Managemen Cartilage Defect

Current Concepts Review

Management of Articular CartilageDefects of the Knee

By Asheesh Bedi, MD, Brian T. Feeley, MD, and Riley J. Williams III, MD

Articular cartilage has a poor intrinsic capacity for healing. The goal of surgical techniques to repair articularcartilage injuries is to achieve the regeneration of organized hyaline cartilage.

Microfracture and other bone marrow stimulation techniques involve penetration of the subchondral plate in orderto recruit mesenchymal stem cells into the chondral defect. The formation of a stable clot that fills the lesion is ofparamount importance to achieve a successful outcome.

Mosaicplasty is a viable option with which to address osteochondral lesions of the knee and offers the advantageof transplanting hyaline cartilage. However, limited graft availability and donor site morbidity are concerns.

Transplantation of an osteochondral allograft consisting of intact, viable articular cartilage and its underlyingsubchondral bone offers the ability to address large osteochondral defects of the knee, including those involvingan entire compartment.

The primary theoretical advantage of autologous chondrocyte implantation is the development of hyaline-likecartilage rather than fibrocartilage in the defect, which presumably leads to better long-term outcomes and lon-gevity of the healing tissue.

Use of synthetic scaffolds is a potentially attractive alternative to traditional cartilage procedures as they arereadily available and, unlike allogeneic tissue transplants, are associated with no risk of disease transmission.Their efficacy, however, has not been proven clinically.

The management of articular cartilage defects continues to beone of the most challenging clinical problems for orthopaedicsurgeons. Articular cartilage is a highly organized tissue withcomplex biomechanical properties and substantial durability1.However, it has a poor intrinsic capacity for healing, anddamage from trauma or degeneration can result in morbidityand functional impairment2. Untreated lesions can lead todebilitating joint pain, dysfunction, and degenerative arthritis.

Cartilage repair strategies include debridement; bonemarrow stimulation; and cell-based, cell plus scaffold-based,and whole-tissue transplantation techniques3. In this review,we discuss the basic science, indications, advantages, short-comings, and outcomes of each of these interventions in orderto provide an evidence-based assessment for the treatment ofthese conditions.

Bone Marrow Stimulation: MicrofractureBone marrow stimulation is the most frequently used techniquefor treating small symptomatic lesions of the articular cartilagein the knee. These procedures are technically straightforward,and the costs are low compared with those of other treatmentmodalities. Bone marrow stimulation techniques involve per-foration of the subchondral plate in order to recruit mesen-chymal stem cells from the bone marrow space into the lesion4,5.The mesenchymal stem cells are able to differentiate into fi-brochondrocytes, which contribute to fibrocartilage repair ofthe lesion. However, the overall concentration of the mesen-chymal stem cells is quite low and declines with age6. Theformation of a stable blood clot that maximally fills thechondral defect is important, and it has been correlated withthe success of bone marrow stimulation procedures7. Unstable

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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COPYRIGHT 2010 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED

J Bone Joint Surg Am. 2010;92:994-1009 d doi:10.2106/JBJS.I.00895

clots that are only partially adherent to or fill only a portion ofthe defect will result in suboptimal repair7.

Reparative fibrocartilage consists of type-I, type-II, andtype-III collagen in varying amounts8,9. The fibrocartilage doesnot resemble the surrounding hyaline cartilage and has lesstype-II collagen. Unlike other cartilage restoration techniques,bone marrow stimulation does not involve transfer of chon-drocytes into the lesion.

Creating a contained lesion is critical to achieving astable base for filling the defect with a clot and adhesion of theclot. If the lesion is not shouldered by a stable rim of healthycartilage, achieving a stable clot may be more difficult10-12. Thecalcified cartilage layer at the base of the lesion must be re-moved as well (Figs. 1-A through 1-D). Removal of this layer isimportant for clot adhesion and the ultimate success of themicrofracture technique13. The prepared channels must be ofsufficient depth to ensure penetration of the subchondral plateand communication with the marrow. Fatty droplets should beseen to emanate from the channel apertures to confirm thatadequate depth has been achieved.

The postoperative regimen after bone marrow stimula-tion procedures is demanding and has been reported to be acritical aspect of the ultimate efficacy14. Patients with a femoralcondylar lesion are initially treated with continuous passivemotion with a 0 to 60 range of motion for six weeks post-operatively15. Studies have shown that continuous passivemotion improves cartilage nutrition and stimulates mesen-chymal stem-cell differentiation16-19. The patient typically re-mains non-weight-bearing with the use of crutches for sixweeks. Patients who have undergone microfracture of a pa-tellar or trochlear defect are allowed to bear weight as toleratedpostoperatively, but knee motion is restricted from 0 to 40 ina brace20,21. Continuous passive motion is initiated immediatelyand used, within this arc of motion, for approximately six toeight hours daily. At two months, unrestricted motion is typ-ically allowed and closed-chain exercises are initiated. Short-arcclosed-chain concentric and eccentric muscle strengthening iseffective and protects the patellofemoral articulation. Typically,a return to full activities is permitted at three months after afull, painless range of motion is achieved20,21.

Outcomes (See Appendix)Steadman et al. reported what we believe to be the first long-term follow-up study of microfracture, in which seventy-oneknees were followed for an average of eleven years20. The pa-tients all had a traumatic full-thickness chondral defect, had nomeniscal or ligament injury, and were less than forty-five yearsof age. At the time of final follow-up, the patients had signif-icant improvement in multiple clinical outcome measures (p 8 mm are harvested, filling of the defectwith biocompatible material may help to prevent morbidity atthe donor site45. Feczko et al. evaluated healing of donor sitedefects treated with hydroxyapatite, carbon fiber, polyglyconateB, compressed collagen, and two versions of polycaprolactonesin a canine model45. While all of these substitutes demonstratedgood integration with the surrounding cancellous bone, onlylimited repair-tissue formation was evident even at thirty weekspostoperatively. Compressed collagen, however, yielded themost favorable fibrocartilage covering as seen on second-lookarthroscopy and histological evaluation.

The effect of surface plug incongruity on articularsurface contact pressures has been evaluated. Koh et al. as-sessed contact pressures with controlled axial loads on swineknees with variable plug positions46. The study demonstratedthat flush or slightly sunk grafts could restore contact pressuresto nearly normal levels, but that elevated angled grafts ad-versely increased contact pressures. The authors also demon-strated that grafts seated 0.5 to 1 mm proud relative to theadjacent surface resulted in a 50% increase in mean contactpressures47.

The biomechanical stability of the plug after autologousosteochondral transplantation is important and is affected byseveral technical factors. In experimental models, osseous in-

Fig. 2-A Fig. 2-B

Fig. 2-C

Figs. 2-A, 2-B, and 2-C Reprinted from: Hangody L,

Rathonyi GK, Duska Z, Vasarhelyi G, Fules P, Modis L.

Autologous osteochondral mosaicplasty. Surgical

technique. J Bone Joint Surg Am. 2004;86 Suppl 1:65-

72. Fig. 2-A Schematic drawing demonstrating the

autologous osteochondral transplantation technique. A

chisel can be used to harvest osteochondral plugs from

the blue-shaded regions along the margins of the

trochlea or adjacent to the notch. Fig. 2-B The donor

region along the trochlear margin can be accessed

through a small arthrotomy and visualized with the knee

in extension. Fig. 2-C Flexion of the knee can expose

the recipient chondral defect through the same expo-

sure and allow placement of grafts in the desired

configuration to fill the lesion.

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MA N AG E M E N T O F AR T I C U L A R CA RT I L AG E DE F E C T S O F T H E KN E E

tegration of the graft and recipient has been observed at fourweeks48. Prior to this healing, the press-fit mechanism is criticalfor maintaining a stable graft position. Plugs of a matcheddepth (i.e., with the donor plug length and recipient defectlength matched) are more stable than short plugs (i.e., with acavity left at the bottom of the defect), which rely exclusivelyon circumferential frictional forces for stability49. This stabilityof short plugs is further compromised in multiple plug con-figurations in which gaps between the round plugs and sur-rounding bone reduce frictional forces50.

The effect of impact loading of the hyaline cartilageduring delivery of the osteochondral plug has been evaluated.Chondrocyte viability is critical, as each cell maintains adiscrete maximum volume of robust matrix around it51,52.Whiteside et al. demonstrated that the percentage of chon-drocyte death was predicted more strongly by the mean forceof impact than by the number of impacts required duringplacement of the graft48. Huntley et al. identified a markedmarginal zone of cell death with a thickness of ;400 mm atthe plug periphery within two hours after harvesting53. Usinga planar model for mosaicplasty, they demonstrated thatapproximately one-third of the mosaicplasty surface wasnonviable (secondary to the 24% rate of marginal zone celldeath and 9% rate of interposed dead space between grafts).Gulotta et al. recently corroborated these findings of chon-drocyte necrosis, apoptosis, and matrix degradation afterpress-fit osteochondral autograft implantation in a rabbitmodel54.

Outcomes (See Appendix)The outcomes of autologous mosaicplasty for symptomaticchondral defects have been encouraging, and the procedurehas been used with success2,55-57. Hangody and Fules evaluatedthe largest series of mosaicplasties (831) performed for local-ized Outerbridge grade-III or IV chondral lesions58 and re-ported good-to-excellent results for 92% of femoral lesions,87% of tibial lesions, and 79% of patellofemoral lesions58. Therate of donor site morbidity, as assessed with the Bandi score58,was 3%. Eighty percent of the second-look arthroscopic pro-cedures performed in eighty-five patients demonstrated con-gruent gliding surfaces and histological evidence of transplantedhyaline cartilage. Ozturk et al. reported on the clinical andradiographic outcomes of nineteen patients with a grade-IVchondral lesion treated with mosaicplasty 59. The mean Lys-holm score27,28 improved from 46 points preoperatively to 88points postoperatively, with an 85% rate of good-to-excellentresults after a mean duration of follow-up of thirty-two months.Magnetic resonance imaging revealed excellent fill and con-gruency of

Fresh AllograftsFresh osteochondral allografts are typically utilized, as freezingand cryopreservation have both been shown to decreasechondrocyte viability. Although the critical threshold of viablechondrocytes necessary to achieve clinical success remainsunknown, chondrocyte function is critical to maintain thedynamic homeostasis of the extracellular matrix and is animportant factor in ensuring long-term allograft survivalin vivo65,66. Traditionally, grafts have been harvested, stored in

lactated Ringer solution at 4C, and transplanted within oneweek. Recently, there has been a shift toward allograft storagein culture medium67. At fourteen days, specimens stored inlactated Ringer solution demonstrated an 80% rate of chon-drocyte viability compared with a 91% rate for those stored inculture medium68. This is particularly important in the settingof modern tissue-banking procedures for microbiologicalscreening and recipient matching, which have necessitatedprolonged periods of storage prior to implantation.

Fig. 3-A Fig. 3-B

Fig. 3-C

Figs. 3-A, 3-B, and 3-C Reprinted from: Williams RJ 3rd, Ranawat

AS, Potter HG, Carter T, Warren RF. Fresh stored allografts for the

treatment of osteochondral defects of the knee. J Bone Joint

Surg Am. 2007;89:718-26. Fig. 3-A Harvesting of an os-

teochondral allograft dowel from a hemicondylar specimen with

the size and radius of curvature matched to the recipient. Fig. 3-B

Implantation with circumferential flush congruity at the recipient

site for the treatment of an osteochondritis dissecans lesion of

the femoral condyle. Corresponding pen marks are made at the

12 oclock, 4 oclock, and 8 oclock positions in an effort to

optimally match the orientation and surface congruity between

the donor graft and the recipient defect. Fig. 3-C Sagittal fast

spin-echo magnetic resonance image made at twenty-four

months after implantation of the osteochondral allograft. There

is excellent lesion fill and congruency with the adjacent native

cartilage interface. The graft demonstrates articular cartilage

signal (arrow) that is isointense compared with the native hyaline

cartilage.

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The matrix properties and chondrocyte viability ofstored fresh osteochondral allografts have been evaluated.Allen et al.69 demonstrated preserved biomechanical andmatrix characteristics but decreased chondrocyte density andmetabolic activity in specimens stored for twenty-one daysbefore implantation. The superficial zone of cartilage wasmost severely affected. Pearsall et al. studied sixteen refrig-erated allografts and reported progressively less matrixstaining with prolonged refrigeration and a mean chondro-cyte viability rate of 67% at an average of thirty days70. Al-though the biomechanical properties and matrix integrity ofhyaline cartilage are preserved for up to twenty-eight days,the number of viable chondrocytes has been shown to de-crease progressively over that time71. Nonetheless, the rate ofchondrocyte viability was approximately 50% at sixty days,which may represent a potentially longer window for suc-cessful implantation.

A number of studies have confirmed the long-term sur-vival of donor chondrocytes after transplantation68,72-74. Hyalinecartilage is a relatively immunoprivileged tissue with an avas-cular matrix that shields donor chondrocytes from the hostimmune reaction. Williams et al. reported on twenty-six re-trieved osteochondral allograft specimens after an average sur-vival time of forty-two months75. The rate of chondrocyteviability was 82%, and there was evidence of allograft boneincorporation in most specimens. The allograft bone is necroticand is replaced by creeping substitution, but it provides astructural scaffold to support the articular surface during thisgradual incorporation.

Cryopreserved AllograftsCryopreservation involves rate-controlled freezing of speci-mens in a nutrient-rich, cryoprotectant medium (glycerol ordimethyl sulfoxide) to minimize cellular freezing and maintaincell viability. Recently, Gole et al. found a 77% rate of chon-drocyte viability at one year in cryopreserved osteochondralallografts implanted into load-bearing sites in an animalmodel76. However, another study demonstrated degenerativechanges at the articular surface of cryopreserved allograftscompared with fresh allografts at five years65. A study of anovine model by Schachar et al. demonstrated that the mem-brane integrity of the allograft chondrocytes immediately fol-lowing cryopreservation is the most reliable predictor of thelong-term outcome of the graft77. Use of cryopreserved allo-grafts achieved an overall intermediate result compared withthe results associated with the use of fresh autografts (thepositive controls in the study).

Fresh-Frozen AllograftsFresh-frozen preservation of allografts offers the advan-tages of reduced immunogenicity and decreased diseasetransmission at the expense of reduced chondrocyte via-bility. The process of deep freezing to 280C destroys theviability of all articular cartilage cells within the graft78, andretrieval studies have demonstrated deterioration of cells andmatrix over time79.

Outcomes (See Appendix)A number of retrospective studies have been performed toassess the outcomes of osteochondral allograft transplantationfor the treatment of focal osteochondral defects of the knee,and they have demonstrated good-to-excellent results. Chuet al. reported on fifty-five knees at a mean of six years aftertransplantation of fresh osteochondral allografts80. Eighty-fourpercent of the knees treated for an isolated focal defect wererated as having a good-to-excellent outcome with use of theMerle dAubigne and Postel scale81, while similar success wasachieved in only 50% of the knees that had undergone trans-plantation for the treatment of bipolar lesions (i.e., articulatingchondral defects on both the tibial and the femoral side).Ghazavi et al. reported the results at a mean of 7.5 years fol-lowing 126 procedures for the transplantation of fresh os-teochondral allografts for the treatment of posttraumaticcondylar defects82. While a good-to-excellent result was achievedin 85% of the knees, an increased rate of failure was seenin the setting of bipolar lesions and limb malalignment andin patients insured by Workers Compensation. Bugbee andConvery reported the outcomes at a mean of fifty monthsafter the use of fresh osteochondral allografts in ninety-sevenknees83. An 86% success rate was achieved in the treatment oflarge unipolar defects (mean size, 8 cm2), whereas only a 54%success rate was seen after the management of bipolar lesions.Other factors contributing to failure in this series includeddiffuse arthritis, inflammatory conditions, and lower-extremitymalalignment. Davidson et al. reported on sixty-seven patientswho had received an osteochondral allograft for the treatmentof a symptomatic femoral chondral lesion84. At a mean of fortymonths postoperatively, significant improvements in both theIKDC26 and the SF-36 scores, as compared with the preoper-ative scores, were noted (p = 0.002). So-called second-lookarthroscopy was performed in ten knees and revealed repairtissue that was grossly similar to native cartilage with a per-sistence of a small seam surrounding the cylindrical grafts.Chondrocyte viability and density in the repair tissue did notdiffer from those of native (control) cartilage retrieved withbiopsy. Overall, these studies indicate that, while allografttransplantation is largely successful when done for appropriateindications, outcomes are less reliable and predictable in thesettings of primary osteoarthritis, inflammatory arthropathy,limb malalignment, and bipolar lesions of the knee.

Favorable results have been reported after allograft trans-plantation for the treatment of osteochondritis dissecans lesionsof the knee. In a study of sixty-three knees followed for a meanof 4.3 years, Bugbee et al. reported an 89% rate of good-to-excellent functional outcomes as rated with the modifiedMerle dAubigne and Postel scale85. Emmerson et al. reportedthe outcomes at a mean of 7.7 years after osteochondral allo-graft transplantation for osteochondritis dissecans lesions86.The mean allograft size was 7.5 cm2, and either a dowel or shelltechnique was utilized on the basis of the lesion location andthe surgeons preference. The authors reported a 72% rate ofgood-to-excellent outcomes as rated with the Merle dAubigneand Postel scale. The preliminary results of osteochondral al-

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lograft transplantation for treatment of condylar osteonecrosishave also been encouraging. Gortz and Bugbee found that 88%of forty-three patients treated with allograft transplantation forosteonecrosis were satisfied with the result, and 82% thoughtthat the condition of the knee was improved87. At a mean of 4.5years, none of the patients had required conversion to a totalknee arthroplasty.

The use of osteochondral allografts for the managementof patellofemoral chondral lesions has yielded variable results.Chu et al. reported a good-to-excellent outcome in five patientsat a mean of six years after they had undergone transplantationof a fresh osteochondral allograft into an isolated patellar de-fect80. Jamali et al., however, reported only a 60% rate of good-to-excellent results at a mean of 7.8 years after transplantationof a fresh osteochondral allograft into the patellofemoral jointof twenty knees88. Five knees in that series subsequently re-quired salvage with revision allograft transplantation, patel-lectomy, arthrodesis, or total knee replacement.

Extended storage time for allografts enhances the effec-tive use of these tissues by allowing improved identification ofsuitable recipients and more feasible scheduling of operativetreatments. Williams et al. demonstrated no correlation be-tween functional outcome scores and graft storage times ofup to forty-two days89. Eighteen of nineteen patients demon-strated a normal appearance of the articular cartilage onmagnetic resonance imaging at a mean of twenty-five months(Fig. 3-C). A similar study corroborated these results as itdemonstrated no correlation between the duration of storageof fresh grafts before implantation and the cellular viability ordensity at a mean of forty months postoperatively84. McCullochet al. reported that 84% of twenty-five patients were satisfiedtwo years following allograft transplantation with use of aprolonged fresh graft that had been stored for a mean oftwenty-four days (range, fifteen to forty-three days)90. LaPradeet al. reported on twenty-three consecutive patients who hadundergone treatment of a focal chondral defect of the femoralcondyle with a refrigerated osteochondral allograft stored for amean of 20.3 days (range, fifteen to twenty-eight days)91. Themean IKDC score improved from 52 points at baseline to 68.5points at the time of final follow-up (at three years), with goodincorporation and a stable position in the host bone in twenty-two of the twenty-three cases.

Osteochondral allograft transplantation has also beeninvestigated in survivorship studies. Gross et al. reported sur-vival rates of 95% at five years, 85% at ten years, and 73% atfifteen years after osteochondral allograft transplantation forposttraumatic femoral condylar lesions92. Sixty-eight percent ofthe patients in their series had concomitant limb-realignmentprocedures, and they were not found to have any differences inoutcomes or complications as compared with the patients whodid not have such procedures. Histological characteristics fa-voring long-term survival included viable chondrocytes,functional preservation of the matrix, and complete replace-ment of the graft with host bone. The authors concluded that ahigh density of viable chondrocytes and mechanical stability ofthe allograft are crucial for long-term survival. In a series of

ninety-two knees that underwent fresh allograft transplanta-tion, Beaver et al. found survival rates of 75% at five years, 64%at ten years, and 63% at fourteen years66. Failure rates werehigher in patients older than sixty years of age or in those withbipolar lesions.

Autologous Chondrocyte ImplantationAutologous chondrocyte implantation, originally described in199493, is an innovative, novel technique to restore cartilagecells into full-thickness chondral defects. The primary theo-retical advantage of autologous chondrocyte implantation isthe development of hyaline-like cartilage rather than fibro-cartilage in the defect, presumably leading to better long-termoutcomes and longevity of the healing tissue. However, theprocedure is not without limitations. It involves a minimum oftwo operations, one for tissue harvest and the other for cellimplantation. Furthermore, autologous chondrocyte implan-tation is technically demanding, and complications related tothe periosteal graft have been reported94,95.

Outcomes (See Appendix)The initial outcomes of autologous chondrocyte implantationwere reported by Brittberg et al.93, in a study of twenty-threepatients ranging in age from fourteen to forty-eight years andwith lesions ranging in size from 1.6 to 6.5 cm2. The averageduration of follow-up was forty-four months. Biopsies showedthat eleven of fifteen femoral transplants and one of sevenpatellar transplants had the appearance of hyaline cartilage.Fourteen of the sixteen patients with a femoral condylar lesionhad a good-to-excellent result. Zaslav et al. recently performeda prospective clinical study to determine the effectiveness ofautologous chondrocyte implantation in patients with failedprior treatments for articular cartilage defects of the knee96.One hundred and twenty-six patients were followed for a meanof four years in this multicenter study. At the time of follow-up, 76% of the patients were deemed to have a good clinicalresult based on knee pain, quality of life, and overall health.The results did not differ if the patient had had a prior marrowstimulation procedure or debridement. The authors concludedthat autologous chondrocyte implantation was effective inproviding pain relief as well as an improved quality of life forpatients who had undergone a previous operative procedurefor the defect.

Many studies have compared autologous chondrocyteimplantation with other cartilage restoration techniques.Anderson et al. compared autologous chondrocyte implantationwith microfracture in a prospective study97. There were twenty-three patients in each group, and all lesions were >2 cm2.There was a mean improvement in the overall condition scorein both groups (1.3 points in the microfracture group and 3.1points in the autologous chondrocyte implantation group, p 8 mm in fivepatients113. With this technique, two membranes are templatedand cut to the size of the defect. The first membrane is securedwith fibrin glue to the base of the prepared defect with itsrough cell-loaded surface facing up. The second membrane isimplanted on top of the first one with the cell surface downand is sealed with fibrin glue to the adjacent cartilage. Withinsix months after the surgery, all five patients had improvedCincinnati knee, Stanmore functional rating, and visual ana-logue pain scores27,28. Four patients had arthroscopy at one yearpostoperatively, and stable reparative tissue (ICRS grade II intwo knees and grade III in two) was seen.

Hyaluronan-Based ScaffoldsHyaluronan-based scaffolds are another approach to cartilagerepair that employs a biodegradable, three-dimensional scaf-

Fig. 4

A: To create tissue-engineered collagen scaffolds, harvested autologous chondrocytes are cultured in

an acellular honeycomb collagen matrix for six weeks with mechanical loads applied to stimulate

matrix production and mature organization. B: An arthroscopic photograph made three months after

implantation of a tissue-engineered collagen scaffold (outlined by red dots) seeded with autologous

chondrocytes for treatment of a focal femoral condyle chondral defect. Note the excellent incorpo-

ration, fill, and congruous margin with the adjacent native cartilage. C: Sagittal fast spin-echo

magnetic resonance image of a focal medial femoral chondral defect (left) and T2-mapping sagittal

images, made at one year (middle) and two years (right) postoperatively, demonstrating progressive

maturation and stratification of repair tissue to approach the appearance of native articular cartilage

(Images courtesy of Dr. Dennis Crawford, MD, Portland, Oregon).

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fold for cell proliferation. A benzylic ester of hyaluronic acidis used to generate a scaffold with variably sized intersticesbetween 20-mm-thick fibers. In addition to providing thestructural support for cell contact and matrix deposition, thethree-dimensional nonwoven scaffold prevents dedifferentia-tion of harvested autologous chondrocytes even after longperiods of ex vivo culture expansion and promotes the ex-pression of chondrocyte-specific markers. Gradual degrada-tion occurs as the cells start secreting their own extracellularmatrix to allow for an optimal transition between newlyformed and existing tissue114-116.

OutcomesThe results of implantation of hyaluronan-based scaffoldsseeded with autologous chondrocytes to treat chondral defectshave been encouraging. Histological analysis has shownhyaline-like cartilage in the lesion as soon as twelve monthsafter implantation. Marcacci et al. reported the clinical out-comes at a minimum of twenty-four months followingarthroscopic implantation of a seeded hyaluronan-basedscaffold in a prospective series of seventy patients with asymptomatic chondral defect117. All lesions were Outer-bridge grade III or IV118, and their mean size was 2.4 cm2.Fifteen patients underwent a second-look arthroscopy attwelve to thirty-six months. There was improvement inthe IKDC subjective and objective scores from the preopera-tive examination to the twenty-four, thirty-six, and forty-eight-month follow-up examinations, although the objectivescores improved more for patients with a traumatic or os-teochondritis dissecans lesion than they did for those with adegenerative lesion. Arthroscopic evaluation revealed com-plete coverage of the defect with a hyaline-like reparativetissue. The outcomes were not compromised by larger de-fects or a concomitant meniscal or lower-extremity realignmentprocedure.

Gobbi et al. evaluated the efficacy of hyaluronan-basedscaffolds seeded with autologous chondrocytes as a treatmentfor symptomatic patellofemoral chondral lesions119. Thirty-twochondral lesions with a mean size of 4.7 cm2 were treated withdebridement and scaffold implantation through an arthro-scopic or mini-arthrotomy approach. Outcomes were assessedwith the ICRS-IKDC score as well as magnetic resonanceimaging at twelve and twenty-four months postoperatively.The ICRS-IKDC scores improved, with only 18% of the pa-tients having a score of A or B preoperatively and 91% havingsuch a score at twenty-four months postoperatively. Magneticresonance imaging at twenty-four months revealed that 71% ofthe cases had complete filling, nearly normal signal, and ab-sence of subchondral edema, with a positive correlation withclinical outcomes. Second-look arthroscopy in six cases re-vealed complete filling of the defects with reparative tissue thatwas characterized as hyaline-like histologically.

Marcacci et al. presented the results of an ongoingmulticenter study of the subjective and functional outcomes ata mean of thirty-eight months following treatment with ahyaluronan-based scaffold seeded with autologous chondro-

cytes in a cohort of 141 patients117. Ninety-two percent of thepatients had improvement in the IKDC score, and 96% hadthe involved knee rated as normal or nearly normal by thetreating surgeon. Kon et al. compared the clinical outcomes,after five years of follow-up, of treatment with a cell-seededhyaluronan-based scaffold and treatment with a microfracturerepair technique in patients with a grade-III or IV chondraldefect120. Both groups showed significant improvement inIKDC scores, but better improvement in the IKDC objectiveand subjective scores was observed in the hyaluronan-based-scaffold group. The return to sports at two years was similar inthe two groups; however, it remained stable after five years inthe hyaluronan-based-scaffold group but not in the micro-fracture group.

Tissue-Engineered Collagen Matrices Seeded withAutologous ChondrocytesTissue-engineered collagen matrices seeded with autologouschondrocytes provide a promising new technology with whichto address chondral lesions of the knee. This procedure involvesharvesting of the autologous chondrocytes from non-weight-bearing aspects of the knee in a manner analogous to conven-tional autologous chondrocyte implantation. The cells are thenloaded onto a type-I bovine collagen honeycomb matrix and arecultured ex vivo (Fig. 4). In distinction to second-generationtechniques, however, the cell-scaffold construct is subsequentlysubjected to mechanical stimulation with use of a proprietarybioreactor that applies hydrostatic pressure to the chondro-cytes for a minimum of seven days. A lack of mechanicalstimulation may be responsible for chondrocyte dedifferenti-ation and inferior mechanical properties, and the applicationof mechanical load stimulates chondrocytes to produce in-creased amounts of type-II collagen, aggrecan, and other criticalcomponents of a hyaline extracellular matrix121-123.

Use of tissue-engineered scaffolds with autologous chon-drocytes requires a staged procedure that begins with an ar-throscopic biopsy for chondrocyte harvest, which is followedby an arthrotomy for implantation. The harvested chondro-cytes are cultured in the acellular honeycomb collagen matrixfor six weeks. A mini-arthrotomy is then performed to providedirect access to the chondral lesion. The lesion is debrided tocreate stable vertical edges, and meticulous hemostasis is ob-tained. A template of the dimensions of the chondral defect isthen obtained, typically with use of a malleable device thatdelineates its vertical margins. The collagen membrane ismeticulously cut to match the shape of the lesion, but withapproximately 10% greater dimensions in anticipation of slightshrinkage after implantation and fixation. The implant is fixedwith use of a proprietary collagen bioadhesive, which is appliedto the base of the defect and evenly coated over the implant andits seam to the adjacent native cartilage.

OutcomesGiven the relatively recent development of this technology,reports on the clinical outcomes associated with tissue-engineered collagen matrices seeded with autologous chon-

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drocytes are very limited. However, Crawford et al. recentlyreported the results of a phase-I clinical trial of eight patientswith twenty-four months of follow-up124. Outcomes were as-sessed with use of a visual analogue pain scale and the IKDCsubjective score. Serial evaluations were performed at six,twelve, and twenty-four months. As a secondary outcome,cartilage repair quality was evaluated with magnetic resonanceimaging at three, twelve, and twenty-four months (Fig. 4, C).No serious adverse events were identified. By twelve months,all patients had decreased pain scores (mean, 0.9 1.5 points)compared with the baseline scores (mean, 3.3 2.8 points). Attwenty-four months, the pain scores remained significantlylower than the baseline scores, and the IKDC score had in-creased in seven of the eight patients, to a mean of 76 17points from a mean of 57 25 points at baseline. Magneticresonance imaging showed that seven of the eight patients hadnearly complete or complete filling of the defect at one year,and six of the eight retained good filling at two years. Magneticresonance imaging was performed to assess the collagen matrixcontent and organization. At twenty-four months, four of theeight patients had stratification of T2 values similar to that ofthe adjacent hyaline cartilage124 (Fig. 4, C). These promisingresults prompted a prospective, randomized phase-II trial ofthirty patients to compare this technique with microfracture;this trial is currently in progress.

OverviewIn conclusion, the management of articular cartilage lesions ofthe knee is a challenging problem for orthopaedic surgeons.While a number of surgical approaches have been described, itremains difficult to compare the efficacy of these techniquesbecause of a paucity of well-designed randomized controlledtrials in the literature (Table I). The current evidence, basedprimarily on large case series, suggests that bone marrowstimulation procedures and whole-tissue transplantation of al-lografts or autografts can achieve favorable outcomes when usedfor the management of focal chondral defects of the knee. Cell-based techniques performed with or without a scaffold havedemonstrated early promise in animal and basic-science models,but additional human trials must be completed in order tovalidate their efficacy in achieving successful clinical outcomes.

AppendixTables summarizing studies in the literature about thevarious techniques described in this review are available

with the electronic version of this article on our web site atjbjs.org (go to the article citation and click on SupportingData). n

Asheesh Bedi, MDRiley J. Williams III, MDHospital for Special Surgery,535 East 70th Street,New York, NY 10021.E-mail address for A. Bedi: [email protected] address for R.J. Williams III: [email protected]

Brian T. Feeley, MDDepartment of Orthopaedic Surgery,University of California at San Francisco,1701 Divisadero Street,Suite 240,San Francisco, CA 94115.E-mail address: [email protected]

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TABLE I Grades of Recommendation for Cartilage Repair

Procedures

Grade*

Marrow stimulation procedures B

Adjuncts to marrow stimulation I

Platelet-rich plasma I

Autologous osteochondral transplantation B

Osteochondral allograft transplantation B

Autologous chondrocyte implantation C

Hyaluronan-based scaffolds seeded withautologous chondrocytes

I

Tissue-engineered collagen matrices seededwith autologous chondrocytes

I

*A = good evidence (Level-I studies with consistent findings) for oragainst recommending intervention, B = fair evidence (Level-II or IIIstudies with consistent findings) for or against recommendingintervention, C = poor-quality evidence (Level-IV or V studies withconsistent findings) for or against recommending intervention, andI = there is insufficient or conflicting evidence not allowing arecommendation for or against intervention.

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