What's new in orthopaedic research

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2010;92:2491-2501. doi:10.2106/JBJS.J.01174 J Bone Joint Surg Am.Maher Scott A. Rodeo, Demetris Delos, Alex Weber, Xiaodong Ju, Matthew E. Cunningham, Lisa Fortier and Suzanne

What's New in Orthopaedic Research

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Specialty Update

What’s New in Orthopaedic ResearchBy Scott A. Rodeo, MD, Demetris Delos, MD, Alex Weber, MD, Xiaodong Ju, MD, Matthew E. Cunningham, MD, PhD,

Lisa Fortier, DVM, PhD, and Suzanne Maher, PhD

There has been continued innovation in orthopaedic basicscience research over the past year. In this review, we highlightnotable studies published in the last twelve months. We havereviewed papers from the annual meeting of the OrthopaedicResearch Society as well as major orthopaedic journals. Thesestudies demonstrate an exciting multidisciplinary approachto understanding the mechanisms underlying tissue degenera-tion, injury, repair, and replacement.

Influence of the Mechanical Environment onTendon and LigamentIt is well established that the mechanical environment influ-ences tendon structure and function. Over the past year,a number of studies have increased our understanding of theeffect of mechanical load on tendon and ligament homeostasis,which will provide further insight into the mechanisms un-derlying tendinopathy and tendon healing.

Rumian and colleagues examined the response of thepatellar tendon of sheep to stress-shielding in vivo1. Their re-sults suggested that stress-shielding caused a significant re-duction in the structural and material properties of the patellartendon compared with mechanically loaded controls. They alsonoted that, on restressing the stress-shielded tendons, therewas recovery in terms of the material and structural properties.This in vivo study substantiates previous in vitro work thatsuggested that mechanical load is necessary for optimal tendonstructure and function.

Maeda et al. studied gene expression in isolated rat tailtendon fascicles exposed to cyclic tensile strain in vitro2. Theyinvestigated the temporal regulation of selected anabolic andcatabolic gene expression in tenocytes subjected to tensilestrain. Two groups of rat tail tendon fascicles were exposed tocyclic tensile strain with a 3% amplitude superimposed ontoa 2% static strain for ten minutes. Following the initial loading,

the control group received no additional loading for the re-mainder of the twenty-four-hour incubation period, whereasthe loaded group received continuous cyclic loading over thesame time period. Six hours after loading, type-III collagenmRNA expression was significantly upregulated in the loadedgroup as compared with the unloaded controls; however, nosignificant differences in type-I collagen or biglycan mRNAexpression were noted between the two groups. There wassignificant downregulation in the expression of the decorincore protein in the loaded group as compared with unloadedcontrols. Matrix metalloproteinase (MMP-3 and MMP-13)mRNA expression was upregulated by the ten-minute appli-cation of cyclic strain in both groups and then showed adownregulation over the course of twenty-four hours in boththe presence and absence of load. This study provides usefulinsight into the balance of anabolic and catabolic gene ex-pression that controls tendon homeostasis. Likewise, this studyfurther substantiates that mechanical load at a physiologic levelis necessary to maintain homeostasis.

Zhang and Wang also explored the homeostatic balance;however, they did so by mechanically loading isolated tendonstem cells in vitro3. They used a loading system to uniaxiallystretch rabbit patellar and Achilles tendon stem cells at ei-ther 4% or 8% strain at 0.5 Hz for twelve hours. They thenexamined the cellular and genetic response to load via quan-titative polymerase chain reaction. After 4% uniaxial loading,the tendon stem cells significantly increased the expression ofthe genetic marker for type-I collagen but not the geneticmarkers for adipocytes, chondrocytes, or osteocytes. In con-trast, after 8% uniaxial loading, the tendon stem cells sig-nificantly increased expression of the genetic markers foradipocytes, chondrocytes, osteocytes, and tenocytes. This resultled the authors to conclude that low levels of mechanical loadmay have a beneficial role in tendon homeostasis whereashigher mechanical loads may be detrimental by promotingtendon stem cells to differentiate into cell types responsible forlipid accumulation, mucoid formation, and tissue calcification,which are all markers of tendinopathy.

Specialty Update has been developed in collaboration with the Board ofSpecialty Societies (BOS) of the American Academy of Orthopaedic Surgeons.

Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a memberof their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

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J Bone Joint Surg Am. 2010;92:2491-501 d doi:10.2106/JBJS.J.01174

Effect of Mechanical Stimulation on AchillesTendon HealingIt is believed that Achilles tendon ruptures that are treated withan initial period of immobilization heal more slowly, whereasearly mobilization improves the functional outcome. Recentstudies have confirmed that immobilization impairs healing ina rat Achilles tendon rupture model. Schizas et al.4 reportedthat daily intermittent pneumatic compression treatment canenhance proliferative tendon repair by counteracting bio-mechanical and morphological deficits caused by immobiliza-tion. They also noted that the underlying reparative mechanismsmay relate to the enhancement of blood flow, neurovascularingrowth, fibroblast proliferation, and sensory neuropeptidesupply to the healing tendon. Bring and colleagues5 sought toinvestigate the exact mechanisms responsible for this mechano-biological transduction. They reported changes in gene expres-sion for substance P (NK1) receptor and calcitonin gene-relatedpeptide (CRLR and RAMP-1) receptors and found that long-term immobilization after Achilles tendon rupture led to an in-ferior healing process. The detrimental effects appeared to berelated to a significant reduction in sensory neuropeptide re-ceptor expression.

The effect of mechanical load on the healing rotator cufftendon was recently evaluated with use of a clinically relevantrodent model of rotator cuff repair and postoperative injectionof botulinum toxin A into the muscle to cause paralysis6. Theanimals were either treated with casting or allowed cage activityad libitum. The experiment also included a control group ofrodents undergoing rotator cuff repair followed by saline so-lution injection and casting. Animals were killed at seven,fourteen, twenty-one, and fifty-six days for histological analysisand at twenty-one and fifty-six days for biomechanical evalu-ations. The saline solution-injected control group had greaterscar volume, cross-sectional area, and structural propertieswhen compared with the paralyzed groups. The group treatedwith paralysis without casting demonstrated improvementsin biomechanical properties as compared with the grouptreated with paralysis with casting. These results led the authorsto conclude that complete removal of mechanical load is det-rimental to rotator cuff tendon healing.

These studies suggest that there is a range of optimalmechanical load that is beneficial to tendon or ligament andthat loads above or below that range are detrimental. In a seriesof studies, Soslowsky (winner of this year’s Kappa Delta AnnDoner Vaughan Award) and colleagues sought to define theoptimal mechanical load range for tendon-bone healing. Toelucidate the effects of passive motion on rotator cuff healing,this group utilized a clinically relevant rodent model of rotatorcuff repair7. Following rotator cuff transection and repair,animals were separated into three postoperative groups: con-tinuous immobilization, passive motion protocol 1 (600 cyclesper day of internal and external rotation at 1 Hz), or passivemotion protocol 2 (300 cycles per day of external rotationonly at 0.5 Hz). Passive motion protocols were derived from

human and dog flexor tendon repair studies in which earlymobilization had shown a beneficial effect on healing. After theinitial two postoperative weeks, all three experimental groupsunderwent a four-week remobilization protocol consisting ofcage activity ad libitum for one week followed by graduallyincreasing treadmill activity over the next three weeks. Passiveshoulder joint mechanics were evaluated for each animal priorto assignment to an experimental group and at two and sixweeks postoperatively. All animals were killed at six weeks,and their muscle-tendon-bone segments were analyzed eitherhistologically or biomechanically. Total range of motion forboth passive motion groups was less than that of the contin-uous immobilization group at two weeks and remained signifi-cantly lower following the four-week remobilization program.Joint stiffness was also greater in the passive motion groups ascompared with the immobilization group at two weeks. At sixweeks, there were no differences between the three groups withregard to collagen organization or mechanical properties. Theresults of this study suggest that immediate postoperativemotion has a detrimental effect on range of motion and jointstiffness but may not affect the mechanical properties of thehealing tendon-bone interface in a rat model of rotator cuffinjury and repair. The authors speculated that passive motionresults in increased scar formation in the subacromial space,thereby resulting in decreased range of motion and increasedjoint stiffness, and concluded that immediate postoperativepassive motion was detrimental to passive shoulder mechanics.

In a separate study, Peltz et al.8 examined the effects ofdelayed mechanical loading in the same rat model of rotatorcuff repair. In that study, rats were treated with an initial periodof immobilization for two weeks, followed by either cage ac-tivity or treadmill exercise for twelve weeks following rotatorcuff repair. Treadmill exercise resulted in significant decreasesin motion, tendon stiffness, modulus, percentage relaxation,and other structural parameters compared with cage activity adlibitum. The authors concluded that two weeks of immobili-zation following rotator cuff repair in the rat was not sufficientto allow resolution of postoperative inflammation and thatat two weeks the healing tendon-bone interface is still relativelyimmature. Therefore, they concluded that increased activityonly serves to produce more disorganized ‘‘scar’’ tissue and isdetrimental to both the shoulder joint mechanics and tendonmechanical properties.

One of the many difficulties with any in vivo animalmodel of mechanical loading is accurately and precisely con-trolling the mechanical load placed on the healing tendon-boneinterface. For example, treadmill running places a greatermechanical load on the healing rotator cuff than cage activity adlibitum does, but the absolute difference is difficult to measure.Likewise, the amount of cage activity ad libitum across specimensmay vary greatly, as might the amount of cage activity withineach specimen across days. To address this limitation, ourgroup has developed a model to precisely control the magni-tude, frequency, and duration of mechanical load transferred to

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VO LU M E 92-A d NU M B E R 14 d OC T O B E R 20, 2010WH AT ’s NE W I N ORT H O PA E D I C R E S E A R C H

What’s New in Orthopaedic Research

the healing tendon-bone interface during healing. We use anexternal fixator and a specially designed motorized loadingdevice to apply controlled daily axial strain in a clinically rel-evant rat model of anterior cruciate ligament reconstruction.Using this model, we recently demonstrated that fifty cycles ofdaily uniaxial cyclic loading (at approximately 2% strain), be-ginning in a delayed fashion (initiated at either postoperativeday 4 or 10), resulted in significantly greater failure loads at twoweeks postoperatively when compared with animals treatedwith immediate loading or immobilization9. Significantly in-creased new-bone formation and tissue mineral content wasalso observed in the tibial tunnels of the delayed-loadinggroups as compared with the immediate-loading and immo-bilization groups at both two and four weeks postoperatively.Increasing the applied axial load to 10% strain resulted inpoorer healing across all loading groups. From this work, wehave concluded that low levels of controlled mechanical load-ing may be most favorable to healing after a period of immo-bilization to allow resolution of postoperative inflammation.This suggests that both the timing and the magnitude of me-chanical stimulation are important for healing in the peri-operative period.

The research presented in this section demonstrates theimportance of mechanical load for optimum tendon and liga-ment structure and function. Future research is required to fur-ther define the timing, magnitude, and frequency of postoperativeloading (which may vary depending on the tendon, ligament,or joint involved) and the cellular and molecular mechanismsinvolved in soft-tissue homeostasis and healing. This future re-search will have clinical implications for guiding postoperativerehabilitation as well as for shaping tissue engineering strategiesfor tendon and ligament healing and reconstruction.

Interface Tissue Engineering for IntegrativeSoft-Tissue HealingTissue engineering techniques have been evaluated as a methodto accelerate tendon-bone and ligament-bone healing. Currentsoft-tissue reconstruction and mechanical fixation methodsfail to restore the native complex enthesis, which may com-promise the clinical outcome. With the long-term goal ofpromoting integrated soft-tissue repair, Lu and colleagues fo-cused on methods to regenerate a functional fibrocartilageinterface on soft-tissue grafts with use of tissue engineeringtechniques. This group demonstrated that the controlled in-teraction of interface-relevant cell populations on a stratifiedscaffold with a biomimetic gradient of structural and func-tional properties can regenerate tissue with structural proper-ties similar to a soft tissue-bone interface10-12.

Recently, Lu et al. reported the design and in vivo eval-uation of a triphasic scaffold for the regeneration of the ante-rior cruciate ligament-to-bone interface11,13. Modeled after themultiple-tissue native insertion site, the scaffold consists ofthree distinct yet continuous phases: Phase A is designed witha polylactic co-glycolic acid (PLGA) mesh for fibroblast culture

and soft-tissue formation, Phase B consists of PLGA micro-spheres and is the interface region intended for fibrocartilageformation, and Phase C is composed of sintered PLGA and45S5 bioactive glass composite microspheres for osteoblastculture and bone formation. After two months of implantation,the biomimetic stratified scaffold design coupled with spatialcontrol over the distribution of interface-relevant cell pop-ulations led to the formation of cell-type and phase-specificmatrix heterogeneity, with a fibrocartilage-like interfaceformed in triculture. Future development may allow the tri-phasic scaffold to be used to guide the reestablishment of ananatomic fibrocartilage interface directly on soft-tissue grafts.

The potential of a degradable PLGA nanofiber-basedscaffold system for rotator cuff repair was recently evaluatedin vitro12. The authors reported that nanofiber organization(aligned versus unaligned) was the primary factor guidinghuman rotator cuff fibroblast morphology, alignment, andintegrin expression. Scaffold mechanical properties were di-rectly related to fiber alignment, and although they decreased asthe polymer degraded, both the elastic modulus and the ulti-mate tensile strength remained within range of native supra-spinatus tendon. These observations demonstrate the potentialof the PLGA nanofiber-based scaffold system for functionalrotator cuff repair.

Application of Adult Stem Cells in Tendon-Boneand Ligament-Bone HealingRecent studies have shown success in enhancing ligamenthealing and tendon-bone osseointegration with use of stemcells. However, there are still inconsistent results. We reportedthat the addition of bone marrow-derived stem cells to thehealing rotator cuff insertion site in a rat model did not im-prove the structure, composition, or strength of the healingtendon-attachment site despite evidence that the cells arepresent and metabolically active14. These data suggest that theaddition of bone marrow-derived stem cells alone is in-adequate to improve healing. However, further study showedthat bone marrow-derived stem cells that have undergoneadenoviral-mediated gene transfer with mouse scleraxis canimprove healing in the same model15. Nourissat et al.16 showedthat bone marrow-derived stem cells could promote theproduction of Achilles tendon enthesis at the bone-tendonjunction in a rat model. In addition, transplantation of hu-man anterior cruciate ligament-derived CD341 cells wasshown to contribute to tendon-bone healing in a rat model ofanterior cruciate ligament reconstruction via enhancement ofangiogenesis and osteogenesis17. In summary, adult stem-celltherapy represents a potential strategy for tendon-bone andligament-bone healing.

A Bioactive Scaffold-Collagen Platelet CompositeEnhances Anterior Cruciate Ligament HealingMurray and colleagues evaluated a collagen platelet compositeas a tissue engineering approach to augment anterior cruciate

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ligament healing. Collagen platelet composite is a bioactivecollagen-based scaffold infiltrated with platelets that has a posi-tive effect on the healing of an anterior cruciate ligament graft,both in terms of improving the strength of the graft and interms of reducing knee laxity after anterior cruciate ligamentreconstruction18. Moreover, in an anterior cruciate ligamentsuture-repair model, Murray and colleagues reported that an-terior cruciate ligament repairs supplemented with collagenplatelet composite enhanced the structural properties of theanterior cruciate ligament19. The improvement was associatedwith increased cellularity within the healing ligament. However,the use of a collagen scaffold alone to enhance suture repair ofthe anterior cruciate ligament was ineffective20.

Effect of MMPs and ADAMTS on Tendon HealingRecent studies demonstrate a potentially critical role of matrixmetalloproteinases (MMPs) and their inhibitors in the path-ophysiology of rotator cuff tears. Our group reported thatdoxycycline treatment after supraspinatus tendon repair ina rat model significantly improved collagen organization at thehealing enthesis, reduced MMP-13 activity, and increased loadto failure21. The tetracycline family of antibiotics inhibitsmammalian matrix metalloproteinase activity by a mechanismthat is independent of their antimicrobial activity. Modulation ofMMP-13 activity after rotator cuff repair may offer a novelbiological pathway to augment tendon-bone healing.

Bell et al. reported on the geometric, viscoelastic, andmechanical properties of flexor digitorum longus and Achillestendons of ADAMTS-5-deficient, ADAMTS-4-deficient, andwild-type mice22. The unique biomechanical changes in theflexor digitorum longus as compared with the Achilles tendonin the absence of ADAMTS-4 and ADAMTS-5 indicate im-portant roles of these enzymes in regulating tendon-specific cellbiological and matrix structural characteristics.

Cytokines and Scaffolds to Accelerate Tendon-Boneand Ligament-Bone HealingRecent studies have continued to evaluate the role of cytokinesand scaffolds in soft-tissue healing. Derwin et al. reported thataugmentation of acute repair of rotator cuff tendons witha newly designed poly-L-lactide repair device improved func-tional and biomechanical outcomes in a canine model23. Thepoly-L-lactide repair device provided a tendon-bone bridgeand scaffold for host tissue deposition and ingrowth, resultingin enhanced healing after rotator cuff injury. Kadonishi andcolleagues applied enamel matrix derivative with propyleneglycol alginate as a carrier to the tendon-bone junction in a ratanterior cruciate ligament reconstruction model and foundthat enamel matrix derivative could accelerate tendon-bonehealing with upregulation of Sharpey fiber formation24.

At this year’s annual meeting of the Orthopaedic Re-search Society, several groups described the positive effects ofcytokines on tendon-bone and ligament-bone healing. Foxet al. reported that augmentation with TGFb-3 in a calcium-

phosphate matrix improved the histological and biomechanicalproperties of the healing enthesis in a rat rotator cuff repairmodel25. Hee and colleagues showed that the application of lowor intermediate-dose rhPDGF-BB (75 or 150 mg) combinedwith a type-I bovine collagen matrix as an interpositional graftat the site of rotator cuff repair augmented and improvedtendon reattachment as evaluated biomechanically and histo-logically in an ovine model26. Leonard and colleagues reportedthat combining the anabolic effects of TGF-b1 and bFGFwith the potent anticatabolic properties of alpha-2 macro-globulin enhanced primary repair of a surgically transectedanterior cruciate ligament in a New Zealand white rabbitmodel27. These results further support the potential role ofgrowth factors as a therapeutic treatment for the augmentationof soft-tissue healing.

Tendon Stem Cells and Treatment of TendinitisStem cells have attracted much interest because of their self-renewing potential and multipotentiality for possible clinicaluse. Recent studies have involved the isolation and character-ization of tendon stem cells from human, mouse, and rattendon and ligament. These cells exhibited the universal stemcell properties of clonogenicity, self-renewal capacity, multi-potency, and specific marker expression in culture28,29. Fur-thermore, mouse treadmill running for three weeks (i.e.,moderate loading) was found to increase the proliferation oftendon stem cells with increased collagen production30; thus,tendon stem cells may play a vital role in maintaining ho-meostasis of tendons when mechanically challenged.

Tendon injuries and tendinitis are notorious for theirslow and functionally inferior healing. Several groups recentlyhave used stem cells and other approaches to treat collagenase-induced tendinitis in an animal model. Nixon and colleaguesreported that mesenchymal stem cell (MSC), IGF-I gene-enhanced mesenchymal stem cell (Ad-IGF-MSC), and em-bryonic stem cell injection into collagenase-induced lesions inhorse flexor digitorum superficialis tendons resulted in sig-nificantly improved tendon biochemical composition andhistological and mechanical characteristics, indicating a benefitof stem cells for the treatment of tendinopathy 31,32.

Meniscal Tissue EngineeringSeveral recent studies have examined the effect of dynamictension on tissue-engineered meniscus. At this year’s annualmeeting of the Orthopaedic Research Society, Ballyns andBonassar examined the effect of mechanical load on bovinemeniscal fibrochondrocytes suspended in 2% (weight pervolume) alginate33. These constructs were loaded via a custombioreactor for an hour twice every other day with an hour ofrest for two weeks between loading cycles. The authors foundthat dynamic compression significantly enhanced extracellularmatrix production and the mechanical properties of anatom-ically shaped tissue-engineered menisci. Baker et al. also ex-amined the effect of cyclic tensile conditioning on a human

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meniscus fibrochondrocyte-laden nanofiber material34. Theconstructs were cyclically loaded to 6% tensile strain at 1 Hz inthe bioreactor for three hours each day for two weeks. Theauthors found that dynamic tensile loading increased the me-chanical properties of engineered nanofiber-based meniscalconstructs.

A cell-based tissue-engineered construct is anotherpromising approach employed for the treatment of meniscallesions. Yoo et al.35 developed a dynamic cell-seeding techniqueand a novel in vivo mouse model with use of a three-layeredconstruct (chondrocyte-seeded scaffold placed between devi-talized meniscal discs) to assess the seeding and culture con-ditions (static and dynamic) for the scaffolds and the healingcapacity of the cell-seeded scaffolds in a meniscal repair model.The authors reported a continuous layer of new fibrous andcartilaginous tissue integrating into the native devitalizedmeniscus tissue in all of the dynamically cultured samples,raising the possibility that meniscal lesions could be repairedwith use of isolated articular chondrocytes seeded onto anappropriate degradable scaffold.

Platelet-Rich PlasmaPlatelet-rich plasma is an autologous blood product that isbeing increasingly used to treat musculoskeletal conditions.Platelets have a rich store of factors and cytokines within theiralpha granules and dense granules, which makes platelet-richplasma an appealing therapeutic alternative. Some of the im-portant factors found within the alpha granules of the plateletinclude platelet-derived growth factor (PDGF), transforminggrowth factor-beta (TGF-b), insulin-like growth factor-1(IGF-1), vascular endothelial growth factor (VEGF), and epi-dermal growth factor (EGF), among others. The dense granulesof the platelet contain neuromodulators and inflammatorymodulators such as histamine and serotonin. Platelets arestimulated to release these growth factors and cytokines by ex-posure either to collagen36 or to thrombin and calcium. Researchinto this therapy has expanded exponentially over the last severalyears.

Platelet-Rich Plasma in Tendon and Muscle HealingRandomized clinical trials involving platelet-rich plasma arelimited, but over the last year, several key studies have beenpublished, with both positive and equivocal results. A ran-domized, double-blind, placebo-controlled trial demonstratedno significant differences between patients managed with ei-ther platelet-rich plasma or saline solution injections for thetreatment of chronic Achilles tendinopathy37. In a recent ab-stract presented at the annual meeting of the AmericanOrthopaedic Society for Sports Medicine, Kauffman and col-leagues reported no significant differences in clinical outcomesbetween platelet-rich-fibrin-membrane-augmented rotatorcuff repairs and controls38. Zumstein et al. noted in a pro-spective, randomized trial that platelet-rich-fibrin-augmentedrotator cuff repairs demonstrated greater vascularization

compared with controls (as measured with power Dopplerultrasound) at six weeks postoperatively but not at threemonths39.

Recent animal studies evaluating platelet-rich plasmaand tendon healing have shown positive results. A placebo-controlled trial in horses that was performed to evaluate theeffect of platelet-rich plasma on the quality of superficial digitalflexor tendon repairs of front limbs (one treated with platelet-rich plasma, the other treated with saline solution) demon-strated that, after twenty-four weeks, the repair tissue in theplatelet-rich plasma group had higher failure strength andgreater elastic modulus. On histological examination, platelet-rich plasma-treated tendons showed better collagen organiza-tion and signs of increased metabolic activity40.

The literature on platelet-rich plasma and muscle healingis limited. However, platelet-rich plasma recently was shown tohave a positive effect on muscle strain healing in a rat model,with improvements in mechanical testing outcomes and muscleregeneration41. It is speculated that platelet-rich plasma maystimulate muscle satellite cells, explaining the increased muscleregeneration.

Platelet-Rich Plasma and Ligament HealingIn their prospective, single-blinded study of fifty anteriorcruciate ligament reconstructions in fifty patients, Radice et al.found that anterior cruciate ligament grafts that were treatedwith platelet-rich plasma gel achieved complete intra-articularhomogeneity on magnetic resonance imaging in an average of179 days, compared with 369 days for anterior cruciate liga-ment reconstruction without platelet-rich plasma gel42. A re-cent animal study demonstrated no positive effect of addingplatelet-rich plasma to suture repairs of anterior cruciate liga-ments in a pig model43. In that study, platelet-rich plasma failedto improve maximum tensile load or linear stiffness of theanterior cruciate ligament repairs after fourteen weeks in vivo.However, earlier work by Murray et al.44 demonstrated a sig-nificant increase in load at yield, maximum load, and linearstiffness at four weeks after anterior cruciate ligament suturerepair augmented with collagen-platelet-rich plasma hydrogelin a pig model, suggesting the importance of an appropriatematrix scaffold to support healing with platelet-rich plasma.

Platelet-Rich Plasma and Bone HealingThe effects of platelet-rich plasma on bone healing have beenmixed in the literature. Bi et al.45 found that an injectablescaffold (tricalcium phosphate/chitosan) with platelet-richplasma led to complete healing of tibial defects in a goat model,at sixteen weeks, with improved mechanical strength, bio-compatibility, and osteoinductive properties as compared withcontrols. However, platelet-rich plasma also has been shownto interfere with the complete differentiation of humanosteoclast precursors, with higher concentrations impairingosteoclast formation at earlier stages of differentiation46.Platelet-rich plasma also was shown to inhibit bone deposition

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in a rabbit calvarial model47. Furthermore, the combinationof mineralized collagen and platelet-rich plasma had no sig-nificant osteoinductive effect in a model of sheep cervicaldiscectomy and fusion48. In a clinical study, Hartmann et al.found that platelet-rich plasma added to bone graft in spinalfusions had the same rate of complete fusion on computedtomography as controls49.

Further study on the effects of platelet-rich plasma onboth mineralized and soft-tissue healing is required. The mo-lecular mechanism by which platelet-rich plasma affects thearea of injury is still unknown. Many other clinical questionsremain unanswered, particularly with regard to the timing oftherapy, the volume and frequency of treatment, and the op-timum vehicle for distribution of the platelet-rich plasmaformulation that will allow for sustained growth factor andcytokine release. An increased understanding will allow formore educated use of this increasingly popular therapy.

Muscle Biology and Molecular Pathways in RotatorCuff Tendon TearsA common clinical problem is muscle atrophy and progressivefatty infiltration following rotator cuff muscle-tendon injury.These abnormalities appear to be largely irreversible and canadversely affect clinical outcome following rotator cuff repair.In their chronic rotator cuff model in sheep, Frey et al. foundthat both Myf-5 (a myogenic transcription factor) and PPARg

(an adipogenic transcription factor) expression were signifi-cantly increased after infraspinatus tenotomy, providing evi-dence that upregulation of adipogenic transcription factorscan occur simultaneously with muscle regeneration50. Con-tinuous traction on the infraspinatus tendon led to increases inMyf-5 and C/EBPb (adipogenic transcription factor) expres-sion; this was followed by decreases in these factors after ten-don fixation. The authors concluded that both adipogenic andmyogenic gene transcription factors play a role in chronicrotator cuff tendon tears in sheep.

A recent study provided evidence implicating Wnt sig-naling in the molecular mechanism of fat accumulation inrotator cuff muscles with ruptured tendons51. In the in vitroportion of the study, the authors noted that reduction ofWnt10b expression was associated with adipogenic differenti-ation of myoblasts. Mimicking canonical Wnt signaling withlithium chloride led to adipogenesis inhibition in vitro. Inthe in vivo portion of the study, the authors noted that ratrotator cuff muscles with torn tendons had decreased geneexpression of Wnt10b. They concluded that the reduction inWnt10b may be a possible molecular mechanism for fat ac-cumulation in rotator cuff muscles with torn tendons.

Muscle HealingIn a rat muscle contusion model, ebselen, an oxygen free radicalscavenger (glutathione peroxidase mimic), was shown to havea positive effect on microcirculation after trauma. Ebselen wasfound to restore muscle perfusion and inflammatory cell in-

teraction to levels found in the noninjured muscle tissue ofcontrols at twenty-four hours after injury, suggesting that eb-selen may have a positive effect on posttraumatic circulationand may protect skeletal muscle from inflammatory tissuedamage52. Using a mouse contusion model, Uehara et al. re-ported that losartan, an angiotensin receptor blocker, couldaccelerate skeletal muscle strength recovery, possibly throughthe expression of follistatin, a positive regulator of skeletalmuscle growth53. The same group also reported on the use ofmuscle-derived stem cells to accelerate skeletal muscle healingafter contusion injury54.

A number of recent studies have investigated the effectsof matrix metalloproteinases and their inhibitors on musclehealing. A synthetic MMP-1 inhibitor was found to increasefibrosis and to reduce the percentage of cells expressing stemcell markers, suggesting that MMP-1 may play a role in musclehealing and regeneration55. In another study, MMP-2 inhibitorwas shown to reduce skeletal muscle atrophy in a mouse Achillestendon transection model56. The same group also found thatdeletion of the MMP-9 gene helped to preserve muscle forcegeneration following Achilles tendon transection in the samemouse model57.

Bearing Surface Materials for Total Joint ArthroplastyUltra-high molecular weight polyethylene (hereafter calledpolyethylene) is a semicrystalline polymer consisting of discreteamorphous and crystalline regions that confer distinct me-chanical characteristics to the polymer. For example, whilecracks can readily move through crystalline areas, the disor-ganized amorphous areas have the effect of blunting the cracks.Efforts to improve the wear resistance of polyethylene havefocused on increasing the degree of molecular crosslinking withuse of ionizing radiation. While increased crosslinking has beenshown to reduce wear rates, the crosslinking occurs primarilyin the amorphous phase, which also has the potentially un-desirable consequence of reducing material fracture toughness.In the quest to balance high fracture toughness with good wear-resistance properties, Oral et al. recently proposed a noveltechnique to produce a depth-dependent variation in crosslinkdensity58. Vitamin E, which blocks crosslinking, is infusedinto polyethylene liners in a depth-dependent manner. A highlevel of vitamin E is infused into the bulk material, whereasa low level is infused into the surface; the entire liner is thensubjected to irradiation. The method of manufacture resultedin a material with a high level of crosslinking at the surface(conferring improved wear resistance to this region), whereasthe bulk of the material had a much lower level of crosslinking(thereby preserving its fatigue characteristics).

The process of crosslinking polyethylene also results intrapped residual free radicals, which over time lead to oxidativedegradation and embrittlement. Post-irradiation treatmentsto eliminate the free radicals involve heating the material toa temperature that is either above or below its melting point(remelting and annealing, respectively). The ability of either

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approach to fully eliminate residual free radicals and therebyavoid in vivo oxidative degradation is being explored by anumber of investigators. At the recent annual meeting of theOrthopaedic Research Society, Currier et al. reported that thefree radical concentration and oxidative index of annealedand remelted highly crosslinked polyethylene liners and tibialtrays in knee arthroplasty implants were measured as a func-tion of time59. Pristine, never-implanted annealed and remeltedcomponents were assessed immediately after removal fromtheir protective packaging and after shelf-aging in air. Eighty-four retrieved bearings from both annealed and remeltedgroups that had been implanted for periods of up to ten yearswere also assessed. The authors found free radicals in the never-implanted annealed components, whereas free radicals werenot found in the remelted group. The free radical content in-creased in the annealed components as a function of time ofshelf-aging, whereas that of the remelted components did not.Finally, oxidation was present in the retrieved annealed andremelted components, both of which increased as a function oftime after in vivo implantation. The clinical relevance of thesefindings will only become clear as the number of retrievedannealed and remelted implants increases. Nonetheless, thedata suggest that careful monitoring of highly crosslinkedpolyethylene components is warranted.

Metal-on-metal is the only bearing combination avail-able for use in surface replacements. However, concerns overthe consequences of the release of metal ions into the local andsystemic environment have led to a number of studies aimed atgaining a more thorough understanding of the wear mecha-nisms of this bearing combination. While it has been previouslyshown that a tribological reactive layer exists between thesurfaces of metal-on-metal articulations, the constituents ofthat layer and its role in wear have only recently been explored.In a seminal paper, Wimmer et al. described the layer as ananocrystalline composite of synovial fluid-derived organicmaterial, ceramic, and metallic constituents60. Moreover, thetribological reactive layer was associated with changes in thebearing surface from that of a purely metallic composition tothat of an organic-metal composite. Given the contents ofthe layer and the associated changes in the bearing surfacematerial, it is likely that the presence of this layer avoids directmetal-on-metal contact, which in turn helps to explain theabsence of adhesive wear in these bearing systems61. The au-thors hypothesized that encouraging the formation and sta-bility of this layer may reduce wear rates and ion release fromthis bearing combination.

What’s New in Spine Basic ResearchHighlights in spine research include advancements in growth-factor delivery, the emergence of a possible naturally occurringcomparative model for idiopathic scoliosis, new markers andphysiology description for the intervertebral disc, and re-finements in tissue engineering toward a biological artificialdisc.

Clinical use of bone morphogenetic protein (BMP) asan autograft substitute for spine fusion has become more andmore prevalent, adding to the already burdensome cost ofbiological and durable spinal implants. Currently, the mostwidely used BMP in spine surgery is BMP-2 (INFUSE; Med-tronic, Minneapolis, Minnesota), which is delivered in milli-gram doses after soaking and adhesion onto collagen sponges.Preclinical studies demonstrated that the collagen sponge isimportant for BMP delivery as it allows the growth factor tobe localized and easily manipulated while limiting the imme-diate diffusion of BMP from the site of implantation. To betterlimit the diffusion of BMPs away from their site of implanta-tion, a synthetic BMP binding protein (BBP) has been de-veloped62. BBP is a cyclic nineteen-amino-acid peptide thatpotentiates the in vitro and in vivo osteoinductive capacity ofBMP-2 and BMP-7 by tightly binding the BMPs and acting asa slow-release reservoir63,64. The affinity of BBP for bindingBMP-2 is in the 0.5-nanomolar range, whereas the affinityfor binding BMP-7 is in the micromolar range64. This tightbinding was shown to produce a much slower elution of BMP-2,with approximately twofold more BMP-2 being retainedat serial time points up to one week when codelivered withBBP64. Interestingly, using the most effective ratios for BBP andthe BMPs, the investigators were able to obtain 90% fusionrates in a rat posterolateral spine fusion model with use ofBMP-2 or BMP-7 dosing that was 10% or 30% of the standardrespective dosing used to obtain 100% fusion. These studiessuggest that further improvement of the BBP or other similarmethods to create slow release of BMPs after implantation mayallow the use of smaller BMP doses clinically, providing im-proved safety from inflammatory complications, reduction inthe cost of these expensive biological agents, and, possibly,greater availability of BMPs.

Adolescent idiopathic scoliosis continues to attract con-siderable attention from investigators attempting to describecauses for this condition. Separate groups recently have re-ported adolescent idiopathic scoliosis-associated genes on thelong arm of chromosome 18 with use of genetic linkage anal-ysis65, case-control methodology, and polymerase chain re-action sequence analysis demonstrating an association betweenadolescent idiopathic scoliosis and specific estrogen receptorpolymorphisms66. Cellular and molecular biology analyses oftissue samples from patients and controls have suggestedthat the leucine-rich repeat protein chondroadherin may beuseful as a marker for adolescent idiopathic scoliosis67. Col-lectively, these studies help to better define the multifactorialcauses of adolescent idiopathic scoliosis. Adolescent idiopathicscoliosis has been found to be sevenfold to eightfold morecommon in girls than boys, to more commonly affect tall andthin children, and to show rapid progression of curves duringpeak growth velocity in adolescents.

Idiopathic scoliosis does not appear to spontaneouslyoccur commonly in other vertebrates, and comparative modelsof scoliosis have required pinealectomy, vertebral column

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stapling or tethering, or other similar procedures. Recentstudies have evaluated curveback guppies as a comparativemodel of spontaneous adolescent idiopathic scoliosis68,69. Thosestudies demonstrated that there is a female bias for severecurves69, that fish with more severe curves have longercorrected-length tails68, and that spine curvatures are typicallystable by the time the fish reach sexual maturity68, findings thatare all quite similar to those associated with human adolescentidiopathic scoliosis. The spinal deformity in the curvebackguppy is in the sagittal plane (kyphosis and lordosis) andtherefore does not look identical to the classical coronal de-formity associated with adolescent idiopathic scoliosis. Thismay prove to be an extremely useful model for further geneticstudies investigating how specific genetic manipulations affectthe sagittal curvature, spine growth, and other structural ob-servations (vertebral size, morphology, and position).

Intervertebral degenerative disc disease is another ‘‘hot’’topic in basic science spine investigations. Degenerative discdisease has considerable financial impact in terms of medicalresource utilization and days of lost work. The ability to detectdegenerative disc disease earlier in the course of the disease mayhelp to initiate appropriate treatment more quickly, and animproved understanding of the normal physiology of the discand the pathogenesis of degenerative disc disease may help toguide therapies to stop or reverse the process. The intervertebraldisc is an avascular structure with large amounts of hydratedproteoglycan and collagens I and II as well as smaller amountsof other structural and regulatory proteins. Sakai et al. identi-fied alpha-2-macroglobulin (A2M) and neural cell adhesionmolecule (NCAM) as two additional molecules present inrelative abundance in the nucleus pulposus70. A2M is a potentproteinase inhibitor and is thought to act as an aggrecanaseinhibitor in the disc, whereas NCAM is a cell surface proteininvolved in contact-mediated cell interactions and plays animportant role in the nervous system and in multiple tissuesduring development. Each of these proteins is thought to playa role in maintaining the normal physiology of the inter-vertebral disc. Iida et al., using rat and human disc cells,reported that proteinase-activated receptor-2 (PAR-2) is up-regulated in severely degenerated discs71. They reported thatPAR-2 activation results in upregulation of mRNA levels ofcatabolic ADAMTS and matrix metalloproteinases, demon-strating that the degenerative disc tissue itself contributes to theexpression of extracellular matrix-destroying enzymes thatfurther damage the disc extracellular matrix in a ‘‘vicious cy-cle.’’ Singh et al. and Furukawa et al. reported complementaryfindings concerning the small leucine-rich repeat proteoglycanprotein biglycan72,73. Small proteoglycans are thought to beimportant for regulating collagen fibril formation and areknown to interact with several extracellular matrix molecules;however, the specific function of biglycan is not known. Withuse of human disc tissue samples from donors ranging in agefrom thirty-two to eighty years, biglycan levels were shown toincrease in disc tissues with age, a finding suggesting that bi-

glycan is upregulated to preserve the disc and to prevent de-generation72. Similarly, biglycan-deficient mice demonstrategreatly accelerated disc degeneration at early ages in compari-son with control animals, suggesting that biglycan is importantfor disc homeostasis. Combining the results of these studies forguiding therapeutics suggests that upregulation of A2M orbiglycan or downregulation of PAR-2 early in the degenerativedisc disease process may help to stop progression of the diseaseprocess and may be valuable markers in comparative studiesassessing molecular therapies74-76.

Tissue engineering a biological alternative for total discreplacement involves the development of a scaffold that re-sembles the intervertebral disc and reproduces its mechanicalproperties, the establishment of cell populations capable ofbecoming native to the anulus fibrosus and nucleus pulposus,and stable integration of the composite engineered disc intothe graft site. Recent advances have been made in the first twoof these steps. Elliott and colleagues reported an update ontheir work with electrospun nanofibrous scaffolds to produceanulus fibrosus-like tissue77,78. Their earlier work utilized apoly-epsilon-caprolactone scaffold seeded with bovine anulusfibrosus cells and showed that the tissue had increasing gly-cosaminoglycan and collagen production over time as well asimprovement in mechanical properties. The subsequent studyinvolved the use of agarose to create a nucleus pulposus anda nanofibrous scaffold seeded with bovine mesenchymal stemcells showing mechanical properties, matrix production, andcell morphologies similar to the native tissues as the discsmatured in long-term in vitro culture.

A somewhat different approach for disc tissue engi-neering was reported by Bowles et al.79. With this approach,a collagen gel is seeded with ovine anulus fibrosus cells and thenis allowed to contract in culture around a polyethylene or al-ginate central nucleus pulposus. Contraction and collagenorientation were measured, and the authors concluded that,with optimization of the technique, replication of the nativecollagen alignment observed in the disc should be possible.Regarding cell populations for seeding onto scaffolds, therehave been reports that multipotent cells derived from fat makeadequate donor cells to repopulate the nucleus pulposus ina canine model80 and that similar multipotent cell populationsexist in the nucleus pulposus81 and anulus fibrosus82 in humansand comparative models83. Successful production of thesefirst-generation composites of in vitro tissue-engineered discssuggests that biological total disc replacements are feasible.The methods and technology for securing these tissue-engineered discs into surgically prepared disc spaces will bean area of future investigation.

Articular CartilageRecently, there have been several important advances in un-derstanding the genetic predisposition to cartilage deterioration,and, as a result, proteomic profiling for cartilage and arthritisresearch is within reach of becoming a clinical tool. Genetic and

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proteomic tools can be used to identify a genetic predispositionto a disorder, and the resulting information can be leveraged toidentify therapeutic targets to address the pathology that resultsfrom the genetic variation.

As an example, in one study, a variant on chromosome 7(the C allele of re3815148 on chromosome 7q22) was foundthat influences susceptibility to the prevalence and progressionof osteoarthritis84. The gene at this site encodes for GPR22,a G protein-coupled receptor that might serve as a therapeutictarget. Another study demonstrated that osteoarthritis-relatedbiomarkers exhibit heritability85. In a large multigenerationalextended family, osteoarthritis-related biomarkers includinghyaluronan, cartilage oligomeric matrix protein, N-propeptideof type-IIA collagen, and type-II collagen neoepitope werefound to have substantial heritable components. With use ofa gene-comparison approach, another report showed clear dif-ferences in gene-expression profiles between patients withKashin-Beck disease, which is endemic in children three to twelveyears of age in northwestern China, and those with primary os-teoarthritis from non-Kashin-Beck-endemic areas in northwest-ern China86. These results challenge the paradigm that Kashin-Beckis caused by environmental pressures (such as mycotoxin pro-ducing fungi in cereal, humic acid in drinking water, or sele-nium deficiency) and rather suggest that there is an underlyinggenetic basis for the disorder. Collectively, genetic approacheswill provide a quantifiable basis to further our understandingof the multifactorial nature of osteoarthritis regardless of race orethnicity and to identify potential therapeutic targets.

Proteomic profiling of osteoarthritis will provide a clearerpicture of the biological activity present during any stage ofcartilage degeneration or repair. Genomics identifies possiblecandidate genes involved in cartilage degeneration, but geno-mic studies do not tell the whole story. They do not take intoaccount post-translational modification of proteins or protein-protein interactions, nor do they account for the effects of

drugs such as corticosteroids on protein function. Blood,plasma, serum, urine, cartilage, synovial membrane, or syno-vial fluid have all been subjected to proteomic analysis and haveidentified novel protein biomarkers of osteoarthritis87. Thesesame technologies have been employed in basic-science in-vestigations to identify novel proteins involved in cartilagedevelopment and the early response to mechanical stress inchondrocytes88.

A clinical vision for proteomic and genomic applicationsin cartilage research is to provide a test to determine a patientand stage-specific biological and biochemical profile. This in-formation could then be used to generate a personally uniquediagnosis and targeted treatment plan to address that specificindividual’s disease characteristics and symptoms.

ConclusionsThe pace of orthopaedic basic research continues to quickenand expand. The development of new laboratory tools andtechniques have resulted in continued advances in basic or-thopaedic research. The challenge for orthopaedic clinicians isto develop ways to test these basic findings in rigorous clinicaltrials. Ultimately, clinician-scientists need to help define theagenda for translational research studies.

Scott A. Rodeo, MDDemetris Delos, MDAlex Weber, MDXiaodong Ju, MDMatthew E. Cunningham, MD, PhDLisa Fortier, DVM, PhDSuzanne Maher, PhDThe Hospital for Special Surgery,535 East 70th Street, New York, NY 10021.E-mail address for S.A. Rodeo: [email protected]

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