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Instructional Course Lecture

The Utility of Biologics, Osteotomy,and Cartilage Restoration in theKnee

Abstract

The management of complex cartilage and meniscal pathology inyoung, athletic patients is extremely challenging. Joint preservationsurgery is most difficult in patients with concomitant knee pathologies,including cartilage defects,meniscal deficiency,malalignment, and/orligamentous insufficiency. Clinical decision making for these patientsis further complicated by articular cartilage lesions, which often areincidental findings; therefore, treatment decisions must be based onthe confirmed contribution of articular cartilage lesions tosymptomatology. Surgical management of any of the aforementionedknee pathologies that is performed in isolation typically results inacceptable patient outcomes; however, concomitant procedures forthe management of concomitant knee pathologies often are essentialto the success of any single procedure. The use of biologic therapy asan alternative to or to augment more conventional surgicalmanagement has increased in popularity in the past decade, andindications for biologic therapy continue to evolve. Orthopaedicsurgeons should understand knee joint preservation techniques,including biologic and reconstructive approaches in young, high-demand patients.

Themanagement of complex kneepathology in young, athletic

patients is challenging. Various jointpreservation strategies have beenintroduced in the past severaldecades, with biologic therapyrecently being incorporated into thetreatment algorithm for complexknee pathology. Although successfuloutcomes can be achieved in patientswith complex knee pathology whoundergo nonsurgical treatment, mostpatients require surgical treatment topreserve and/or restore joint bio-mechanics and function. The abilityto perform complex and concomitantknee joint preservation procedures inthese patients is increasing givenrecent advances in surgical tech-niques, instrumentation, and imaging

modalities, as well as the availabilityof off-the-shelf implants and biologicagents.One of the main challenges in the

treatment of patients with multipleknee pathologies is determiningwhich pathology is symptomatic,which pathology must be managed(even if asymptomatic), and whichpathology can remain unmanaged.Although every effort should bemadefor joint preservation in thesepatients, disadvantages, includinginherent surgical risks and uniquerehabilitation protocols, are associ-ated with each joint preservationtechnique; therefore, care must betaken to avoid overmanagement ofasymptomatic lesions. Surgical deci-sion making is challenging in patients

Rachel M. Frank, MD

Eric J. Cotter, BS

Eric J. Strauss, MD

Andreas H. Gomoll, MD

Brian J. Cole, MD, MBA

From CU Sports Medicine,Department of Orthopaedics,University of Colorado School ofMedicine, Boulder, CO (Dr. Frank),the Department of OrthopaedicSurgery, Rush University MedicalCenter, Chicago, IL (Mr. Cotter, andDr. Cole), New York University,Langone Medical Center, New York,NY (Dr. Strauss), and Brigham andWomen’s Hospital, Boston, MA(Dr. Gomoll).

This article, as well as other lecturespresented at the Academy’s AnnualMeeting, will be available March 2018in Instructional Course Lectures,Volume 67.

J Am Acad Orthop Surg 2018;26:e11-e25

DOI: 10.5435/JAAOS-D-17-00087

Copyright 2017 by the AmericanAcademy of Orthopaedic Surgeons.

January 1, 2018, Vol 26, No 1 e11

Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.

http://dx.doi.org/10.5435/JAAOS-D-17-00087

with tibiofemoral malalignment, lig-amentous instability, and chondral/meniscal damage; therefore, all jointpreservation options must be con-sidered.1 Historically, correctiveprocedures for the management ofany of the aforementioned kneepathologies that are performed inisolation result in adequate patientoutcomes; however, concomitantprocedures for the management ofconcomitant knee pathologies oftenare essential to the success of anysingle procedure. Some patients mayhave limited access to timely care,especially with respect to allograftavailability, and orthopaedic sur-geons must account for potentialdisparities in healthcare access withregard to surgical decision making.The last option for patients with

debilitating and advanced joint linepain is joint arthroplasty, such asunicompartmental knee arthroplastyor total knee arthroplasty (TKA),both of which result in consistentpain relief and restoration of functionin appropriately selected patients.Although knee arthroplasty is effec-tive, such procedures are not ideal foryounger and/or active patients, espe-cially those with moderate- to high-demand activity levels.1 Younger agehas been reported to be a negativeprognostic factor for clinical out-comes and revision surgery inpatients who undergo knee arthro-plasty,2-4 which highlights the

importance of knee joint preserva-tion rather than knee replacement inthese patients. Orthopaedic surgeonsmust determine the chronologic andphysiologic age of patients in whomjoint preservation procedures areconsidered. For example, olderpatients who historically may havebeen considered candidates for jointarthroplasty only may be excellentcandidates for joint preservationsurgery, depending on their weight,overall health, activity level, andsurrounding joint anatomy. Con-versely, younger patients who his-torically would never be consideredcandidates for joint arthroplastybecause they are too young may notbe good candidates for joint preser-vation based on their weight, overallhealth, postoperative expectations,and overall joint health. An under-standing of the potential activityrestrictions after joint preservationprocedures is particularly importantfor younger patients, who are morelikely than older patients to placehigher demands on their jointspostoperatively.

Knee Pathologies

Patients with complex knee pathol-ogy often have one or more of thefollowing diagnoses: meniscal insuf-ficiency, articular cartilage lesions,ligamentous instability, and/or mal-

alignment. These concomitantpathologies often are linked,with oneunderlying pathology being a strongcontributor to a successive pathol-ogy, such as meniscal insufficiencyleading to cartilage damage. In gen-eral, patients with a history of kneeinjury have a 7.4 times increased riskof knee osteoarthritis progressioncompared with patients without ahistory of knee injury.5

Meniscal InsufficiencyInjury to the meniscus is a particularproblem for the future health of aknee. Baratz et al6 reported thatpatients who underwent total men-iscectomy experienced increasedpeak contact stresses of .235%compared with patients who hadknees with intact menisci. Lee et al7

reported a linear relationshipbetween increases in knee contractstresses and the extent of partialmeniscectomy. Many studies havedescribed the detrimental effect ofmeniscectomy with regard to kneearthritis progression, reporting thatpatients who undergo total or sub-total meniscectomy have a 14 timesincreased relative risk of uni-compartmental arthritis.8-10 Inferioroutcomes in patients who undergopartial meniscectomy have beenassociated with younger age, chon-dral damage discovered at the timeof meniscectomy, ligamentous

Dr. Strauss or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Arthrex; servesas a paid consultant to Joint Restoration Foundation, DePuy Synthes Mitek Sports Medicine, and Vericel; and has received research orinstitutional support from Dynasplint, NuTech, and Omeros. Dr. Gomoll or an immediate family member has received royalties from NuTech;serves as a paid consultant to or is an employee of Aesculap/B. Braun, CartiHeal, Joint Restoration Foundation, NuTech, RegentisBiomaterials, and Vericel; has received research or institutional support from Joint Restoration Foundation, NuTech, and Science forBioMaterials; and serves as a board member, owner, officer, or committee member of the European Society of Sports Traumatology, KneeSurgery and Arthroscopy and the International Cartilage Repair Society. Dr. Cole or an immediate family member has received royaltiesfrom Arthrex and DJO Global; serves as a paid consultant to Arthrex, Regentis Biomaterials, and Zimmer Biomet; has stock or stock optionsheld in Carticept and Regentis Biomaterials; has received research or institutional support from Aesculap/B. Braun, Arthrex, CytoriTherapeutics, MEDIPOST, the National Institutes of Health (NIAMS & NICHD), and Zimmer Biomet; has received nonincome support (suchas equipment or services), commercially derived honoraria, or other non–research-related funding (such as paid travel) from Athletico,Össur, Smith & Nephew, and Tornier; and serves as a board member, owner, officer, or committee member of the American OrthopaedicSociety for Sports Medicine, the American Shoulder and Elbow Surgeons, the Arthroscopy Association of North America, and the Inter-national Cartilage Repair Society. Neither of the following authors nor any immediate family member has received anything of value from orhas stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Frank andMr. Cotter.

The Utility of Biologics, Osteotomy, and Cartilage Restoration in the Knee

e12 Journal of the American Academy of Orthopaedic Surgeons


instability, and tibiofemoral mal-alignment.11-13 In addition, theresults of meniscal repair and me-niscal allograft transplantation(MAT) are poorer in patients withunmanaged ligamentous instability,malalignment, and/or articular carti-lage disease.1,14-17 Concurrent kneepathologies have a considerable effecton the results of meniscal procedures.

Articular Cartilage LesionsAlthough articular cartilage damagemay result frommeniscal insufficiency,articular cartilage lesions also occur inisolation. Overall, articular cartilageinjuries are extremely common, withstudies reporting cartilage lesions in60% to 65% of patients who undergoknee arthroscopy regardless of thesurgical indication.18-20 The effects offull-thickness articular cartilagedefects on a knee may be considerable.These lesions have been reported toalter the distribution ofweight-bearingforces in the knee; concentrate stressesat the rim of the defect and on theopposing articular surface; decreaseoverall contact area, which furtherincreases peak stresses; and lead todegenerative changes and symptomsin the knee.

Ligamentous InstabilityLigamentous instability, particularlywith regard to the anterior cruciateligament (ACL), may contribute todegenerative changes in the knee.21

In a recent study of 364 patients withan isolated ACL tear who underwentnonsurgical treatment, Sanderset al22 reported hazard ratios of 18and 14.2 with regard to the risk ofsecondary meniscal tears andarthritis, respectively, comparedwith an age- and sex-matched cohortof persons without an ACL tear.Lohmander et al23 reported that50% of patients with ACL and me-niscal tears had symptomatic osteo-arthritis 10 to 20 years postinjury. Ina study of 56 patients with an ACL

tear (with or without a concomitantmeniscal tear), Zhang et al24 re-ported considerably less flexionduring gait analysis in all of theACL-deficient knees, regardless ofthe status of the meniscus, comparedwith ACL-intact knees. In addition,the authors reported that concomi-tant meniscal injury altered kneekinematics by allowing for anincrease in anterior tibial translationduring level walking activity, whichfurther highlights the link betweenmultiple knee pathologies.24

MalalignmentMalalignment is a common source ofknee pain and may have detrimentaleffects on the overall health of a knee.Under normal physiologic condi-tions, 60% of body weight is sup-ported by the medial compartment ofthe knee, and 40% of body weight issupported by the lateral compart-ment of the knee. Varus malalign-ment results in overload of themedialcompartment of the knee, whereasvalgus malalignment results in over-loadof the lateral compartment of theknee. Varus malalignment has beenreported to predict a loss of medialtibial plateau cartilage volume and anincrease in tibial and femoral denudedbone.25 Malalignment may be clini-cally asymptomatic, becoming clini-cally relevant only after a patientsustains an injury that results in painand/or mechanical symptoms localizedto one of the knee compartments. Acommon clinical scenario involves apreviously asymptomatic patient whohas lived his or her entire life withvarus malalignment and sustains aninjury that results in a new, large,symptomatic medial femoral condylechondral defect. After the decision ismade to proceed with surgical man-agement of the chondral defect, sur-geons must determine if a concomitanthigh tibial osteotomy (HTO) should beperformed to correct the varus mal-alignment and offload the newly

managed medial femoral condylelesion (Figure 1). The same surgicaldecision making must be applied tothe management of newly symptom-atic lesions in the lateral compartmentof the knee of a patient with valgusmalalignment.The benchmark for the management

ofmalalignment,whetherperformed inisolation or via a combined approach,is a realignment osteotomy, with anHTO most commonly performed forthe management of varus malalign-ment and a distal femoral osteotomymost commonly performed for themanagement of valgus malalignment.Although an osteotomy often is neces-sary to allow for successful concomi-tant joint preservation strategies,osteotomy is associated with risks,including infection, fracture,nonunion,malunion, hardware failure, and neu-rovascular damage.26,27 AlthoughTKA is more technically challenging inpatients in whom an osteotomy wasperformed, the clinical outcomes andsurvival rates of patients who undergoTKA after an osteotomy are similar tothose of patients who undergo TKAwithout a prior osteotomy.28-31

Evaluation

The evaluation of patients with con-comitant knee pathologies has been

Figure 1

Intraoperative photograph of a kneewith varus malalignment showingplate fixation during a high tibialosteotomy.

Rachel M. Frank, MD, et al

January 1, 2018, Vol 26, No 1 e13


described in detail.32-34 In general,evaluation of this patient populationmay be difficult, even for experi-enced surgeons. Patients with con-comitant knee pathologies oftenhave undergone multiple prior ipsi-lateral knee surgeries, and it may bedifficult to determine whether apatient’s current symptoms arerelated to an original injury, priorsurgery, or a new injury. In addition,in patients with multiple knownpathologies, such as articular carti-lage and meniscal damage, it may bedifficult to determine the lesion thatcontributes to most of a patient’ssymptoms. Common history andphysical examination findings in

patients with concomitant kneepathologies are listed in Table 1.Diagnostic studies, including radio-

graphs and advanced imaging studies,are extremely helpful in the evaluationof patients with complex knee pathol-ogy (Table 2). The initial diagnosticworkup should always includeweight-bearing, double-stance, long-leg mechanical axis radiographs toevaluate the alignment of the limb inquestion (Figure 2). If available, sur-gical reports and intraoperativeimages and/or video from priorarthroscopic procedures should bereviewed to better understand proce-dures that already have been attemp-ted and may provide important details

with regard to the reason prior pro-cedures have been unsuccessful (Fig-ure 3). The details obtained from thepatient history, physical examination,and imaging studies should helporthopaedic surgeons determine if apatient is an appropriate candidate forknee joint preservation surgery.Understanding patient expectationsand counseling patients and familieswith regard to potential activityrestrictions after knee joint preserva-tion surgery are important to ensuresuccessful outcomes that are satisfac-tory to patients.

Outcomes of Knee JointPreservation Surgery

In general, patients in whom knee jointpreservation techniques are consideredoften have debilitating pain and limitedfunction. Usually, these patients haveundergone one ormore prior ipsilateralsurgical procedures and are seeking asurgical alternative to nonsurgicaltreatment. Nonsurgical managementoptions that may help alleviate paininclude weight loss, activity modifica-tion, oral anti-inflammatory medica-tions, unloader bracing, cryotherapy,compression therapy, physical therapy,injection therapy via intra-articularcorticosteroids, viscosupplementation,and biologic injections. Although non-surgical treatment can be attempted if apatient prefers, most patients havesevere symptoms and pathology thatwarrant surgical treatment. Surgicalmanagement options for knee jointpreservation vary and depend on thespecific pathology or pathologies beingmanaged. A summary of the surgicaltechniques for knee joint preservation,which can be performed in isolation orvia a combined approach, is presentedin Table 3.

Concurrent Versus StagedProceduresDepending on patient indications,surgical techniques for knee joint

Table 1

Findings in Patients With a Focal Chondral Defect and Concomitant KneePathology

Patient history findingsIntermittent joint line pain at rest or at night

Effusion (if not present, extra-articular sources of pain should be considered)

Mechanical symptoms (clicking, catching, locking)

Pain localized to the involved joint line during weight bearing

Physical examination findings (contralateral side examined forcomparison)

Inspection

Assess for malalignment, atrophy, and signs of early arthritis

Note prior surgical incisions

Assess patellar tracking

Palpation

Joint line pain

Evaluate meniscus via flexion McMurray test

Crepitus

Range of motion

Assess passive and active motion for subtle flexion contractures

Evaluate ipsilateral hip and knee

Strength

Assess quadriceps, hamstrings, and core muscles

Patellar examination

Assess patellar tilt, apprehension, J-sign, and Q-angle

Ligamentous status

Assess stability of ACL, PCL, MCL, LCL, and posterolateral corner

Neurovascular status

Assess distal neurovascular function, evaluate for edema

ACL = anterior cruciate ligament, LCL = lateral collateral ligament, MCL = medial collateralligament, PCL = posterior cruciate ligament




preservation can be performed con-currently or in a staged manner (Fig-ure 4). A concurrent approachrequires a single surgery but oftenrequires a longer surgical duration,which may be associated with a moredifficult postoperative recovery. Astaged approach is advantageousbecause it involves a shorter surgicalduration and a potentially easierpostoperative recovery but requiresmultiple surgeries, each of which isassociated with anesthetic and sur-gical risks. The cost-effectiveness ofconcurrent versus staged knee jointpreservation procedures has notbeen evaluated in enough detail todetermine the superiority of oneapproach over the other. Althoughdetermining the most appropriateprocedures for the management ofmeniscal deficiency, ligamentousinstability, and malalignment issomewhat straightforward, deter-mining the optimal procedure for themanagement of a full-thicknesschondral lesion is more controver-sial.33,35-37 The continuous devel-opment of novel, biologic solutionsfurther complicates the decision-making process because suchtreatments often offer attractive, less-invasive options compared with

traditional techniques but lack clin-ical evidence to support their use.Overall, it is extremely difficult todetermine which combination ofavailable procedures is absolutelynecessary for a given patient inwhom joint preservation surgery isconsidered. Often, it is unclear whichpathology is responsible for symp-toms. In addition, in many patients,the appropriate treatment option isclear, but the anticipated post-operative activity goals of a patientmay be unreasonable after thatprocedure.Because patientswho undergo joint

preservation procedures oftenundergo concomitant procedures forthe management of multiple under-lying pathologies, interpretation ofthe clinical results of a single jointpreservation procedure may be diffi-cult. In addition, defining a good orexcellent outcome versus a pooroutcome and defining a failed pro-cedure is a challenge because of theheterogeneity of reported outcomes.Standard patient-reported outcomes(PROs) may not adequately portraythe clinical outcomes of patients whoundergo cartilage restoration. Forexample, many surgeons may con-sider unplanned knee surgery after a

joint preservation procedure, such asarthroscopic débridement, to be anindication of a failed joint preserva-tion procedure, whereas the patientmay be extremely satisfied with theoverall outcome.38,39 Many studieson the clinical outcomes of patientswho undergo knee joint preservationsurgery are retrospective in designand are subject to the weaknessesand biases inherent to level IV ret-rospective studies.40 Despite theselimitations, many clinical studieshave been published on the out-comes of patients who undergo kneejoint preservation surgery.17,38,39,41-45

Key outcomes of patients whoundergo concomitant knee jointpreservation procedures are listed inTable 4.

MAT and OsteochondralAllograft TransplantationMost knee joint preservation studiesfocus on the outcomes of articularcartilage restoration and MAT. In aretrospective review of 172 patients

Figure 2

AP weight-bearing, double-stance,long-leg mechanical axis radiographof a lower extremity demonstratingmild varus malalignment.

Table 2

Diagnostic Workup for Patients with Complex Knee Pathology

RadiographyStandard knee radiographs (AP, lateral, weight-bearing PA in 45� of flexion, andMerchant views)

Other views for further evaluation of meniscal or chondral pathology ormalalignment

Weight-bearing double-stance long-leg mechanical axis views

Sizing radiographs if MAT or OCA is an option

MRIBetter resolution for soft tissue, meniscus, and ligamentous structures

Better evaluation of bone marrow edema

CTGood for visualization of bone, particularly for the assessment of bone tunnelsfrom previous ACL reconstruction

ACL = anterior cruciate ligament, MAT = meniscal allograft transplantation, OCA =osteochondral allograft transplantation


January 1, 2018, Vol 26, No 1 e15


who underwent MAT that was per-formed by a single surgeon, 41% ofwhom underwent isolated MAT and59% of whom underwent MAT anda concomitant procedure, Mc-Cormick et al39 reported an overallallograft survival rate of 95% at amean follow-up of 5 years, withfailure defined as revision MAT orconversion to TKA. The authors re-ported a 32% revision surgery rate,with arthroscopic débridement beingthe most common procedure per-formed for revision surgery. Sec-ondary surgery within 2 years ofindex MAT was a negative prog-nostic factor for failure, and patientswho underwent secondary surgeryhad an 8.4 times odds ratio forfuture TKA or revision MAT.39

Given the high incidence of proce-dures performed in combinationwith MAT in the patients in thestudy, it remains unclear whether thepatient outcomes and revision sur-gery rates reported are a result ofMAT alone. In a survival analysis of180 patients who underwent os-teochondral allograft transplantation(OCA), 48% of patients underwentOCA only and 52% underwent aconcomitant procedure.38 Of thepatients who underwent a concomi-

tant procedure, 36% underwentMAT. Frank et al38 reported anoverall OCA survival rate of 87% ata mean follow-up of 5 years, withfailure defined as revision OCA orconversion to TKA. The authors re-ported a 37% revision surgery rate,with arthroscopic débridement beingthe most common procedure per-formed for revision surgery.Although most of the patients hadundergone prior ipsilateral knee sur-gery (96%), the number of previoussurgeries was predictive of revisionsurgery and failure.38 The authorsreported that concomitant MAT wasnot a risk factor for revision surgeryor failure. Patients in whom revisionsurgery was required had sub-stantially improved PROs; however,their outcomes were considerablyinferior compared with those ofpatients in whom revision surgerywas not required.Getgood et al46 conducted a sur-

vivorship analysis of 48 patients(median age, 35.8 years) whounderwent concurrent MAT andOCA.Most of the patients (43 of 48)had undergone prior ipsilateral kneesurgery, with a median of threeprocedures being performed. Bipolar(tibiofemoral) osteochondral allo-grafts were used in 24 of the patients,

and meniscal allografts were trans-planted via their attachment to acompound tibial plateau osteochon-dral allograft in 36 patients. Failurewas defined as any procedure thatresulted in removal or revision of oneor more of the grafts.46 The authorsreported an overall 22.9% failurerate and a 54.2% revision surgeryrate, with considerable improve-ments in PROs reported in patientswith intact grafts at a mean clinicalfollow-up of 6.8 years. A trendtoward poorer outcomes wasobserved in patients who underwentbipolar tibiofemoral OCA for themanagement of arthritis, whichsuggests that earlier intervention viaMAT in combination with OCAmay be advantageous in patientswith a less advanced disease pro-cess.46 Overall, the results ofGetgood et al46 align with those re-ported in the aforementioned studiesin that the overall success rate ofconcurrent MAT and OCA is com-parable with the overall success rateof either procedure in isolation.

Effect of Lesion SizePatients with bipolar articular cartilagelesions who undergo joint preservationsurgery have poorer outcomes than

Table 3

Surgical Techniques for Knee Joint Preservation

Pathology Surgical Techniquesa

Articular cartilage lesion DébridementMarrow stimulationb (ie, microfracture)Surface allograftb,c

Autologous chondrocyte implantationb

Osteochondral autograft transferOsteochondral allograft transplantation

Meniscal insufficiency Meniscal débridementMeniscal repairMeniscal allograft transplantation

Ligamentous instability Ligament reconstruction

Malalignment Realignment osteotomy

a Each of the described techniques can be augmented with biologic therapy.b Subchondral bone should be normal or near-normal.c Surface allografts include commercially available allograft-containing biologic products.

Figure 3

Intraoperative arthroscopic image ofa large medial femoral condyle full-thickness articular cartilage defect(International Cartilage RepairSociety grade IV).




patients with unipolar articular carti-lage lesions who undergo joint preser-vation surgery,46 and patients withlarger femoral condyle lesions whoundergo joint preservation surgeryhave poorer outcomes than patientswith smaller femoral condyle lesionswho undergo joint preservation sur-gery. In a study of 32 patients whounderwent concurrent MAT andOCA, Abrams et al47 reported aninverse relationship between post-operative PROs and femoral condyledefect size. At a mean clinical follow-up of 4 years, considerably greaterimprovements in International KneeDocumentation Committee (IKDC)scores, Knee Injury and OsteoarthritisOutcome Scores (KOOS), andLysholm Knee scores were reported inthe patients with a femoral condyledefect ,4 cm2 compared with thepatients with a femoral condyle defect.4 cm2.

Realignment OsteotomyStudies on the outcomes of patientswho undergo realignment osteotomyin combination with MAT and/orarticular cartilage restoration are

limited. In a study of 18 patients(mean age, 34 years) who underwentrealignment osteotomy in combina-tion with MAT and articular carti-lage restoration, most of whom hadundergone prior ipsilateral surgery(mean number of previous surgeries,2 6 1), Harris et al45 reported afailure rate of 11.2% and a revisionsurgery rate of 55.5% at a meanfollow-up of 6.5 years, with consid-erable improvements reported inKOOS, IKDC scores, and LysholmKnee scores. Although this study is asmall series, it highlights the clinicalutility of concurrent knee jointpreservation procedures to fullymanage all knee pathologies.

Multiple ConcomitantProceduresSeveral efforts have been made tosummarize the available literature on

the outcomes of patients whoundergo knee joint preservation sur-gery. Harris et al48 conducted a sys-tematic review of six studies thatincluded 110 patients who under-went MAT in combination witharticular cartilage restoration(medial compartment in 66 patients,lateral compartment in 44 patients).Autologous chondrocyte implanta-tion (ACI) was performed in 73patients, OCA was performed in 20patients, osteochondral autografttransfer was performed in 17patients, and microfracture wasperformed in 3 patients. Additionalconcurrent surgery, includingrealignment osteotomy, cruciate orcollateral ligament reconstruction,and/or hardware removal, was per-formed in 36 patients. Harris et al48

reported that the clinical results ofMAT in combination with cartilagerestoration were similar to those of

Table 4

Outcomes of Concomitant Knee Joint Preservation Procedures

MAT and OCAMAT performed in combination with OCA is not an independent risk factor forfailure or revision surgery.

The number of prior ipsilateral knee surgeries is predictive of revision surgeryand failure in patients who undergo OCA.

Patients with bipolar lesions and patients with lesions.4 cm2 who undergo OCAin combination with MAT have poorer outcomes compared with patients withunipolar lesions and patients with smaller lesions.

The outcomes, including survivorship, of patients who undergo MAT incombination with OCA are not considerably different from those of patients whoundergo isolated MAT.

Realignment osteotomy procedures (HTO, DFO, TTO)No differences in the patient-reported outcomes of patients who undergoisolated cartilage repair and patients who undergo cartilage restoration incombination with osteotomy 6 MAT.

Patients who undergo HTO in combination with cartilage restoration have somewhatbetter 5-year survival rates compared with patients who undergo isolated HTO orHTO in combination with MAT (98%, 92%, and 91%, respectively).

Patients with patellar or trochlear lesions who undergo ACI in combination withTTO have considerably improved pain and improved function compared withpatients with patellar or trochlear lesions who undergo isolated ACI.

Patients who undergo ACI in combination with realignment osteotomy may haveimproved outcomes compared with patients who undergo isolated ACI, dependingon the location of the lesion and patient anatomy (Q-angle and MPFL status).

ACI = autologous chondrocyte implantation, DFO = distal femoral osteotomy, HTO = high tibialosteotomy, MAT = meniscal allograft transplantation, MPFL = medial patellofemoral ligament,OCA = osteochondral allograft transplantation, TTO = tibial tubercle osteotomy

Figure 4

Intraoperative photograph of a kneewith a large medial femoral condylefull-thickness articular cartilagedefect showing osteochondralallograft transplantation andconcomitant high tibial osteotomy.


January 1, 2018, Vol 26, No 1 e17


either procedure in isolation; how-ever, revision surgery was requiredin.50% of patients who underwentconcomitant procedures. In a sys-tematic review of 69 studies thatincluded 4,557 patients (mean age,53 years) who underwent HTO withor without articular cartilage resto-ration and/or MAT, Harris et al49

reported a considerably higher sur-vivorship rate in patients whounderwent HTO in combinationwith articular cartilage restoration(98.7%) compared with patientswho underwent isolated HTO(92.4%) and patients who under-went HTO in combination withMAT (90.9%) at a follow-up of 5years. These results are encouragingfor patients in whom HTO is beingconsidered as part of a knee jointpreservation strategy.

Patellofemoral JointPreservationTypically, patellofemoral joint pres-ervation is considered separate fromfemoral condyle joint preserva-tion.50-57 Reconstructive proceduresfor the patellofemoral joint consist ofcartilage restoration with or withoutrealignment osteotomy. A carefulevaluation of the literature is criticalbecause patellofemoral joint recon-structive procedures can be per-formed with or without medialpatellofemoral ligament (MPFL)repair/reconstruction for joint pres-ervation and for the management ofpatellar instability. Patients withsymptomatic chondral defects of thepatella and/or trochlea who havenormal patellar stability do notrequire MPFL repair/reconstructionbut may require a tibial tubercleosteotomy (TTO) to offload a newlymanaged chondral lesion.52 Patientswith recurrent patellar instabilitythat leads to patellar cartilage dam-age require cartilage restoration incombination with MPFL repair/reconstruction and TTO. In patients

with a normal tibial tuberosity-trochlear groove distance, a TTOtypically is performed as an anterio-rization osteotomy (without medial-ization), whereas in patients with anabnormal tibial tuberosity-trochleargroove distance (.15 mm), a TTOtypically is performed as an antero-medialization osteotomy. Therefore,surgeons must be aware of theindications for surgical managementin a study if extrapolating the find-ings of that study to a specificpatient.In a study of 62 patients (mean age,

32 years) who underwent ACI of thepatellofemoral joint, Pascual-Garrido et al53 reported consider-able postoperative improvements inmost of the PRO scores, includingLysholm Knee scores, IKDC scores,KOOS, Tegner activity score, andCincinnati Knee Rating Scale scores,at a mean follow-up of 4 years, witha trend toward better outcomes inthe patients who underwent con-comitant anteromedialization TTOcompared with the patients whounderwent isolated ACI. An overallfailure rate and a revision surgeryrate of 7.7% and 44%, respectively,were reported. Trinh et al58 con-ducted a systematic review of 11studies that included 366 patients(mean age, 33 years) who underwentisolated patellofemoral compart-ment ACI (77%) or ACI in combi-nation with osteotomy (23%). Ofthe defects managed, 78% werelocated on the patella, and 22%werelocated on the trochlea. The authorsreported considerable clinicalimprovements and a similar revisionsurgery rate in both groups at a meanfollow-up of 4.2 years; however, inan analysis of the three studies thatdirectly compared the outcomes ofpatients who underwent isolatedACI with those of patients whounderwent ACI in combination withTTO, the authors reported consid-erably better improvements in thePRO scores of the patients who

underwent ACI in combination withTTO.58

In a multicenter study of 110patients who underwent ACI in thepatella, 75 of whom underwent con-comitant realignment osteotomy,Gomoll et al52 reported statisticallysignificant and clinically relevantimprovements in pain and functionin all PRO scores at a mean follow-up of 7.5 years and that 92% ofpatients stated they would undergothe procedure again. The authorsreported an overall failure rate of8%, with no considerable differencesreported in the outcomes or failurerate of the patients who underwentTTO in combination with ACI andthose of the patients who underwentisolated ACI; however, the TTO andACI group included a substantiallygreater number of patients than theACI-only group, which suggests thatthe study was underpowered todetect such a difference.52 In addi-tion, most of the patellar lesions inthe study were medial or centrallesions (87%) rather than laterallesions, which may respond morefavorably to TTO. The authorshighlighted the importance of pre-operative planning and understand-ing surgical indications in patientswho undergo cartilage restoration todetermine if concomitant realign-ment procedures are appropriate.

Role of Biologic Therapy

Recently, the use of biologics for themanagement of articular cartilagelesions has increased considerably.Although scientific and clinical evi-dence on biologic therapy is evolving,biologics may help prevent articularcartilage lesion progression and mayplay a role in the nonsurgical andsurgical management of osteoarthri-tis and focal chondral lesions.59-61

Although knee joint preservationsurgery is effective in appropriatelyindicated patients, revision surgery




rates are relatively high, and failurerates increase with longer follow-up.Given the relatively young age ofmost patients who undergo kneejoint preservation surgery, efforts toimprove the short-term function andlong-term duration of knee jointpreservation surgery are under way,with a major focus on biologicaugmentation. In general, biologicagents are believed to inhibitinflammation and promote tissuehealing. The biologic agents mostfrequently used for articular cartilageand meniscal management includeplatelet-rich plasma (PRP), mesen-chymal stem cells (MSCs), and bio-logic scaffolds. Research has beendone to attempt to evaluate the effectof these biologic agents and growthfactors, such as transforming growthfactor-b1, bone morphogenetic pro-tein 7, and insulin-like growth factor1, all of which have been reported toincrease chondrocyte syntheticactivity in in vitro studies.62

PRP, which is an autologous, highlyconcentrated product containinggrowth factors and inflammatorymediators, has been reported toenhance chondrocyte proliferation,and ongoing studies are attempting toevaluate the differentiation and func-tionality of those chondrocytes.61,63,64

PRP is an autologous product that isproduced by harvesting peripheralblood via standard venipuncturetechniques, spinning the peripheralblood in a centrifuge to concentrateplatelets above baseline levels, andinjecting the finished product into anaffected area. Platelets are of interestbecause they contain a variety ofgrowth factors that are known tostimulate the proliferation of localprogenitors, direct cell differen-tiation, and modify inflammatoryresponses.59,65 Considerable variationexists with regard to the manner inwhich PRP is harvested and spun,66-71

whichmakes comparison of the resultsof PRP in one study with those inanother study almost impossible.

A variety of factors, includingdonor-related variables (eg, age, sex,nutritional status), processing-related variables (eg, collection andstorage conditions, spin protocol,activation agent), and delivery-related variables (eg, delivery vehi-cle, timing of delivery relative toharvest, injury chronicity), influencethe growth-factor profile ofPRP.59,66,67 The volume of leuko-cytes in PRP is one factor of con-siderable interest.71,72 PRP isclassified as leukocyte-rich orleukocyte-poor, depending on itsfinal leukocyte concentration beforeinjection. Leukocytes are present inthe buffy coat layer, which often ismerged with the platelet-rich por-tion.73 Because PRP preparationprotocols are not standardized, PRPpreparation may or may not sepa-rate the buffy coat layer from theplatelet-rich portion.74,75 The dif-ferences between leukocyte-richPRP and leukocyte-poor PRP arenot completely understood, espe-cially with regard to treatmentindications. Several preclinicalstudies reported that leukocyte-poor PRP may be better suited forintra-articular use than leukocyte-rich PRP.71,72 In a prospective,double-blind, controlled clinicaltrial of 111 patients with mild tomoderate knee osteoarthritis whowere randomized to intra-articularinjections of leukocyte-poor PRP orhyaluronic acid, Cole et al76 re-ported no differences in WesternOntario and McMaster UniversitiesOsteoarthritis Index pain subscoresbetween the patients in the twogroups; however, several otheroutcome measures favored PRPmore than hyaluronic acid.Although the study was performedin patients with knee osteoarthritis,the results may be translatable topatients with focal chondral or os-teochondral defects. Additionalresearch is necessary to determinethe long-term clinical effects of PRP

on knee cartilage pathology,including osteoarthritis.In general, stem cells are classified

as embryonic stem cells, inducedpluripotent stem cells, or adult stemcells.61 Stem cells are subclassified asautologous or allogeneic. Autolo-gous adult MSCs are mostly har-vested from bone marrow andadipose tissue. Allogeneic stem cellscan be harvested from placental andamniotic tissues. The advantages anddisadvantages of stem cells used forknee joint preservation are listed inTable 5. In a prospective, single-blind, placebo-controlled trial of 25patients with bilateral knee painattributed to bilateral osteoarthritiswho were randomized to receive anintra-articular injection of iliac-crest–derived bone marrow aspirateconcentrate (BMAC) in one kneeand saline placebo in the contralat-eral knee, Shapiro et al77 reportedsimilar outcomes with regard to painrelief in both the BMAC-treated andthe placebo-treated knees 1 week, 3months, and 6 months postinjection.The use of scaffolds to augment

knee joint preservation surgery hasbeen more consistently described inthe literature compared with the useof PRP or stem cells, mainly becausescaffolds are used during advancedACI (matrix-induced ACI, matrix-assisted ACI) for the management ofarticular cartilage lesions.54,78-82

Meniscal repair and replacementwith the use of scaffold-based tech-nology has been described in Europe,with encouraging short-term resultsreported.83-92 In general, scaffoldsare categorized based on whetherthey incorporate cells and whetherthey are synthetic or biologic inorigin.93 Other important features ofscaffolds include their mechanicalproperties and the type of tissue theytarget (ie, articular cartilage, menis-cus, ligamentous tissue). Scaffoldmaterials used for cartilage restora-tion include protein polymers (ie,collagen and fibrin), carbohydrate


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polymers (ie, hyaluronic acid), syn-thetic polymers, and polymercomposites.94

Interpretation of the literature onthe use of PRP, stem cells, and scaf-folds to augment knee joint preser-vation surgery is a challenge becauseof the paucity of studieswithmidtermto long-term follow-up and the het-erogeneity of the agents used. Evenamong studies that analyzed the sameagent, such as PRP, preparationsmaydiffer, which makes the interpreta-tion of results a challenge.67,69,71,95

With regard to intra-articular kneepathology, PRP has been used for thenonsurgical, injection-based man-agement of knee pain that is attrib-uted to a variety of etiologies butmainly osteoarthritis. In addition,PRP has been used to augment thesurgical management of articularcartilage defects, with encouragingpreclinical results reported.66,96,97

For this augmented procedure, acommercially available biologicscaffold of micronized allograftarticular cartilage matrix is aug-

mented with PRP and placed in thedefect bed after microfracture toinduce type II hyaline cartilage ratherthan the type I fibrocartilage typi-cally produced via traditional mar-row stimulation techniques.Recent studies on allogeneic and

autologous stem cells for the man-agement of articular cartilage defectsand osteoarthritis have reportedacceptable safety profiles andencouraging short-term results. In asmall safety study of six patients withknee osteoarthritis who received asingle intra-articular injection ofcryopreserved particulated humanamnion and amniotic fluid cells,Vines et al98 reported considerablyimproved PROs, including KOOS,IKDC scores, and Single AssessmentNumeric Evaluation scores, andconsiderably increased serumimmunoglobulin G and immuno-globulin E levels at a follow-up of 12months.Other studies have assessed the

effect of adipose-derivedMSCs in themanagement of focal chondral

lesions of the knee and generalizedknee osteoarthritis. In a controlledtrial of 80 patients who were ran-domized to microfracture with orwithout adipose-derived MSC aug-mentation (covered with fibrin glue),Koh et al99 reported complete carti-lage lesion coverage in 65% of thepatients in the MSC group and in45% in the microfracture-onlygroup based on MRI obtained atfollow-up of 2 years. In addition,improvements in mean KOOS painand symptom subscores were con-siderably greater in the patients inthe MSC group compared with thepatients in the microfracture-onlygroup at a mean follow-up of 27.4months; however, no substantialdifferences in the other KOOS sub-scores were reported between thepatients in the two groups. Similarencouraging outcomes have beenreported in older patients with dif-fuse knee osteoarthritis who undergotreatment with the use of adipose-derived MSCs during knee arthros-copy.100,101 Perdisa et al102

Table 5

Advantages and Disadvantages of Stem Cells Used for Knee Joint Preservation

Stem CellType Source Advantages Disadvantages

Embryonic Fertilized blastocyst Pluripotent Ethical issuesAble to become cells from alltissues

Must be used allogeneicallyPotentially tumorigenic

Enhanced expansion

Inducedpluripotent

Viral or chemical reprogramming,CRISPR/CAS vectors

Same as embryonic, but avoidsethical issues

Autologous use; therefore,engraftment potential

Safety issuesPotential mutational changesPotentially tumorigenic

Autologous Bone marrow, adipose tissue,banked placental tissue, etc.

Engraftment potential Limited source materialLonger persistence in body Effectiveness of cells influencedby

patient health and ageUsually requires extra step/procedure to obtain (not off theshelf)

Allogeneic Bone marrow, adipose tissue,banked placental tissue, amnioticfluid

Off the shelf and ready to useMore source material thanautologous

Cell donor health and age mayinfluence effectiveness

Limited to no engraftment potential

CAS = CRISPR-associated, CRISPR = clustered regularly interspaced short palindromic repeats




published a systematic review thatsummarized the evidence supportingadipose-derived MSCs for the man-agement of articular cartilage dis-ease. The authors reviewed 39studies, including 28 animal studiesand 11 clinical studies. Of the 11human clinical studies, the authorsreported that the methodologiesvaried, with MSC harvest locationsincluding the buttocks, the abdomi-nal area, and the infrapatellar fat padand with administration protocolsvarying from a single injection of 3to 5 mL with or without PRP (orhyaluronic acid) to a single injectionof 3 to 5 mL with or without PRP (orhyaluronic acid) after arthroscopicdébridement. Follow-up durationalso varied, ranging from 3 to 36months. Overall, most of the studiesreported improvements in pain andfunctional scores.102 Although theseresults are encouraging, they must beinterpreted with caution given thelow overall number of patients, theheterogeneity of methodology, andthe lack of consistent follow-up.The use of BMAC as a biologic

solution for knee joint preservationalso has been recently described103-107

(Figure 5). Although BMAC contains

a relatively low concentration of stemcells, it is believed to contain numer-ous growth factors that are importantbecause of their anabolic and anti-inflammatory properties.103 In arecent systematic review of 11 studieson the clinical efficacy of BMAC inthe management of knee cartilagepathology (three studies on themanagement of osteoarthritis, eightstudies on the management of focalcartilage injuries), Chahla et al103

reported good to excellent outcomesin all of the studies. In a non-randomized study of 37 patients withpatellofemoral chondral lesions whowere treated with BMAC or matrix-induced ACI, Gobbi et al104 reportedconsiderable improvements in thePROs of the patients in both groupsat a minimum follow-up of 3 years,with no significant differences inimprovement with regard to mostPROs between the patients in the twogroups; however, higher IKDC sub-jective scores were reported in thepatients in the BMAC group (P =0.015).Allograft tissue is considered a

biologic treatment option for patientswho undergo knee joint preservation.In addition to fresh osteochondraland meniscal allografts, other allo-graft products include particulatedjuvenile cartilage allograft tissue;

three-dimensional osteochondralallograft matrices; and cryopreservedosteochondral allografts that containnative viable chondrocytes, growthfactors, and extracellular proteins(Figure 6). These surface allograftsare commercially available off theshelf and may be a viable alternativeto fresh osteochondral allografts andosteochondral autograft; however,surface allograft transplantationshould be considered only in patientswith normal or near-normal sub-chondral bone. Although encourag-ing early clinical outcomes have beenreported in patients who undergoparticulated juvenile cartilage allo-graft transplantation for the man-agement of focal chondraldefects,108-113 no clinical studies areavailable on the outcomes of patientswho undergo treatment with the useof other off-the-shelf surfaceallografts.Although thenumberof clinical trials

on MSCs and PRP has increased sub-stantially in the past decade, manyearly studies were conducted beforeunderlying disease processes and ther-apeutic mechanisms were completelyunderstood.109,110 Given the increasedinterest in PRP, MSCs, scaffolds, andother cell- and tissue-based products,industry, orthopaedic surgeons, andregulatory agencies must collaborate

Figure 5

Intraoperative photograph of a kneeshowing the technique for harvest ofbone marrow aspirate concentratefrom the posterior iliac crest.

Figure 6

Intraoperative photographs of a knee showing the appearance of two smalltrochlear chondral lesions before (A) and after (B) particulated juvenile cartilageallograft transplantation.


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to conduct efficient, high-qualityresearch.59,60,108 Early data on PRP,MSCs, and other biologics are prom-ising; however, additional studies arenecessary to further elucidate themechanisms via which these biologicsexert their effects so that their ultimatepotential can be realized in patientcare.

Summary

Patients with concomitant kneepathologies, including articular car-tilage defects, meniscal deficiency,ligamentous insufficiency, and/ormalalignment, are the patients whoare most difficult to treat via jointpreservation. Clinical decision mak-ing for these patients is a challenge,particularly because most patientsare young and have expectations toreturn to high-demand activity. Thecurrent literature supports multipleknee joint preservation strategies,including realignment osteotomy, ifindicated. In the past decade, thenumber of clinical studies on biologictherapy has increased exponentially,with most studies reporting acceptablesafety profiles and encouraging short-term results. Therefore, the use of bio-logic therapy as an alternative to or toaugment more conventional knee jointpreservation techniques is likely toincrease. Additional long-term studiesare necessary to determine the efficacyand cost-effectiveness of knee jointpreservation techniques.

References

Evidence-based Medicine: Levels ofevidence are described in the table ofcontents. In this article, references36, 57, 76, and 79 are level I studies.References 6, 7, 24, 25, 50, 71, 77,99, and 104 are level II studies.References 2-5, 9-11, 22, 30, 72, 80,83, 89, 96, and 107 are level IIIstudies. References 1, 8, 12, 17-20,27-29, 31, 38-41, 43-49, 51-56, 58,

63, 78, 81, 82, 84-86, 90-93, 95, 98,100-103, 105, 106, 108, 109, and 111are level IV studies. References 13-16,21, 23, 32-35, 37, 42, 59-62, 64-70,73-75, 87, 88, 94, 97, 110, 112, and113 are level V expert opinion.

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