Cartilage Surface Treatment: Factors Affecting Success and Failure Mechanisms

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Cartilage Surface Treatment: Factors Affecting Success and Failure Mechanisms Gergo Merkely MD , Jack Farr MD , Daniel Saris MD, PhD , Christian Lattermann MD PII: DOI: Reference:

S1060-1872(19)30085-1 https://doi.org/10.1016/j.otsm.2019.150711 YOTSM 150711

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Operative Techniques in Sports Medicine

Please cite this article as: Gergo Merkely MD , Jack Farr MD , Daniel Saris MD, PhD , Christian Lattermann MD , Cartilage Surface Treatment: Factors Affecting Success and Failure Mechanisms, Operative Techniques in Sports Medicine (2020), doi: https://doi.org/10.1016/j.otsm.2019.150711

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Cartilage Surface Treatment: Factors Affecting Success and Failure Mechanisms. Gergo Merkely MD 1, Jack Farr2 MD, Daniel Saris3 MD, PhD, Christian Lattermann MD 1

1 Dept. Orthopaedic Surgery, Division of Sports Medicine, Center for Cartilage Repair, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2 Cartilage Restoration Center, OrthoIndy, Greenwood, Indiana, USA 3 Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, U.S.A.

Corresponding author: Dr. Jack Farr, Cartilage Restoration Center, OrthoIndy, OrthoIndy South, Suite 100, 1260 Innovation Parkway, Greenwood IN 46143

Abstract: The key to any successful procedure is the proper indication, technique, postoperative management, and learning from failures. As we have learned, articular cartilage surface treatments (marrow stimulation techniques and cell therapy approaches) are sensitive to the integrity of the subchondral bone and certain defect characteristics that may influence outcomes. Optimized surgical technique and adequate postoperative rehabilitation are crucial in providing an optimal environment for chondrogenesis and/or maturation of the graft with maximized graft protection. Finally, if surface treatment fails, the decision making on which subsequent technique to choose can be challenging due to possible alterations in the subchondral bone, or progression of the disease. This article will discuss insights into the basic premise of articular cartilage surface treatment techniques, their requirements and limits and how to strategize after a failed surface treatment.

Introduction Cartilage restoration has gradually evolved over the past 25 years. Most identify the beginning of the era of cartilage repair with the work of Peterson and Brittberg on chondrocyte cell therapy. However, like all things in orthopedics, “nothing is new”. The first osteochondral allograft is, in fact, credited to Lexer in 19081 and the first reports of “marrow stimulation” date back to 1959 by Pridie2. Along with cutting edge innovation comes the privilege of learning from failures. One of the most important factors to success is the critical evaluation of failure, which, if managed appropriately will promote improvements that may lead to better outcomes. In this spirit, we will discuss and review aspects of the indication, surgical technique, postoperative rehabilitation, and early and late clinical failures of cartilage surface treatments broadly categorized as marrow stimulation and cell therapy.

In order to learn from failures, it is important to look at the root cause(s). Therefore, it is imperative to strive to separate the many potential etiologies. Before even considering the weaknesses of specific technique, it is important to review the indications: the best technology cannot be expected to work for the wrong indication; for example, stretching the indications to include osteoarthritis (OA). In the same vein, within a few years, genetic testing will identify individuals at risk for developing OA. Any cartilage restoration technique will have challenges in these patients. Currently, all we can do is document a family history of arthroplasty at a young age, evaluate the other compartments of the knee with MRI or arthroscopy and assess in our own minds the stage of “chondrosis” of the particular compartment under consideration for restoration. The next hurdles are co-morbidities such as alignment, meniscal function, ligamentous patholaxity and obesity. Left unaddressed, all restorative efforts will have a suboptimal outcome. Once the above factors are optimized there remain three obstacles to success: technique, post-operative management and the biology of the restorative procedure.

It is beyond the scope of this paper to address all of these factors but we will focus on some aspects of early degenerative changes, subchondral bone condition, surgical technical elements, post-operative management and strategies to analyze failures of surface treatments

“Early chondrosis” and subchondral bone: This paragraph will focus on the subchondral unit and the defect characteristics which are essential elements of our decision-making algorithm of whether cartilage surface treatments can be used. “Early chondrosis”: The term “early chondrosis” is not clearly defined but constitutes an attempt to describe a situation that indicates generalized chondral changes that are not visible as a singular or discrete defect but rather as an overall thinning and rarefication of the chondral matrix. Some recent attempts have been made to try to describe this appearance of the articular cartilage in a knee compartment. Madry et al.3 proposed a scheme to identify early osteoarthritic changes as diffuse or focal using a combined approach of arthroscopy, MRI and x-ray imaging. Madry postulated that chondral destruction can be a consequence of a single focal chondral lesion or follow a diffuse ill-defined process of cartilage loss. We know from the work of Messner and Maletius4, that chondral defects (with minimum of 1 cm in diameter) are associated with radiographic OA 10-14 years later. This has been corroborated by Potter et al.5 who showed that subchondral marrow lesion size detected on MRI after ACL injury is significantly associated with increased cartilage loss at year 1 and 2 in the area of the subchondral signal. Lattermann et al reported that bone marrow lesions with actual chondral injuries at the time of ACL injury were associated with significantly worse patient reported outcomes at 2 and 6 years after ACL injury and reconstruction, classifying these patients subjectively in the “early arthritis category” as measured by the KOOS.6

The diagnostic “holy grail”, however, would be to identify a definitive marker to determine if a chondral surface is beyond repair/restoration, and how long a potential repair may be able to provide an adequate surface to restore clinical function. In order to fill this critical knowledge gap some early attempts have been made to describe the early phases of knee OA using biomarkers of chondral decline. A biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic process, pathogenic processes, or pharmacologic responses to a therapeutic intervention”.7 The presence of structural collagenous proteins from articular cartilage or bone in synovial fluid, serum or urine may present the best opportunity to date to assess joint health with regards to the chondral surface. Some early attempts have been made regarding the differentiation of “early OA”, “established OA” and Rheumatoid Arthritis. Ahmed et al. proposed the measurement of citrullated protein (CP), anti-CP (citrullated protein antibody) and Hydroxyproline as biomarkers. The different ratio of these three markers allows for the differentiation between early OA, advanced OA and RA.8 The caveat is that “early” OA was defined as Kellgren-Lawrence (K-L) Grade 2 changes on plain x-rays, which may already be beyond the cutoff for cartilage repair procedures. That is, with the <50% joint space narrowing of KL-2, the compartment may already have developed extensive deep diffuse areas of chondrosis while the radiographic joint space is maintained at 50% by small “shoulder” areas with moderated disease. Albrecht et al. have been able to identify IL-1 as a marker highly associated with failure of a chondral surface treatment (Histogenics, Aesculap) based upon biopsies of the repair tissue. High concentrations of IL-1 indicating a chronic inflammatory response were found in the repair tissue that failed. Unfortunately, the disadvantage of this marker is that it only describes the current condition of the graft, while not having a predictive function. Nonetheless, it may be of some clinical use to inform the decision making process on whether to redo surface treatment. Recent work by the Oswestry Research Group showed that it may be possible to differentiate between responders and non-

responders to a cell surface treatment (ACI) based upon the levels of MMP-1 and S100 calcium binding protein 13 at the time of biopsy and the time of implantation. In 10 ACI responders compared to 7 non-responders they were able to statistically define that a significant increase of MMP-1 and a significant decline in S100 calcium binding protein 13 between harvest and implantation of the chondrocyte culture is associated with having a result as a non-responder. While this is preliminary data and requires further scrutiny, it certainly shows how biomarkers may be able to predict success of chondral repair.9 There are technical barriers to this approach as it would require a preclinical cell culture before the definitive decision for implantation, which is currently not logistically feasible. A second study from this research group looked at a broader approach utilizing two distinct proteomic analysis techniques (iTRAQ nLC-MS/MS and LF LC-MS/MS). Large datasets from the proteomic analysis can be analyzed further using a pathway analysis to identify major pathways that may be responsible for the responder / non-responder determination of patients after ACI. This study identified the “acute-phase response” pathway as significantly altered, and, in fact overstimulated, in patients who classified as non-responders. A similar phenomenon is found in patients with end stage radiographic OA. The significance of this finding is that this overstimulation may contribute to the joint’s inability to recover from surgical trauma due to a dysregulation of the natural acute-phase response system that is designed to allow an initial inflammatory response but also dampen an inflammatory overstimulation after injury .10,11

While fluid analyses cannot be performed routinely at present, it is certainly possible to develop assays that will allow for a better detection of potential non-responders in the near future using proteomics analysis. The identification of these patients may inform on the potential need for a biologic pretreatment of the joint to dampen/ modulate a potential postsurgical inflammatory response or may help the decision to utilize a different chondral repair strategy.

Importance of the intact subchondral unit: Articular cartilage is a hypocellular and highly specialized tissue, with only 4% of its wet weight consisting of chondrocytes. The main components of articular cartilage are water (65% to 85% of weight) and the extracellular matrix (ECM) composed of type II collagen (15-20% of weight) and proteoglycans (PGs) (310% of weight). 12 The ECM of mature articular cartilage production is related directly to the chondrocyte volume or function, and is composed of 3 major types of macromolecules: fibers (collagen and elastin), proteoglycans, and glycoproteins, which are synthesized and maintained by chondrocytes.

13

Together, these components help to retain water within the

ECM, which is crucial to maintaining its unique mechanical properties. Articular cartilage has a highly organized structure composed of 4 zones: the superficial (tangential) zone, middle (transitional) zone, deep (radial) zone, and calcified zone.14 The chondrocyte phenotype, cell shape, and the ECM structure vary among the different zones.

15

The deep zone is separated

from the calcified zone by the tidemark, which is a thin basophilic line that usually can be seen in a slide stained with hematoxylin and eosin. This represents the boundary between the mineralized and unmineralized regions.13 Underneath the calcified zone the subchondral plate can be appreciated. The relationship between cartilage and the underlying subchondral bone has particular importance when assessing joint health and determining treatment strategies. The articular cartilage is anchored to the subchondral bone via an interface of calcified cartilage, which as a whole makes up the “osteochondral unit”. Subchondral bone lies under the calcified cartilage, separated by the cement line. The subchondral bone plays a key role in mechanically and metabolically supporting the articular cartilage. The subchondral bone attenuates about 30% of the impact load, whereas cartilage only

attenuates 1-3%.16

Therefore, the physiologic cartilage subchondral bone unit is critical for the transfer of load to allow for normal joint articulation and movement. In contrast to articular cartilage, the subchondral bone is richly innervated by sensory and sympathetic nerve fibers, which

modulate bone regeneration, bone remodeling and articular surface homeostasis, and can be involved in pain generation.17 Furthermore, the subchondral bone contains blood vessels that penetrate into the calcified cartilage and metabolically support the deep layer through diffusion.

18

These vessels provide at least 50% of nutrient supply of the cartilage including

glucose, oxygen and water and can also transfer signaling molecules between the bone, cartilage and surrounding tissues.19 Posttraumatic changes to the subchondral bone result in imbalanced osteochondral homeostasis. Surface repairs are sensitive to subchondral bone changes as subchondral edema and subchondral sclerosis as a result of previous microfracture have been linked to a significant decline in

long-term results.20 Preoperative magnetic

resonance imaging (MRI) is an important tool to evaluate the status of the subchondral bone. The subchondral bone changes include: underlying subchondral cystic change, bone marrow edema (stress response), intralesional osteophyte and sclerosis (Figure 1, Figure 2 and Figure 3). Generally, bone marrow edema is recognized as a non-specific reaction of the bone to trauma, both acutely and from chronic repetitive injury due to overload, and may represent numerous non-specific histological characteristics that can include microtrabecular fracture/fracture healing.

21,22

Most importantly, subchondral bone and the adjacent calcified

articular cartilage undergoing repetitive microinjuries have the potential to initiate a chronic repair mechanism that eventually results in the formation of new bone (subchondral sclerosis). This is a common finding particularly after prior marrow stimulation techniques (MST) (intralesional osteophyte formation, bone marrow edema), which might be the underlying reason behind a recently reported 3 to 8 times higher failure rate and decreased satisfaction rate among patients who underwent MST prior to autologous chondrocyte implantation (ACI). 20,23-28 In our practice, in the presence of severe subchondral edema, large subchondral cysts or intralesional osteophytes, surface treatment is not indicated. Instead, replacement of the entire subchondral unit through osteochondral allograft transplantation is the preferred technique.

Note that this is an ongoing refinement of our institution’s cartilage restoration algorithm, as Ebert et al have reported less of a correlation between MRI edema and outcomes (MACI).29

Defect characteristics: Defect size, location, containment and chronicity have to be considered before the utilization of any surface treatment technique. MST represents the primary surface treatment option for smaller defects (< 2-4 cm2) on the femoral condyle. Even though it results in the formation of a fibrocartilage repair tissue which is mechanically inferior to hyaline cartilage, it appears adequate to fill smaller defects in this compartment.

30,31

For larger lesions (> 2-4 cm2) or cartilage defects in the patellofemoral

compartment, ACI or particulated juvenile allograft transplantation have reported satisfactory results.

32-38

For multiple and bipolar defects (etc. patella and trochlea) ACI demonstrated

good long-term results and is currently used in our practice as well.39 Containment of the defect also has to be considered, as vertical healthy cartilage shoulders around the defect are important both to contain the clot of MST and to minimize the potential for disruptive loads that could damage the graft. There are multiple techniques to make an uncontained defect contained, such as the use of an osteochondral autograft on the uncontained side, suturing the graft through small drill holes through the bone, or to the synovium. Generally, it is better to leave a minimally chondromalacic cartilage border than to remove the border and create an uncontained lesion. Furthermore, the chronicity of the cartilage lesion and the severity OA has to be considered as well. MST procedures are usually utilized for acute lesions while other surface therapies can be used for both acute and chronic defects.32-35,40,41 Moreover, in general, cartilage restoration demonstrates unfavorable clinical outcomes in the setting of advanced degenerative OA and therefore, surface treatment is not suggested for patients with more than 50% of joint space narrowing.

Technical aspects of Surface treatment options

Marrow stimulation techniques (MST): MST are widely used procedures and include subchondral drilling, abrasion arthroplasty, and microfracture.30,31 These techniques demonstrate good to excellent results in 60% to 80% of patients

42,43

with low morbidity,

comparatively quick recovery and a low complication rate. However, outcomes are poor and unpredictable for lesions in the patellofemoral compartment or when size of the defect is greater than 2-4 cm2.

44

Another limitation of MST procedures is their durability.

outcomes of MST have been shown to decline between 18 to 36 months.

24,26,44

40,41

The

Numerous

studies have shown postoperative changes in the subchondral bone plate after prior MST. 24-27 Animal studies have demonstrated osteocyte necrosis after microfracture

45

, as well as

changes in the subchondral bone in 30% to 50% of animals treated with microfracture, such as sclerosis, thickening of the subchondral bone, subchondral cysts, and osseous over-growth resulting in the formation of intralesional osteophytes and bone marrow edema.20,24,25,27 These findings are similar to those seen in chronic defects, which have yielded lower success rates after any type of cartilage repair.22 Revision cartilage repair with ACI demonstrates a higher failure rate and worse functional outcomes after prior failed MST,

20,23-25

which might be a consequence of the

subchondral bone changes following MST. Even though intralesional osteophytes can be removed surgically during ACI, they has a tendency to regrow.28 Moreover, the presence of severe bone marrow edema following MST may be predictive factor for ACI graft failure.20 Consequently, the indication of MST in our practice is largely limited to the athletic young population which have a small (< 2 cm2) isolated acute defect on the femoral condyle.

Case presentation I. Preparation of prior marrow stimulation treated lesion to allow for ACI/MACI

Fifteen-year-old male referred for continued lateral pain after marrow stimulation of a lateral femoral condyle lesion. At the staging arthroscopy (with concomitant distal femoral varus osteotomy), the monopolar focal lateral femoral condyle defect was noted to have friable fibrocartilage with suggestion of basilar vascularity. The appearance was confirmed at arthrotomy (Figure 4/A). The fibrocartilage was debrided to healthy bone with vertical marginal walls (Figure 4/B). Had there been resultant bone loss of greater than 6 mm, cancellous autograft bone would be impacted. To reduce the “contamination” of the ACI/MACI cells with marrow cells, after hemostasis is achieved with the tourniquet deflated, a deep collagen I-III patch is secured with glue (and suture as needed) to the bony base with chondrocytes facing toward the joint (Figure 4/C). The final step is placing a second collagen I-III membrane on the first in the case of MACI or suturing the membrane flush with the surrounding cartilage, sealing with fibrin glue and then injecting cultured chondrocytes in the case of ACI (Figure 4/D). During 2nd look arthroscopy at 6 months follow-up the ICRS score was 12/12 with mild overgrowth (Figure 4/E) that was debrided to the level of surrounding cartilage (Figure F).

Autologous Chondrocyte Implantation (ACI) ACI, and its successor, Matrix Associated Chondrocyte Implantation (MACI) is a well-established cartilage repair procedure with a high satisfaction rate over a long-term follow up. 32-34 Several studies with follow-up of up to 20 years demonstrated good outcomes in more than 80% of patients with ACI for the treatment of chondral defects of the femoral condyles and more than 70% in the patellofemoral joint

32-35

Bipolar cartilage lesion can be

successfully treated both in the tibiofemoral and the patellofemoral joint . 46-48 However, the implantation of immature, minimally pre-differentiated chondrocytes has the draw back that a structured and phased rehab progression is necessary to protect the graft while it matures. These phases are generally perceived to be: proliferative stage, in

which chondrocytes are proliferating and the tissue fills the defect (up to 6 weeks); transition stage with soft, primitive repair tissue (6-12 weeks); early maturation stage, where repair begins to solidify and matrix consists mainly of type-II collagen, aggrecan, and other matrix proteins (12-26 weeks); and finally the late maturation stage, with fully matured chondrocyte and matrix (26 weeks to 3 years).34,35 Consequently, the graft is sensitive to loading (especially shear forces) until the late maturation stage, which requires close follow-up of the patient with a strict and relatively long postoperative rehabilitation.

ACI / MACI is a 2-stage procedure. The first stage is an arthroscopic assessment of the joint and a cartilage biopsy. The biopsy is taken from a non-weightbearing area of the joint, our preferred location is the superior and the lateral intercondylar notch. The current generation of the ACI in the US is termed MACI. Here, the chondrocytes are cultured on a collagen membrane (Type I/III bilayer collagen membrane) before shipping. The secondary stage is the implantation of the MACI membrane, most commonly through an arthrotomy. The cartilage defect is exposed and prepared. Defect preparation is critical: radical debridement of all fissured and undermined articular cartilage surrounding the full-thickness chondral injury to healthy contained cartilage is desirable. Early failures have been seen due to inadequate debridement with poor integration to adjacent cartilage or the bone base, leading to progression of disease in the adjacent nondebrided fissured cartilage or delamination of the repair tissue from the damaged native tissue. Small ring or closed curettes are used to debride any degenerated articular cartilage back to healthy host cartilage. Maintaining an intact subchondral bone plate without subchondral bone bleeding is important. It is essential not to perforate the subchondral bone plate so that a mixed marrow cell population does not populate the chondral defect in addition to the end-differentiated chondrocytes that have been grown in vitro.49

For patients with prior MST, if there are alterations of the subchondral bone (sclerosis or intralesional osteophytes) and ACI is the chosen technique due to the location or number of defects, these alterations have to be addressed with use of a high-speed bur under constant cold irrigation to avoid overheating the bone and the surrounding cartilage to the level of the adjacent subchondral bone.28 If subchondral bleeding occurs it can be managed with the application of fibrin glue to the subchondral bone surface.

Definition of partial or complete graft failure: Treatment failure may be defined very broadly as recurrent symptoms of pain and loss of patient reported function and outcomes as measured by a PROM instrument. Single end point definitions of treatment failure such as the conversion to a total knee replacement are generally misleading as there may be numerous reasons why patient have not converted. Those definitions may have a place for the cost benefit analysis as compared to total joint arthroplasty, however, they typically do not inform about the patient’s perception or objective function of the knee joint. Graft failure of a surface procedure can be defined morphologically, with MRI or arthroscopic surgery demonstrating partial or complete delamination of the graft, inadequate filling or fibrosus filling of the defect. Partial graft failure is defined as the removal of less than 25% of the graft area or less than 25% of the defect being underfilled. Complete graft failure is defined as more than 25% of the implanted graft being removed or more than 25% of the defect being underfilled. Another type of failure is the progression of disease, when cartilage lesions develop in a different part of the joint or more severe OA changes are apparent (etc, joint space narrowing, osteophyte formation) in the joint.

Partial cell surface graft failure: In case of partial graft failure, a decision has to be made whether the integrity of the entire surface repair is threatened, or if just a portion of the graft may have delaminated without compromising the remainder of the repair tissue.

Additional consideration has to be given to the question whether this constitutes a biologic or a mechanical failure as this may inform on the choice of the revision technique. Biological failure can usually be suspected if patchy shallow repair islets are present that lack complete integration into the surrounding tissues. This type of failure can easily be mistaken for a partial failure but, in fact, constitutes a complete failure of the implant, and the patient is therefore not an ideal candidate for a partial “rescue” procedure. If the failure of the graft is limited to one portion of the graft, appears to be well circumscribed and constitutes a delamination or tear in the repair cartilage, it may more likely be a true mechanical reinjury of the graft tissue. In that case a rescue procedure can be utilized. In our practice debridement of the delaminated graft and/or abrasion arthroplasty are most commonly utilized, providing a well-contained defect. If the debridement exposes subchondral bone, a limited microfracture procedure can be performed. In some cases, there may have been marginal malalignment (e.g., 3° varus) that was not corrected, and correction should be considered as part of revision surgery. A special case of partial failure is the situation of a persistent painful subchondral edema underlying the intact chondral graft. (Figure 6). This is a difficult situation to salvage as it requires the indirect treatment of the subchondral bone without disrupting the repair tissue. We have used a targeted subchondroplasty approach for this purpose in a limited number of patients and were able to show that we could reduce pain for an average of 19 months before the implant eventually failed clinically as defined by a decline in KOOS scores. The use of bone marrow concentrate plus demineralized bone matrix injections may be able to provide a better rescue of these “stress fracture reactions”, however, we do not have any scientific rationale at this time to support this notion.

Revision of complete ACI graft failure: Revision of a complete failure of a cell-based procedure such as ACI/ MACI will need to address the primary reason for failure. If the

subchondral bone integrity is the reason for failure it may not be a recommended strategy to redo a cell surface procedure. In that case, the use of a subchondral bone restoring approach, such as an osteochondral allograft, may be preferred. In case of a biological failure or disease progression a careful analysis of the joint environment has to be performed. It is generally advisable to critically re-assess additional pathologies such as meniscal loss and malalignment. Particularly axial alignment should be carefully scrutinized. If a mechanical re-injury and complete delamination is suspected, then a revision cell surface procedure such as ACI/MACI can be attempted. However, ideally, the reason for the mechanical failure should be identified and corrected. In the presence of significant bone marrow edema, subchondral cysts, or sclerotic subchondral changes, not only the failed ACI graft, but also the altered subchondral bone has to be revised with a technique that replaces the subchondral bone such as OCA or, in limited cases, sandwich ACI. The hardest decision for surgeon and patient is if the cause of failure is determined to be progression of disease. Patients in the older age range for cartilage repair procedures (45-50 years), progression to MRI and X-ray criteria indicating moderate OA or the late identification of systemic inflammatory arthritis (RA, Psoriatic etc) should be carefully evaluated. Typically, a revision chondral repair procedure in this patient population may not be cost effective or satisfactory to the patient or the surgeon due to the risk of recurrent failure. In those cases, conservative therapy and, eventually, unloading osteotomy, partial or total knee arthroplasty should be discussed as the next therapeutic step.

Case presentation II. Rescue of a partially failed ACI Sixteen-year-old female with persistently symptomatic focal medial femoral condyle lesion treated with ACI (Figures 5/A & B). At one year post-op, her lateral symptoms had improved but not completely resolved. The ACI was predominantly healed in the periphery but had a

region of full and near full thickness failure in the central region (Figure 5/C). This was treated with a single autograft osteochondral plug (Figure 5/D).

Particulated juvenile allograft transplantation (PJACT) Recent technological advances in the field of cartilage restoration methods have led to the utilization of particulated juvenile allograft cartilage (DeNovo NT Natural Tissue Graft ,Zimmer, Warsaw, IN, USA).50 This prepackaged allograft consist of juvenile live chondrocytes within their native extracellular matrix from donors typically younger than 13 years. These chondrocytes demonstrated 100-fold increase in proteoglycan production and faster growth compared to adult chondrocytes with no immunologic reaction.51 The graft is prepared as approximately 1mm3 cubes and stored in blister packs containing storage medium. One blister pack can cover up to 2.5 cm2 defect area.37 PJAC can be utilized for focal articular cartilage defect(s) with stable shoulders (contained) or in conjunction with OATS or OCA when the defect cannot be completely covered with the osteochondral graft. In the second case the PJAC is applied around the OCA. In our practice PJAC is primarily indicated for focal patella defects with intact subchondral bone. Several studies demonstrated improved functional outcomes, hyaline-fibrocartilage filling histologically and normal to near normal cartilage repair on MRI.36-38

PJACT Surgical Procedure PJACT can be performed open and arthroscopically. In both techniques the cartilage defect is identified and the defect is prepared as described above: debridement of all fissured and undermined articular cartilage; vertical cartilage shoulders; removal of the calcified layer without entering the into the subchondral bone. Open technique: - 2 techniques can be utilized: -

In situ gluing: PJAC is applied to defect and fibrin glue is applied directly to PJAC graft.

-

Ex situ gluing: foil mold is made of the defect and the PJAC graft is distributed in the mold. The fibrin glue is then added to the cartilage and the glue is allowed to cure (3-10 min). Following, the fibrin glue/PJAC construct is separated from the fold in one piece, and fresh fibrin glue is applied to the base of the defect and then the fibrin glue/PJAC construct is transported to the defect.

We suggest the utilization of the first technique (in situ gluing), which requires less construct manipulation and may provide better fixation to the subchondral bone. Important factors to keep in mind is the size requirement of 1 package of graft per 2.5 cm2 defect with larger defects requiring additional packages. Moreover, the monolayer construct must be thinner than the surrounding cartilage shoulders to minimize the potential for disruptive loads which could result in graft loss. Arthroscopic technique: First the joint is emptied of fluid, the PJAC graft is loaded into a 2.7-4 mm arthroscopic cannula retrogradely, and the PJAC is delivered to the defect using the corresponding trochar. The graft is then smoothened using a probe and fibrin glue is injected into the defect area using a needle. Subsequently, the probe is used to shape the graft (below the surrounding cartilage shoulders) and the fibrin glue is allowed to set. Note: Do not fill the joint with fluid for arthroscopy following PJACT as it can dislodge and/or dissociate the graft. The stability of the graft is tested with repetitive passive movements of the joint after any of the techniques and if there is concern, the PJAC can be protected with a collagen I-III membrane. PJACT failure: A recent study by Tan et al.52 evaluated (second-look arthroscopy, histology) four patients who failed PJCAT for osteochondral defects in the talus. Of those, 2 patients demonstrated a lack of integration of the allograft into the surrounding cartilage, and 2 had failures associated with impingement. Histological examination demonstrated fibrotic repair tissue (Type 1 collagen) with depleted proteoglycan and Type II collagen. In these cases, all patients had a large lesion (≥15 mm in diameter) that was initially treated with

microfracture and no additional patient or operative factors associated with poor outcomes were identified. This study is in line with our observations that intact subchondral bone is necessary for a successful surface treatment. In case of partial graft failure (< 25%) debridement of the delaminated graft and/or MST is performed as a first step. If this procedure fails, osteochondral autograft or OCA is our next choice. In case of complete failure either ACI or OCA can be used depending on the status of the subchondral bone, defect characteristics, patient characteristics and reason of the failure as we discussed above.

Postoperative rehabilitation after Cell Surface procedures: Appropriate rehabilitation of chondral procedures has been largely focused on the weight bearing status of the post-operative period. Early motion is emphasized in the first 6 weeks using continuous passive motion (CPM), active and isometric straight leg raises, stationary bike by 3 weeks and touchdown weight-bearing. Delayed early rehabilitation and restrictions to ROM may result in limited knee motion and development of arthrofibrosis. From 7-12 weeks patients progress from partial to full weight bearing. Ebert et al53 have described “accelerated” rehabilitation protocols allowing weight bearing progressively after 6-8 weeks of non-weight bearing. After learning about significant non-compliance regarding the non-weight bearing status of our patients in some preliminary qualitative research work, we have empirically moved past these guidelines and have generally adopted a weight bearing as tolerated approach unless the lesion is very large (>8cm2) or additional procedures (radial meniscus repair or medial meniscus transplant) preclude an early weight bearing concept. Functional activities are allowed from 4 months onwards including bicycle, treadmill, elliptical trainer, outdoor distance walking, hiking and swimming. Jogging is allowed starting at 12-14 months if a normal knee exam is present and near normal MRI, (minimal subchondral bone marrow edema and isotonic appearance of the ACI graft to the adjacent articular cartilage). Patients are restricted from inline impact

activities (running) for 12 to 18 months and cutting sports are allowed after 18 months. The ACI rehabilitation protocol considers each patient’s individual surgical reconstruction, graft maturation, and previous activity level, which are incorporated into individualized variations in the rehabilitation protocol. 24 An additional problem that has a large influence on the overall outcome is the recovery of muscular control and strength in the operative leg. Particularly, large surgical approaches and multiple procedures can lead to severe weakening of the quadriceps muscle. In a study evaluating eccentric and concentric quadriceps strength Howard et al. observed that the recovery of quadriceps strength takes up to one year and quadriceps isolated tasks such as sit-to-stand, and step-up and over may not return to normal levels even after that time.54 Therefore it is important to address extensor mechanism weakness continuously and employ potential new technologies such as blood flow restrictive therapy and high intensity quadriceps training in order to overcome quadriceps weakness.55,56

Conclusion It is well established that a portion of all biologic procedures fail. The key to success in the long-term is admitting/recognizing the failures, identifying the root causes and then modifying revision treatment strategies to optimize outcomes. Articular cartilage surface treatments are sensitive to the integrity of the subchondral bone and certain defect characteristics. With intact subchondral bone, MST represents the primary surface treatment option for smaller defects (< 2-4 cm2) on the femoral condyle, while for larger lesions (> 2-4 cm2) or cartilage defects in the patellofemoral compartment ACI or PJACT showed good results. With compromised subchondral bone, other techniques such as OATS, OCA or sandwich ACI are preferred. Optimized surgical techniques and adequate postoperative rehabilitation is crucial to provide an optimal environment for chondrogenesis and/or maturation of the graft with maximized graft protection.

If surface treatment fails, the decision-making process on which subsequent technique to choose can become challenging due to possible alterations in the subchondral bone, or progression of the disease. Following failed MST, revision ACI has demonstrated a higher failure rate and worse functional outcomes, which might be the consequence of subchondral bone changes following MST. Consequently, if preoperative MRI indicates severe bone marrow edema below the cartilage lesion following prior MST, utilization of OCA or sandwich ACI is recommended instead of ACI. In case of partial graft failure following either ACI or PJACT, a rescue procedure (debridement and/or abrasion arthroplasty) can be utilized if failure of the graft is limited to one portion of the graft, is well circumscribed and constitutes a delamination or tear in the repair cartilage. If the debridement exposes subchondral bone, a limited microfracture procedure can be performed. In case of complete graft failure, the primary cause for failure should be identified and addressed. If a subchondral bone alteration is felt to be the reason for failure a subchondral bone restoring approach, such as OCA, may be preferred. If a mechanical re-injury and complete delamination is suspected, then a revision cell surface technique can be considered. In case of a biological failure a careful analysis of the joint environment has to be performed. It is generally advisable to critically re-assess additional pathologies such as meniscal deficiency and malalignment. Finally, if the reason for failure is progression of disease, especially with progression to X-ray criteria indicating moderate OA in a patient in the older age ranges for cartilage repair procedures (45-50 years), conservative therapy and eventually unloading osteotomy, partial or total knee arthroplasty should be discussed as the next therapeutic step.

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Figures

Figure 1. Magnetic resonance imaging (3 Tesla) of a full thickness cartilage defect with a subchondral cyst. Axial (A) and sagittal (B) fat-suppressed intermediate-weighted images demonstrating a full thickness cartilage lesion with an underlying subchondral cyst

Figure 2. Magnetic resonance imaging (3 Tesla) of a subchondral bone edema and delaminated fibrocartilage following microfracture. MRI also indicates a posterior meniscus root tear. Sagittal (A) and coronal (B) fat-suppressed intermediate-weighted images

demonstrating a subchondral bone edema and delaminated fibrocartilage following failed microfracture.

Figure 3. Magnetic resonance imaging (3 Tesla) of an intralesional osteophyte after prior failed microfracture. Sagittal (A) and coronal (B) fat-suppressed intermediate-weighted images demonstrating an intralesional osteophyte after prior failed microfracture.

Figure 4. Case presentation I. – Surgical images of an autologous chondrocyte implantation after prior failed microfracture. (A) Monopolar focal lateral femoral condyle defect with friable fibrocartilage after prior microfracture. (B) Fibrocartilage was debrided to healthy bone with vertical marginal walls and the defect was measured. (C) Deep collagen I-III patch is secured with glue and sutures to the bony base with chondrocytes facing toward the joint. (D) A second collagen I-III membrane on the first membrane, in the case of MACI the chondrocytes are facing down or in case of ACI the membrane is sutured flush with the surrounding cartilage, sealing with fibrin glue and then the cultured chondrocytes are injected. (E and D) Second look arthroscopy at 6 months follow-up. (E) Mild cartilage overgrowth (ICRS score was 12/12). (F) Overgrowth was debrided to the level of surrounding cartilage.

Figure 5. Case presentation II. – Surgical images of a partially failed ACI rescue. (A and B) Focal medial femoral condyle lesion treated with ACI. (B and C) Revision surgery 1 year after primary ACI. (C) ACI was predominantly healed in the periphery but the central region of the graft had a near full thickness failure. (D) Revision surgery with a single autograft osteochondral plug to the central region.

Knee Injury and Osteoarthritis Outcome Score (KOOS)

Figure 6. Results of 6 patients after subchondroplasty for intact chondral repair procedures with persistent painful subchondral bone edema. Case example of a patient after ACI to the medial femoral condyle.