Extract
Advances continue to be made in our understanding of the basic biology of numerous musculoskeletal tissues. Research in diverse fields such as biomaterials, stem cell biology, molecular biology, tissue engineering, and genetics have also provided further insight relevant to orthopaedic tissues. This review will synthesize major developments over the past year in the areas of cartilage injury and repair, meniscal injury, tendon and ligament pathology, muscle injury, tissue engineering and stem cell approaches to soft-tissue repair, and spine pathology.
Advances continue to be made in our understanding of the basic biology of numerous musculoskeletal tissues. Research in diverse fields such as biomaterials, stem cell biology, molecular biology, tissue engineering, and genetics have also provided further insight relevant to orthopaedic tissues. This review will synthesize major developments over the past year in the areas of cartilage injury and repair, meniscal injury, tendon and ligament pathology, muscle injury, tissue engineering and stem cell approaches to soft-tissue repair, and spine pathology.
Recent work has shown that not all osteoarthritis is the same and there is a specific subset of patients affected with posttraumatic osteoarthritis. In the past year, there has been substantial progress in understanding the very early events in posttraumatic osteoarthritis and how the clinical profile for patients with posttraumatic osteoarthritis differs from that for patients with other causes of osteoarthritis1,2. It is recognized that understanding the very early events following injury is important as it provides an opportunity for intervention through medication or modification of exercise or diet, whereas once osteoarthritis is established, treatments are largely palliative.
Impact trauma to articular cartilage results in physical disruption of the extracellular matrix, chondrocyte death, and release of inflammatory mediators involved in several pathways. After injury, cartilage death continues to increase over time3. Within twenty-four hours after single-impact trauma, there is a release of prostaglandin E2, IL-6 (interleukin-6), and nitric oxide4. The increase in catabolic mediator release is temporal, with a predominantly early release of prostaglandin E2 and a late induction of nitric oxide. The involvement of nitric oxide in the pathophysiology of posttraumatic osteoarthritis implicates a mitochondrial-cytoskeleton association for the release of reactive oxygen species5. The release of reactive oxygen species after cartilage impact has been shown to be mitochondrial in origin6, and scavenging reactive oxygen species with n-acetylcysteine after impact reduces chondrocyte death7. Mitochondria are physically attached to the cytoskeleton8, and collectively these results suggest that impact forces are transmitted to the mitochondria via the actin cytoskeleton, which results in mitochondrial production of reactive oxygen species. The role of the mitochondria in cartilage and posttraumatic osteoarthritis is just beginning to be studied, but evidence suggests that mitochondrial metabolism might be a target to stop the progression of cell death, matrix deterioration, and the development of posttraumatic osteoarthritis.
Despite a lack of comprehensive understanding regarding the pathophysiology of posttraumatic osteoarthritis, preventive measures are being investigated. In the laboratory, treatment of injured cartilage with dexamethasone for six days abolished the catabolic effects of mechanical injury9. Obesity has been demonstrated to increase the severity of posttraumatic osteoarthritis in mice subjected to closed intra-articular knee fractures10. Obesity is thought to exacerbate posttraumatic osteoarthritis through increased joint load as well as by general catabolic influences of IL-12, which is increased in obese individuals.
Finally, the impact of genetic background on bone and cartilage changes during the development of posttraumatic osteoarthritis continues to be investigated. New developments have indicated that the ability to repair tissue and the susceptibility to posttraumatic osteoarthritis are similarly affected by genetic background11. Mice of different strains showed variability in similar physiological processes such as tissue regeneration (healing of ear punch) and susceptibility to development of posttraumatic osteoarthritis. Understanding more specifically the region of the genome responsible for this variability might provide a means to identify patients who are most at risk for the development of posttraumatic osteoarthritis and therefore the target population of greatest interest.
Enhancing Currently Used Techniques
Long-term prospective randomized studies are critical for allowing us to more fully understand the comparative functional performance of autologous chondrocyte implantation, mosaicplasty, and microfracture and the potential benefits of variants of each of these procedures12. The technique of autologous chondrocyte implantation, in particular, has been altered in a number of ways in an effort to avoid the problems associated with periosteal overgrowth, dislodgement of the periosteal flap, variable cellular response, and a burdensome rehabilitation protocol. Modifications to this widely used procedure generally fall into three categories: (1) variations on cell-processing techniques, (2) use of a membrane instead of a periosteal flap, and (3) use of scaffolds to hold the cells in the defect site.
Variations on Cell-Processing Techniques
Characterized chondrocyte implantation (ChondroCelect; TiGenix, Leuven, Belgium) is a procedure similar to autologous chondrocyte implantation, but the expansion process is altered to separate out only highly chondrogenic cells capable of maintaining their chondrogenic phenotype13. A prospective randomized study comparing the five-year outcomes of characterized chondrocyte implantation with those of microfracture demonstrated similar Knee Injury and Osteoarthritis Outcome Scores (KOOS) for both groups. Characterized chondrocyte implantation resulted in significantly better results than microfracture in patients who were managed within three years after the onset of symptoms, whereas it resulted in less predictable outcomes for those who received delayed treatment. The Cartilage Autograft Implantation System (CAIS; DePuy Mitek, Raynham, Massachusetts) represents another modified autologous chondrocyte implantation procedure. This procedure does not involve the injection of cells into the affected site; instead, fragments of autologous cartilage isolated from minimally weight-bearing areas (the intercondylar notch or trochlear edge) are minced and then seeded into a synthetic, absorbable scaffold. A prospective randomized clinical trial in which the CAIS procedure was compared with microfracture after two years of follow-up demonstrated that the CAIS procedure is safe and effective in the short term14.
Scaffold Use
HYAFF (Hyalograft C; Fidia Advanced Biopolymers, Padua, Italy) is a porous hyaluronic acid-based degradable scaffold that is seeded with chondrocytes prior to implantation. A prospective cohort study in which microfracture was compared with HYAFF indicated that high-level athletes had a similar rate of return to sports regardless of the procedure (80% in the microfracture group, compared with 86% in the HYAFF group)15. The International Knee Documentation Committee (IKDC) subjective score showed similar results at two years of follow-up but showed significantly better results in the HYAFF group at the time of the latest evaluation at 7.5 years15.
Efforts are also under way to biologically enhance microfracture with the goal of increasing the migration and chondrogenic differentiation of the subchondral progenitor cells. At the forefront of these efforts is the use of autologous conditioned plasma, platelet-rich plasma, and bone marrow-derived mesenchymal stem cells. In a sheep model of a full-thickness chondral lesion, autologous conditioned plasma-augmented microfracture resulted in gross and histological improvements compared with the microfracture-alone group at up to twelve months postoperatively16. In a horse model, the use of bone marrow stromal cells to augment microfracture was explored17. A chondral defect was created bilaterally and was subjected to microfracture. One month after the creation of the chondral defects, bone marrow stromal cells suspended in hyaluronic acid (Hyvisc; Anika Therapeutics, Woburn, Massachusetts) were injected into one joint, whereas hyaluronic acid alone was injected into the contralateral joint. The bone marrow stromal cell group had significantly higher levels of aggrecan in the repair tissue, suggesting that the tissue that filled the defect site had superior mechanical properties at six months.
The Biological Frontier: Stem Cells and Growth Factors in Cartilage Repair
It is reasonably well accepted that mesenchymal stem cells act primarily to modulate their local environment through the production of cytokines to stimulate the repair and recruitment of local stem cells by means of immunomodulation through a variety of mechanisms, including the secretion of anti-inflammatory cytokines and the suppression of T-cell proliferation18,19. The efficacy of mesenchymal stem cells in the enhancement of cartilage regeneration was demonstrated by means of direct intra-articular injection of xenogeneic (human) mesenchymal stem cells suspended in hyaluronic acid into the knee joints of Hartley strain guinea pigs with spontaneous osteoarthritis20. Five weeks after injection, cartilage repair was superior in the mesenchymal stem cell group as compared with the control group. There were mesenchymal stem cells residing within the repair cartilage, suggesting that mesenchymal stem cells migrate to the site of cartilage damage.
A goal in the use of mesenchymal stem cells is to produce a stable chondrocytic phenotype as opposed to one in which cells terminally differentiate, undergo apoptosis, and produce matrix with inferior mechanical properties. Thus, concerns remain about the potential hypertrophy and calcification of tissue formed by mesenchymal stem cells. In a study that was performed to address these concerns, it recently was shown in vitro that co-culturing of mesenchymal stem cells with juvenile chondrocytes promotes a chondrogenic phenotype without hypertrophy21.
The ability of growth factors to positively affect chondrocyte physiology has been well established in vitro. Extensive efforts to harness these powerful mediators have started to impact clinical care in the form of seminal clinical trials designed to establish safety. In a recent phase-I clinical study, allogeneic chondrocytes, some of which were retrovirally transduced to express transforming growth factor (TGF)-β1 (TissueGene-C; TissueGene, Rockville, Maryland), were injected directly into knee joints in patients with advanced osteoarthritis22. The study demonstrated the short-term safety of the procedure, and a randomized, double-blinded, placebo-controlled, phase-II study has since been commenced.
Growth factors also may be useful by stimulating the stem cell niche that is present in all tissues. Cytokines such as TGF-β3 and SDF-1β (stromal cell-derived factor-1β) not only induce chemotaxis of stem cells derived from synovium, bone marrow, and adipose tissue, but these chemotactic agents also enhance chondrogenic differentiation of the recruited mesenchymal stem cells23. Similarly, platelet-rich plasma, which contains a variety of growth factors, stimulates migration and chondrogenic differentiation of mesenchymal stem cells derived from the subchondral bone24.
Diagnosis of Meniscal Pathology
Advanced magnetic resonance imaging (MRI) techniques are being developed and clinically tested in an effort to provide early diagnosis of meniscal degeneration. At the forefront of these efforts is the ultra-short echo time-enhanced T2* mapping (UTE-T2*). Williams et al. found significant elevations of UTE-T2* values in the menisci of subjects with an anterior cruciate ligament (ACL) injury without clinical evidence of meniscal abnormality25. As tests continue to determine whether or not elevated subsurface meniscal UTE-T2* values predict the progression of meniscal degeneration and the development of osteoarthritis, it is envisaged that this novel technique can be used not only to diagnose injuries but also to assess healing following meniscal repair26.
The development of models capable of simulating dynamic, everyday activities in cadaveric knees has improved our ability to assess the functional consequences of meniscal injury and the ability of meniscal repair to improve knee mechanics. A multidirectional dynamic cadaveric model designed to mimic the activity of gait demonstrated that large radial tears of the lateral meniscus in the region of the popliteal hiatus show unfavorable dynamic contact mechanics that are not significantly different from those resulting from a partial lateral meniscectomy27, whereas large tears of the medial meniscus were not as detrimental to the contact mechanics but were significantly worse when a partial meniscectomy was performed28,29. In both models, a partial meniscectomy adversely affected contact mechanics, suggesting the importance of finding a suitable material to replace the removed meniscal tissue.
Surgical Options for Meniscal Replacement
The past year has seen a number of promising reports regarding the use of meniscal scaffolds. Two such scaffolds being used clinically, although not in the United States, are a collagen-based implant (Menaflex; Regen Biologics, Hackensack, New Jersey) and a polyurethane-based implant (Actifit; Orteq, London, England). Both materials are sutured into the defect site and are intended to act as a scaffold into which the host cells migrate and lay down matrix. The degradation time for the scaffolds differs, with Menaflex degrading at a faster rate than Actifit.
Fifty-two patients with irreparable partial meniscal defects (including thirty-four with medial defects and eighteen with lateral defects) were managed with the Actifit implant in a prospective, single-arm, multicenter, proof-of-principle study30. Eighty-eight percent of the patients had had one to three previous surgical procedures on the index meniscus. Clinically important and statistically significant improvements compared with baseline were reported in all scores, and stable or improved International Cartilage Repair Society cartilage grades were observed in 93% of patients between baseline and twenty-four months. Seventy-one adverse events with a possible, probable, definite, or unknown relationship to the scaffold and/or procedure were reported. The rate of treatment failure (defined as the need for reoperation) was 17%, with the majority of failures being in the lateral compartment.
Thirty-three nonconsecutive male patients (mean age, forty years) with meniscal injuries were enrolled in a study and were managed with either Menaflex or unfilled partial meniscectomy31, with the choice of treatment being decided by the patient. At a minimum of ten years of follow-up, significant improvements in terms of pain, activity level, and radiographic outcomes were noted in association with use of Menaflex. A reduction in the size of the scaffold was noted in a subset of patients. While the clinical importance of this finding is unknown, efforts to enhance the biological incorporation of the scaffold with the host tissue are focusing on biologically augmenting the scaffold. A recent study by Petri et al. investigated the influence of continuous perfusion and mechanical stimulation on the response of bone marrow stromal cells seeded into the Menaflex scaffold32. The authors found that cell proliferation can be enhanced with use of continuous perfusion and that differentiation is fostered by mechanical stimulation. It is hoped that the response of cell-laden constructs to mechanical stimulus can be harnessed to develop functional tissues capable of mimicking the high modulus properties of the native tissue they are intended to replace.
The Biological Frontier: Stem Cells and Growth Factors in Meniscal Repair
Efforts are underway to mimic the complex collagen network of the meniscus with use of fiber-spinning technology. With use of a technique called electrospinning, the orientation, content, and density of fibers can be controlled to impart required mechanical properties, without limiting the ability of cells to migrate into the scaffold33. Mechanical stimulation can be used to further enhance the matrix-generating potential and mechanical properties of the included cells34.
The use of scaffold-free stem cells to help to elicit meniscal repair is also being explored with use of in vitro and in vivo models. In particular, evidence that mesenchymal stem cells hone to the site of meniscal injury is being re-explored. In a meniscal defect rabbit model, synovial mesenchymal stem cells adhered to sites of meniscal injury, differentiated into cells resembling meniscal fibrochondrocytes, and enhanced both the quality and quantity of matrix generated in the avascular zone of the defect site compared with an untreated defect35. This effect was more pronounced for meniscal tears that were treated acutely. As advances are made in scaffold and stem cell technology, we have the opportunity to design prospective randomized clinical trials with improved postoperative imaging assessment tools.
Influence of Mechanical Environment on Tendon and Ligament
The mechanotransduction mechanism by which tenocytes sense the external environment remains relatively unclear. Over the past year, studies have pointed to the importance of the tendon cell’s primary cilia as a critical component of the mechanosensory apparatus. The presence of transmembrane integrin receptors on the cilium suggests that it has the necessary molecular machinery to serve as a mechanosensory linkage between the extracellular matrix and the inner cellular environment.
Gardner and colleagues established that the primary cilia of tenocytes were sensitive to mechanical stimulus by evaluating the effect of stress deprivation and mechanical load on the length of the primary cilia in tenocytes in situ36. Freshly harvested tenocytes from rat tails were stress deprived in tissue culture conditions at twenty-four-hour intervals up to seventy-two hours. The authors reported that structural changes were detected in the cilia within twenty-four hours of stress deprivation. The tenocyte cilia increased in length by an average of 159% relative to control in response to a lack of mechanical stimuli. Subjecting the stress-deprived cilia to mechanical load reversed the lengths of the cilia back to control conditions. The authors postulated that the change in cilia length may be an attempt by the tendon cell to amplify weakened mechanical stimuli in a stress-deprived state.
Lavagnino et al. similarly evaluated the sensitivity of tenocyte cilia to different load conditions by observing the effect of tensile loads on cilia orientation and deflection37. The authors demonstrated that distinct changes in ciliary deflection angles and shape correlated with increasing applied strain on the tenocytes, which did not completely return to baseline after removal of the strain stimulus. While the studies by both Gardner et al. and Lavagnino et al. demonstrated that tendon cell ciliary length and shape are responsive to changes in the extracellular matrix mechanical environment, the precise role of these observed ciliary changes and the subsequent mechanotransduction pathway within the tendon cells remain to be elucidated.
Tendinopathy and Emerging Cell Therapy for Tendon Healing
Tendinopathy is a chronic degenerative process that is typically characterized by tendon structural and biochemical alterations leading to subsequent loss of collagen fibril organization. The use of animal models simulating chronic overuse injury and tendinopathic changes has begun to elucidate the molecular mechanism underlying the development of tendinopathy. Recent work has focused on the cellular phenotypic metaplasia that may be occurring at the site of tendinopathy, which may explain the lack of a tendon healing response in patients with chronic degeneration. Attia et al. evaluated the role of phenotypic cellular alteration and glycosaminoglycan (GAG) composition in early tendon degeneration in a rat model of rotator cuff overuse injury38. Following two weeks of overuse, the authors found evidence of supraspinatus tenocytes shifting toward a more chondrocytic phenotype. By four weeks of overuse, total GAG content within supraspinatus tendons significantly increased and remained elevated for the duration of the study (sixteen weeks).
Similarly, Lui and colleagues reported the presence of chondrocyte-like cells with ectopic expression of chondro-osteogenic bone morphogenetic proteins (BMPs) at the site of tendon degeneration in a failed tendon healing animal model39. The authors found increasing expression of BMP-4/7 in the healing tendon fibroblast-like cells and matrix at two weeks and again at twelve and sixteen weeks after collagenase-induced tendon degeneration. The authors further corroborated the animal findings by reporting a similar phenomenon in a series of degenerated human patellar tendon tissues procured at time of tendon debridement40. The studies by Attia et al. and Lui et al. suggest that erroneous differentiation of tendon progenitor cells toward a chondrocytic lineage may play a role in chronic tendon degeneration and the failed tendon healing phenomenon.
Given the challenges associated with tendon healing, much research continues to focus on biologic augmentation in the hope of improving healing rates. Recent studies have evaluated cells isolated from human placental, amnion, and umbilical cord for musculoskeletal repair. These cells have demonstrated the capacity to differentiate into various tissues, including bone, cartilage, muscle, and tendon41-45. Preclinical studies in animals have demonstrated that amniotic-derived stem cells are capable of participating both directly and indirectly in tendon repair42,46. Certain cell populations, such as placenta-derived stromal cells, also have immunomodulatory and angiogenic properties, which may be desirable for tendon healing and regeneration47.
Platelet-Rich Plasma and Tendon Healing
The efficacy of platelet-rich plasma on tendon healing continues to be a topic of debate. An area of recent interest has been the different preparations of platelet-rich plasma, particularly the leukocyte content. Sundman et al. evaluated and characterized different human platelet-rich plasma specimens from two different commercial platelet-rich plasma systems48. The investigators found that the leukocyte-rich preparation resulted in higher content of inflammatory/catabolic mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-1β, which may be detrimental for tendon healing. Dragoo and colleagues evaluated the in vivo effect of leukocyte-rich preparations in healthy rabbit tendons. The authors reported a greater inflammatory response five days after healthy tendons were treated with leukocyte-rich platelet-rich plasma when compared with leukocyte-poor platelet-rich plasma, which resulted in greater early disruption of the tendon architecture, higher vascularity, and fibrosis histologically49. While the long-term effects and contributions of leukocytes to tendinopathy and healing remain unclear, these two studies highlight the importance of knowing the composition of the platelet-rich plasma when interpreting clinical results following the use of platelet-rich plasma.
Muscle Injury and Muscle Response to Injury
Little is known regarding the molecular processes resulting in heterotopic ossification following muscle injury. Jackson et al. recently evaluated human muscle tissue collected during debridement following orthopaedic trauma50. The authors generated a cytokine profile from post-traumatized muscle tissue with the goal of elucidating the molecular mechanisms underlying heterotopic ossification. The authors reported uniform upregulation of cytokines associated with fibrosis (TGF-β1) and osteogenic induction (BMP-1) localized to areas of injured muscle tissues. Future work building on these findings therefore may define key events leading to fibrosis and posttraumatic heterotopic ossification, which may lead to novel targets or prophylactic or therapeutic interventions.
Fatty Degeneration of the Rotator Cuff
Muscle atrophy with fatty degeneration is frequently seen in patients with massive rotator cuff tears. Muscle degeneration diminishes the success of surgical repair and does not reverse after surgical repair. Loss of mechanical load and stimulus as a result of torn tendon insertions may contribute to fatty degeneration of the rotator cuff muscle. Das et al. established that the mechanical environment is critical for the development and maintenance of rotator cuff tissue51. Using a neonatal animal model, the authors serially injected the supraspinatus tendons of mice with botulinum toxin A. The paralysis resulted in decreased muscle bulk (with 46.5% and 51.2% decreases at twenty-eight days and 64.2% and 67.2% decreases at fifty-six days in comparison with contralateral muscles injected with saline solution and normal muscles, respectively) and reduced supraspinatus muscle tetanic force (with 43.7% and 48.8% decreases at twenty-eight days and 64.3% and 70% decreases at fifty-six days in comparison with contralateral muscles injected with saline solution and normal muscles, respectively). In addition to decreased function, paralysis of supraspinatus muscles also resulted in upregulation of adipogenic transcription factors, such as C/EBPα (CCAAT-enhancer-binding proteins) and PPARχ2 (peroxisome-proliferator-activated receptor-χ2).
In addition to research on external factors that contribute to fatty muscle degeneration, recent work has begun to elucidate molecular pathways that may contribute to fatty degeneration. The work by Itoigawa and colleagues has implicated the Wnt pathway in rotator cuff muscle degeneration both in vitro and in vivo52. The authors demonstrated that activation of the Wnt10b pathway in myogenic cells maintained in adipogenic culture medium resulted in significant reduction of adipogenic transcription factor expression and adipogenic differentiation. These data suggest that alteration of Wnt10b expression may be a potential avenue for the prevention or treatment of rotator cuff fatty degeneration.
Spinal Fusion
Recent studies have demonstrated a positive effect of platelet-rich formulations for the augmentation of vertebral fusion. In the study by Landi et al., fourteen patients who had undergone posterolateral fusion with autologous bone were managed with platelet-enriched gels and their recovery was tracked53. The authors reported more rapid bone formation in the first three months and denser bone formation by six months in the regions treated with platelets as compared with the fusion sites not augmented with the gel.
While the story of the role of BMPs in spinal fusion continues to unfold, many studies have investigated BMP expression in the setting of degenerative disc disease. Tang et al. described the spatial and temporal expression of BMPs and BMP antagonists in and around the site of posterolateral spinal fusion in a rabbit model54. That study shed light on the interaction of the graft and local tissue. The authors evaluated BMP-2, BMP-4, BMP-7, noggin, chordin, Sox9, and Runx2 with use of reverse-transcription polymerase chain reaction and immunohistochemistry. Various cell types at the fusion site, including osteoblasts, osteoclasts, and chondrocytes, also exhibited upregulated BMP expression.
Intervertebral Disc Markers
Research into intervertebral disc pathology has been limited by the absence of well-accepted tissue-specific markers of the inner nucleus pulposus compared with the anulus fibrosus or cartilaginous end plates. Recently, several papers have identified new nucleus-specific markers. Dahia et al. identified sonic-hedgehog (Shh) specifically in the nucleus pulposus of developing Friend Virus B-type (FVB) mouse disc55. Power et al. showed the potential for using carbonic anhydrase XII (CAXII) as a nucleus-specific target in humans in a study of sixteen discs from six donors56. While both Shh and CAXII are more widely expressed in the body and would not be suitable for driving tissue-specific knockouts, their utility might come in providing targets for the delivery of such treatments as nanoparticle therapy.
Previous work demonstrated that specific mutations in COL9 (collagen IX) give rise to tryptophan polymorphisms, which appear to be risk factors for degenerative disc disease. Zhu et al. built on this work by identifying the specific expression of collagen IX in healthy and degenerative discs57. While collagen IX was expressed at negligible levels in healthy adult discs, it was detectable at sites of degeneration and was likely expressed as part of a repair response.
MRI scans of degenerative discs often show an area that is termed the high-intensity zone, which is believed to correlate with the inflamed regions around an anular tear. Dongfeng et al. evaluated T2-weighted MRI scans of degenerative discs and reported that TNF-α (tumor necrosis factor-α) and CD68 (a marker for macrophages) were expressed at elevated levels in tissue from the high-intensity zone and that the zone could be a specific signal for an inflammatory response in patients with discogenic back pain58.
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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.