Verdonk et al. demonstrated tissue ingrowth in 81% of patients who were available for follow-up at twelve months as assessed with MRI and second-look biopsy30. Seventy-six percent of patients had stable articular cartilage grades in the index compartment between one week and twelve months of follow-up, whereas worsened grades were reported for 11% of patients and improved scores were reported for 13% of patients. All biopsy specimens contained fully vital material with no sign of necrosis or cell death; a regional variation in the matrix that filled the scaffold and an exterior fibrous capsule was observed. It is envisaged that a prospective randomized clinical trial and longer-term follow-up will further explore the efficacy of this treatment.
Nondegradable Synthetic Menisci
Targeted predominantly at patients in whom the meniscus is damaged to the extent that repair is impossible and large partial meniscectomies are required, nondegradable implants are intended to restore “normal” joint mechanics to the affected knee, thereby avoiding the consequences of large segmental meniscal removal. Holloway et al. proposed a fiber-reinforced composite, the mechanics of which can be controlled to result in modulus values that approach those of the native meniscus31. This is achieved by varying the percentage of drawn ultra-high molecular weight polyethylene (UHMWPE) fibers as distributed through poly(vinyl alcohol) (PVA) hydrogels. El-Amin et al. reported that, on implantation, the contact mechanics of these constructs matched that of allografts32; however, the goal of any such treatment is to match the contact mechanics of the native meniscus. A free-floating polycarbonate-urethane meniscal implant is also under preclinical and clinical evaluation outside the U.S., but results are not yet available.
Porous trabecular metals are being increasingly used to enhance implant fixation for arthroplasty of the hip, knee, shoulder, and spine. In an in vitro study, Sagomonyants et al. demonstrated that human female osteoblasts seeded on tantalum proliferated fourfold to sixfold more rapidly than those seeded on titanium fiber mesh33. Osteoblasts from younger female patients (less than forty-five years old) had increased levels of cell adhesion, proliferation, and mineralization in comparison with osteoblasts from older patients (more than sixty years old). However, after three weeks of culture, mineralization of osteoblasts from older patients was significantly higher on tantalum surfaces as compared with titanium mesh. The finding that tantalum stimulates cell proliferation and improves the ability of human osteoblasts from older patients to form bone further supports its use as a suitable implant surface in that population. Indeed, not only has porous tantalum been particularly useful for patients who have limited bone-forming abilities, but, more recently, its use in complex revision cases has been reported. In theory, the high-friction porous metals can provide good initial stability while the modulus of the constructs can be controlled to match that of cancellous bone, further providing an environment suitable for cell ingress and matrix generation; early-stage clinical studies are emerging to support these claims. For example, Lachiewicz et al. retrospectively reviewed twenty-seven patients in whom thirty-three tantalum cones had been used for complex knee revision arthroplasty34. After a minimum of two years of follow-up, all but one cone demonstrated osseointegration; one patient had a deep infection and two patients had a reoperation for the treatment of a femoral shaft fracture and superficial wound dehiscence. Howard et al. also reported that, after an average duration of follow-up of thirty-three months, all cones used for the treatment of large segmental femoral defects at the time of knee revision arthroplasty were well fixed radiographically, with no evidence of complications in relation to the cone35. All authors concluded that metaphyseal fixation with tantalum cones can be achieved but that longer-term follow-up and a large patient cohort are required to fully establish if the osseointegration formed is durable.
This past year saw the emergence of a heated debate on the benefits versus disadvantages of metal-on-metal articulations for hip replacement. The debate was ultimately triggered by a medical device alert issued by the Medicines and Healthcare products Regulatory Agency in the U.K. (MDA/2010/33) advocating close follow-up of patients with metal-on-metal articulations because of the risk of development of progressive and painful soft-tissue reactions to the wear debris associated with this articulation. During revision, soft-tissue pseudotumors, sometimes referred to as aseptic lymphocytic vasculitis-associated lesions (AVALs) or adverse local-tissue reactions (ALTRs), were identified. The exact cause of these reactions is not well understood but is being thoroughly investigated with histopathological assessments. Evidence thus far suggests that their formation can be caused by either excessive wear or metal hypersensitivity36. At the forefront of the research into metal-on-metal articulations is the quest to identify patients who are at highest risk for revision. Regular follow-up of patients who have metal-on-metal implants is advocated (www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/MetalonMetalHipImplants/ucm241667.htm), but well-functioning implants often can result in elevated serum ion levels, pain, and the formation of pseudotumors. As the importance of patient selection, component position, and close follow-up is emphasized, the future of metal-on-metal articulations remains uncertain.
While the use of BMPs to augment spine fusion and bone healing is well known, a new molecule has recently been investigated that may have comparable effectiveness. Nell-1 is a growth factor distinct from BMP. In a sheep model of spinal fusion, the addition of Nell-1 and demineralized bone matrix (DBM) significantly improved fusion rates compared with controls37. Further studies are needed to determine if it is clinically useful.
The use of gene technology in adolescent idiopathic scoliosis and genetic comparative spine models have also seen advancements in the past year. Joining the curveback guppy as aquatic genetic models for spine deformity genetic research are the zebrafish38 and the triploid grass carp39. Gorman et al., in an update on their curveback guppy spine deformity investigations, reported that they have defined a genetic locus of approximately 100 genes that is tightly linked in a recessive pattern to the trait40. Contained within the region is the MTNR1B gene, a candidate gene for human adolescent idiopathic scoliosis.
Perhaps the most important advance in the past year for spine deformity genetics was reported by Ward et al., who described the extraordinary positive and negative predictive values for a genetic test for adolescent idiopathic scoliosis (Scoliscore; Axial Biotech, Salt Lake City, Utah)41. The test involves the collection of a saliva sample and a genetic assessment against fifty-three defined polymorphisms combined with limited clinical data with use of a proprietary algorithm that generates a risk score for the patient. Risk scores (possible range, 1 to 200) are stratified into low (1 to 50), intermediate (51 to 180), and high (181 to 200) classifications, with 99% of patients in the low-risk group not progressing to a severe curve. However, of the patients in the high-risk group, 98% progressed to a severe curve that ultimately required surgery. This genetic test may develop into an important basic research tool as well as a clinical screen to allow earlier and less invasive interventions for children who are predicted to have a severe adolescent idiopathic scoliosis curve.
Schreiber et al.42, in a study of twenty-five patients with a mean age of 71.3 years, described the correlation between bone mineralization density data from dual x-ray absorptiometry (DXA) scans and Hounsfield units interpreted from CT scans. Positive correlations were found between the two parameters, suggesting that CT scans that are performed for alternate purposes may be able to be used to determine relative regional bone mineral density clinically without the patient undergoing additional procedures. In another aspect of the study, the authors evaluated polyurethane blocks with CT scanning and reported positive correlations between compressive strength and Hounsfield units. These mechanical results certainly must be confirmed in biological (cadaveric, comparative, and clinical) models, but they offer a potentially novel solution to preoperative assessment of the osteoporotic patient with regard to planning of instrumentation (type, density of implants, technique) if the strength of bone can be shown to be directly proportionate to a radiographic parameter.
The past year of orthopaedic research has been productive in terms of advancing our understanding of the mechanism of diseases and ways to manipulate those mechanisms to develop therapies. Many of these discoveries are still far away from clinical application, and the ones that are currently in practice require continued evaluation for long-term effectiveness and adverse reactions.
Specialty Update has been developed in collaboration with the Board of Specialty Societies (BOS) of the American Academy of Orthopaedic Surgeons.
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Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.