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Focal articular chondral lesions are a common finding among patients presenting with knee pain. If symptomatic and unresponsive to conservative treatment, cell transplantation techniques offer a unique solution to address larger defects by engineering chondrocytes to integrate within the subchondral bone of the lesion and regenerate cartilage.
Objectives
The purpose of this article is to review the evaluation of, and clinical decision making for, patients being considered for cell transplantation and the available techniques an orthopaedic surgeon has at their disposal.
Methods
A review of recent literature regarding cartilage defects in the knee and cell transplantation techniques was performed to provide strategies for evaluating and treating chondral defects with matrix-induced autologous chondrocyte implantation (MACI) or particulated juvenile allograft cartilage (PJAC) procedures.
Results
Chondral defects in the knee can be treated with patients’ own chondrocytes embedded into a collagen membrane as a MACI procedure, or minced autologous donor cartilage that is then implanted onto a scaffold as a PJAC procedure. These cell transplantation techniques offer advantages compared to bone marrow stimulation or mosaicplasty, and have shown clinically significant improvements in outcome scores with low rates of complications.
Conclusion
Cell transplantation techniques such as MACI and PJAC offer treatment options that can effectively address large full-thickness chondral defects in the tibiofemoral joint or patellofemoral joint that may respond poorly to bone marrow stimulation or mosaicplasty.
While all cartilage defects are not symptomatic, they do have a propensity to cause pain, joint dysfunction, and interfere with a patient's quality of life to levels equivalent of those in a patient suffering from end stage OA awaiting knee arthroplasty.
Focal cartilage defects in the knee impair quality of life as much as severe osteoarthritis: a comparison of Knee injury and Osteoarthritis Outcome Score in 4 patient categories scheduled for knee surgery.
Cell transplantation techniques such as autologous chondrocyte implantation (ACI) and particulated juvenile allograft cartilage (PJAC) are treatment options with the goal of using healthy chondrocytes to restore the patient's knee cartilage surface congruity. Cartilage restoration surgery for focal osteochondral defects results in improved patient reported outcomes, delayed OA progression on advanced imaging, and delayed clinical need for total knee arthroplasty.
Here we discuss the evaluation of, and clinical decision making for, patients being considered for cell transplantation and the available techniques an orthopaedic surgeon has at their disposal.
MACI is the third-generation of a cartilage restoration procedure aimed at treating symptomatic medium-to-large full-thickness chondral lesions by engineering patients’ own chondrocytes to integrate within the subchondral bone of the defect and regenerate cartilage.
The chondrocytes are embedded within a collagen matrix and have the ability to reproduce a hyaline-like layer similar to native cartilage, as opposed to an inferior fibrocartilage layer found following drilling, microfracture, or debridement.
The first description of cell engineering used in a clinical setting was by Peterson et al in 1984, who pioneered the first generation periosteal patch ACI (p-ACI).
This procedure involved harvesting chondrocytes from a healthy, lesser weight-bearing site of distal femur cartilage during first-look arthroscopy. The chondrocytes were cultured for 14-21 days before a second, open procedure during which the cells were injected into the defect. The filled defect was then covered with a periosteal flap harvested from the patient's tibia that was sutured into place.
Results generally showed clinically significant improvements in pain and function over medium and long-term follow up, but there remained issues with the implants forming fibrous hyaline cartilage that contributed to worse clinical grades and reoperation.
Issues found with this first-generation ACI include the need for a second surgical procedure to harvest the periosteal flap from the tibia, and then the process of suturing the periosteal flap into place over the treated defect.
To address some of the problems with harvesting a periosteal flap, a second-generation ACI procedure was designed to replace the periosteal flap with new cover consisting of porcine collagen I and III bi-layer membrane (c-ACI).
Articular cartilage treatment in high-level male soccer players: a prospective comparative study of arthroscopic second-generation autologous chondrocyte implantation versus microfracture.
followed 41 professional and semiprofessional male soccer players who received either microfracture or c-ACI over a minimum of 4 years (mean 7.5). The athletes who received microfracture returned to sport earlier (8.0 months vs 12.5 months) and both groups had a significantly improved International Cartilage Repair Society (ICRS) score at 2-year follow-up. However, the final percentage of athletes who returned to sport was not statistically different between groups. Additionally, those who received microfracture had a decrease in ICRS score from 2 year to final follow up while those with c-ACI had stable ICRS scores over that time, ending with significantly higher scores at final follow up.
Articular cartilage treatment in high-level male soccer players: a prospective comparative study of arthroscopic second-generation autologous chondrocyte implantation versus microfracture.
Despite changing the substance that would cover the filled defect, the second-generation procedure still had similar drawbacks. For both p-ACI and c-ACI, once the chondrocytes are injected into the defect, they are subject to gravity and thus may not integrate in a uniform pattern across the articular lesion.
Despite the covering material, these chondrocytes may still be expelled from the defect and thus exists the possibility of graft hypertrophy, delamination, or failure.
Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: a randomized clinical trial.
As a therapeutic option aimed at avoiding the complications associated with the first two generations of ACI and simplifying the procedure, a third-generation procedure was conceived and met United States Food and Drug Administration approval in 2016. For MACI, chondrocytes harvested in an initial arthroscopic procedure are expanded in a laboratory setting and then suspended in a resorbable Type I/III collagen membrane scaffold before being implanted into the chondral defect and covered with fibrin glue.
This eliminates the need for a native periosteal patch, and because the chondrocytes are embedded within the matrix, they can uniformly fill the defect and withstand the influence of gravity.
Evaluating candidates for MACI
Evaluation of a patient who presents with a chondral defect who may be a candidate for MACI starts with the history and physical examination. While not specific nor sensitive for focal cartilage lesions vs other intra-articular etiologies, a history and clinical examination are important to determine the timeframe of symptoms, prior treatment, malalignment, instability, or concurrent pathologies.
Cartilage lesions may present after an acute traumatic injury, such as a fall or twisting injury that may be accompanied by an ACL rupture, meniscus tear, or patellar dislocation. Alternatively, patients may have an insidious onset of pain associated with recurrent microtraumas causing degeneration of the cartilage. Physical examination can be the first line of detecting lower extremity malalignment such as genu valgum/varum, malrotation, or patellofemoral maltracking.
Routine radiographic imaging of the symptomatic knee should be ordered with the following views: Anteroposterior, perfect lateral, merchant, 45-degree flexion posteroanterior weight-bearing, and full-length standing limb length. These radiographs may reveal loose bodies or fracture because of a traumatic cartilage injury, skeletal malalignment, patella alta, trochlear dysplasia, or evidence of more widespread osteoarthritic joint changes.
Advanced imaging with computed tomography or magnetic resonance imaging (MRI) allows for better characterization of the lesion to best counsel the patient and guide treatment.
However, caution should be taken when estimating lesion size as preoperative MRI has been shown to underestimate total lesion size by 65% compared to measurements taken at time of open cartilage repair.
MRI will also help reveal an accompanying meniscal or other ligamentous injury that should be considered with surgical decision making.
Indications
MACI is indicated as first line treatment for patients less than 55 years of age with single or multiple Outerbridge Grade III or IV full-thickness chondral lesions ≥2 cm2, traditionally without bony involvement although MACI has been Food and Drug Administration-approved for symptomatic defects both with and without bony involvement in adults.
Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study.
Because of the ability to cut the MACI scaffolding to the defect's exact dimensions and nature of the cells being embedded into the matrix, this technique is more easily performed in both patellofemoral joint (PFJ) and tibiofemoral joint (TFJ) spaces. Along with this, outcomes of MACI in the PFJ have been reported to be superior to those in the TFJ.
Contraindications
Absolute contraindications to MACI include inflammatory arthritis, a recent or active infection, uncorrected congenital blood coagulopathies, diffuse joint OA, allergy to porcine or bovine products or aminoglycosides such as gentamicin, and any inability to adhere to the strict postoperative rehabilitation protocol. Because chondral defects can be caused by musculoskeletal comorbidities such as genu valgum/varum, recurrent patellar instability, or meniscal/ligamentous insufficiency, these pathologies left uncorrected are risk factors for failure following isolated cartilage repair and, therefore, are contraindications to MACI unless addressed before or at the time of the MACI procedure.
Stage 1—Diagnostic arthroscopy and cartilage biopsy
Most patients presenting with a symptomatic chondral lesion should first trial a period of conservative treatment consisting of activity modification and physical therapy. This nonoperative period should generally be 3 to 6 months, though it can be less in younger patients presenting with traumatic etiology.
In those who fail conservative therapy, the next step should be a diagnostic arthroscopy. This allows the surgeon to better visualize the location and extent of cartilage damage along with any concurrent intra-articular injury. This stage should be performed as a standard knee arthroscopy using medial and lateral portals while patient is supine. The medial and lateral tibiofemoral compartments along with PFJ should be visualized to identify the chondral damage and presence of loose bodies and meniscal or ligamentous pathology. Once identified, the edges of the chondral defect can be debrided until the lesion's rims are stabilized.
If the defect is determined to be amenable to MACI treatment, a biopsy should be taken from a healthy region of nonweight-bearing cartilage. This can usually be taken from the superolateral region of the intercondylar notch using a curette. The biopsied cartilage should total 200 to 300 mg which will then be sent for chondrocyte isolation and expansion.
This process of chondrocyte culturing takes approximately 6 weeks. During this time, many patients may experience symptomatic relief due to arthroscopic debridement of their defect and thus may not require the second-stage chondrocyte implantation.
Cultured cells are able to be kept in a cryopreserved state for up to 5 years, so a patient who initially experiences symptomatic relief after debridement but has recurrence or progression of symptoms within this 5-year window will not require a repeat cartilage biopsy.
Stage 2—Implantation of the MACI graft
The second stage of MACI treatment was originally described as an open procedure, though arthroscopic implantation has proven to be a safe alternative offering a significantly shorter hospital stay and faster recovery with improvements in clinical and radiologic scores at short- and mid-term follow-up.
Arthroscopic treatment of patellar and trochlear cartilage lesions with matrix encapsulated chondrocyte implantation versus microfracture: quantitative assessment with MRI T2-mapping and MOCART at 4-year follow-up.
Arthroscopic implantation may be done through the standard medial and lateral arthroscopic portals for most defect locations. The arthrotomy technique depends on location of the defect—preferred approach for patellofemoral lesions is via a lateral parapatellar approach to maintain the integrity of the medial patellofemoral ligament and avoid the vastus medialis as well as iatrogenic patellofemoral instability. The same approach should be taken for lesions of the lateral femoral condyle. Lesions of the medial femoral condyle may necessitate a medial parapatellar approach to allow for adequate visualization of the condyle, but again care should be taken to avoid iatrogenic damage to the medial patellofemoral ligament or to the menisci and healthy regions of cartilage.
After visualization has been achieved with arthrotomy or arthroscopy, all damaged and fibrous tissue in the defect is debrided to the level of subchondral bone, making sure to remove the calcified cartilage layer so that the implanted cell sheet has contact with the subchondral bone. It is important to ensure the defect has stable, vertical walls and that you do not penetrate the subchondral bone (Fig. 1). It may be helpful to deflate the tourniquet after debridement has finished to test if the lesion's base experiences significant bleeding. This should be controlled prior to moving on to graft implantation, as significant bleeding may displace the MACI graft.
Fig. 1A patellar chondral lesion after debridement to ensure vertical, stable walls perpendicular to the defect's base. Note that the subchondral bone has not been penetrated.
The MACI kit comes with a template sheet that can be cut to the proper dimensions of the defect. The MACI implant is packaged as a 3 cm × 5 cm cellular sheets of a resorbable porcine Type I/III collagen membrane that has a rougher side that has been seeded with the chondrocytes that will face the subchondral bone. The density of these MACI implants are 500,000 cells/cm2 to 1,000,000 cells/cm2. The opposite, smoother side of the matrix will face the articular surface. The sheet should remain cell-side facing up and hydrated with the accompanying media. The modified template is placed underneath the MACI sheet, only coming into contact with the smooth side, and the MACI implant is cut to the dimensions of the template (Fig. 2).
Before the MACI implant is placed into the defect, care should be taken to ensure there is no active bleeding at the subchondral bed before a very thin layer of fibrin glue is applied to the defect base (Fig. 3). The MACI implant is then placed with the correct orientation ensuring that the rough, cell-embedded side is face down. Light pressure is held on the implant for 3 minutes, before a layer of fibrin glue is applied to the edges of the MACI implant (Fig. 4). Chondrocytes will translocate from the fibrin glue matrix to subchondral bone following the procedure.
Consensus on rehabilitation guidelines among orthopedic surgeons in the United States following use of third-generation articular cartilage repair (MACI) for treatment of knee cartilage lesions.
According to this consensus, patients with a contained lesion of the PFJ can initiate full weight bearing immediately postoperatively and can be released to unrestricted activities of daily living as early as 3 months, with release to running at 7 to 9 months. Conversely, poorly contained lesions require partial weight bearing (PWB) no more than 20% body weight with longer time before progression. Additionally, patients who receive concomitant osteotomy require a period of nonweight bearing for 2 weeks, then PWB at 2 to 4 weeks so long as they have improved pain and are gaining a normal gait pattern.
Consensus on rehabilitation guidelines among orthopedic surgeons in the United States following use of third-generation articular cartilage repair (MACI) for treatment of knee cartilage lesions.
For patients receiving tibiofemoral treatment, they should expect to be PWB for 2 weeks if the treated lesion was small, and 6 weeks PWB for patients with larger lesions. Gait training along with closed chain strengthening exercises can begin at 8 weeks postoperatively. Return to full activities should be expected around 8 months postoperatively.
All patients, regardless of defect location or concomitant osteotomy, should immediately start continuous passive motion from 0° to 45° and increase by 15° each week with the goal of achieving full range of motion at 7 to 9 weeks on average.
Consensus on rehabilitation guidelines among orthopedic surgeons in the United States following use of third-generation articular cartilage repair (MACI) for treatment of knee cartilage lesions.
Consensus on rehabilitation guidelines among orthopedic surgeons in the United States following use of third-generation articular cartilage repair (MACI) for treatment of knee cartilage lesions.
Those with multiple defects treated or concomitant procedures may require a slower return to activity personalized to their case and progress.
Outcomes of MACI
A total of 15,609 cartilage procedures were performed from 2010-2016, with a linear increase over this period. ACI was performed 2.6 ± 1.7 per 100,000 procedures and overall increased by 626.6% in this span.
Management of chondral lesions of the knee: analysis of trends and short-term complications using the national surgical quality improvement program database.
In examining the data from the first 1000 consecutive patients to receive MACI (Vericel), Carey et al found an evenly split ratio of male-to-female (49.6%-to-50.4%) recipients with a mean age of 34.0 years.
The same meta-analysis compared outcomes of cartilage restoration techniques within the PFJ but grouped all generations of ACI/MACI together as the chondrocyte cell–based therapy group. This group consisted of 38 studies and was compared to pooled results of osteochondral allograft transplantation (OCA), osteochondral autograft transfer, bone marrow stimulation therapy, and scaffold treatment. Chondrocyte cell-based therapy had an overall failure rate of 5.7% [95% CI 3.9%-8.2%], which was not statistically different than the overall pooled failure rate of all cartilage treatments studied (6.8%; 95% CI, 4.7%-9.5%). 83% of ACI/MACI studies had significant improvement in clinical outcome scores.
Third-generation MACI outcomes have been reported across numerous case series, comparative cohort studies, and randomized controlled trials (RCTs), with significantly improved clinical and patient reported scores from baseline for both tibiofemoral and patellofemoral defects at short-, mid-, and long-term follow up out to 10 years postoperatively.
Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: a randomized clinical trial.
Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study.
Kon et al followed 32 patients treated with MACI to the PFJ over 10 years and found their International Knee Documentation Committee (IKDC) subjective scores, EuroQol visual analog scale scores, and Tegner scores all significantly improved from baseline and remained stable through final follow up.
One patient progressed to total knee arthroplasty due to persistent pain and swelling, and there was a total failure rate of 12.5% when including patients who did not achieve a clinically significant improvement.
Of note, in analyzing the influence of other variables on the final outcomes, the authors found that women with patellar lesions who required an additional realignment procedure had worse IKDC subjective outcome at the 10-year follow-up.
In a prospective RCT evaluating clinical outcome measures following MACI vs microfracture over 24 months, MACI was found to be significantly more effective than microfracture in terms of Lysholm (P = .005), Tegner (P = .04), ICRS patient (P = .03), and ICRS surgeon (P = .02) scores at final follow up.
The Superiority of MACI implant to Microfracture Treatment, or SUMMIT, trial prospectively randomized patients to receive MACI or microfracture for symptomatic chondral defects >3 cm2 on the femoral condyles or trochlea.
The study group found mean Knee injury and Osteoarthritis Outcome Score (KOOS) pain, function, activities of daily living, knee-related quality of life, and other symptoms subscores to be significantly more improved from baseline to 2-year follow-up in MACI patients compared to those receiving microfracture.
At 5-year follow-up, KOOS pain, function, and activities of daily living subscores remained significantly more improved from baseline in the MACI group compared to microfracture.
Improvements in KOOS quality of life and other symptoms subscores were nonsignificantly greater in the MACI group at the 5-year timepoint. At both 2- and 5-year follow-up, the degree of defect fill seen on MRI (measured by the scale of Whole Organ MRI Score) was nonsignificantly greater in the MACI group. There were no significant adverse events with either group through final follow-up.
There is a paucity of research comparing MACI directly to other cartilage restoration procedures such as OCA. In a 2012 prospective RCT with minimum 10-year results published by Bentley et al, 100 consecutive patients with symptomatic cartilage defects in the knee were randomized to receive either second-generation ACI or OCA mosaicplasty.
Minimum ten-year results of a prospective randomised study of autologous chondrocyte implantation versus mosaicplasty for symptomatic articular cartilage lesions of the knee.
Patients receiving ACI had significantly greater improvements in the modified Cincinnati knee score (P = .02) and better Stanmore-Bentley functional rating scores, though this did not reach significance (P = .27). The failure rate for ACI (17%) was significantly less than seen with mosaicplasty (55%; P < .001), displaying the advantage that even older generations of ACI have over OCA mosaicplasty when treating large articular cartilage defects (mean size 4.41 cm2 in the ACI group and 4.0 cm2 in the mosaicplasty group).
Minimum ten-year results of a prospective randomised study of autologous chondrocyte implantation versus mosaicplasty for symptomatic articular cartilage lesions of the knee.
Andrade et al completed a systematic review including 25 studies evaluating ACI/MACI in the PFJ. This analysis found clinically significant improvements in all studies measuring IKDC and Kujala for ACI/MACI patients. Only 2 studies did not achieve the minimum clinically important difference for Lysholm score and 1 for the KOOS score. ACI/MACI had a weighted mean patient satisfaction of 84% and weighted failure rate of 5%.
The low rates of failure within the PFJ suggest that ACI/MACI is well adept at reconstituting the native articular topography in a region that may be difficult to otherwise match congruity with other cartilage restoration procedures.
Another factor to consider when evaluating a patient who may need MACI is any prior history of microfracture or other marrow stimulation procedure. Schuette et al
Primary autologous chondrocyte implantation of the knee versus autologous chondrocyte implantation after failed marrow stimulation: a systematic review.
performed a systematic review of 7 studies including a total of 1335 patients comparing outcomes in primary ACI vs secondary ACI after failed bone marrow stimulation for large chondral lesions (mean 5.43 cm2). The authors found improvement in patient reported outcomes for both groups, but patients who received ACI after a failed primary marrow stimulation procedure tended to have worse subjective outcome scores and higher incidence of ACI failure, potentially due to the compromise of the subchondral plate from initial marrow stimulation.
Primary autologous chondrocyte implantation of the knee versus autologous chondrocyte implantation after failed marrow stimulation: a systematic review.
PJAC is a cartilage restoration procedure in which autologous donor cartilage is minced and implanted on a scaffold which is placed into a chondral defect, either arthroscopically or through an open approach, in a single-stage procedure. While early applications of particulated cartilage were allograft, there are distinct biological benefits of juvenile articular cartilage that make it superior. Animal and preclinical models have shown the reproduction of hyaline-like tissue following implantation.
Pro cartilage repair gene expression profiles are increased in juvenile chondrocytes compared to adults. Specifically, juvenile chondrocytes demonstrate increased proteoglycan content and exhibit increased gene expression of collagen type II and type IX, factors that direct cartilage growth and expansion.
In vitro, juvenile chondrocytes are found to have low immunogenicity, as well as increased metabolic activity, cellular density, and proliferation rate compared to adult chondrocytes.
Mincing the graft tissue allows for liberation of the chondrocytes from their native extracellular matrix and allows them to construct new matrix and hyaline-like cartilage.
Following this model, several studies were published in the early 2000s where animal models demonstrated the efficacy of transplantation of minced cartilage pieces in the repair of chondral defects.
In vivo evaluation of autologous cartilage fragment-loaded scaffolds implanted into equine articular defects and compared with autologous chondrocyte implantation.
The first commercialized iteration of particulated cartilage grafts in the US was the Cartilage Autograft Implantation System (CAIS) from Depuy Mitek that utilized autograft cartilage from the patient. In a randomized trial vs microfracture, CAIS demonstrated significantly higher patient reported outcomes over 2 years of follow up.
Around the same time that CAIS was being developed and tested, Zimmer introduced their version of particulated cartilage graft, DeNovo NT, a cartilage repair system utilizing deceased juvenile donor chondrocytes which had been shown to improve extracellular matrix production compared to autologous adult chondrocytes and demonstrated positive early outcomes.
DeNovo NT, still commercially available, is harvested from femoral condyles of pediatric donors aged 0 to 13. Like other fresh allografts, the tissue has a shelf-life of 45 days from harvest for which it must be implanted to avoid substantial loss of chondrocyte viability. Each package of DeNovo NT contains graft from a single donor capable of treating defects up to 2.5 cm2 where larger lesions can be treated with multiple packages. It is currently marketed for use in the knee, ankle, hip and shoulder.
Indications
Indications for PJAC can be considered similar to those for a MACI with regards to patient age, location of the lesion, and the size of the chondral lesion being treated. Currently, PJAC use is limited to the treatment of patellofemoral and tibiofemoral chondral lesions in active patients 55 or younger with BMI <35 kg/m2. These are general guidelines, as case by case exceptions can be made based on physiologic age and other contributing factors such as quality of healthy cartilage and overall arthritic burden. Chondral defects treated with PJAC should be at least a grade 3 or higher on the ICRS scale and range from 1 to 6 cm2 following debridement.
Main contraindications to the use of PJAC include ICRS grade 1 or 2 lesions, extensive subchondral bone edema, uncorrected ligamentous instability that can risk damage to the graft, anatomical malalignment, meniscal deficiency, and osteochondritis dissecans lesions with >6 mm of subchondral bone loss.
Relative contraindications include bipolar lesions as well as uncontained lesions and those with subchondral insufficiency as adjuncts such as collagen membranes and bone grafting have been used successfully with PJAC.
Much of the surgical technique of PJAC is similar to that of MACI, up until the transplantation of the cellular agent. PJAC should also be preceded by a diagnostic knee arthroscopy to further characterize the cartilage defect and identify other potential pathologies that might indicate or contraindicate the use of PJAC.
However, in the case of PJAC, there is no biopsy and culture of native cartilage so the procedure itself can be done at the same time as diagnostic arthroscopy if indicated. After arthroscopic evaluation and debridement of the chondral lesion(s) to attain stable edges, PJAC can be performed.
Arthrotomy incisions will again depend on defect location as described in the MACI technique section. The lesion should be debrided to the level of subchondral bone and the lesion's rims should have stable, vertical walls.
Once the defect has been prepared for PJAC application, the graft material may be applied directly into the chondral defect. The knee should be positioned so that the defect base is parallel to the floor so that the PJAC cubes can be positioned in a uniform manner across the entire base of the defect to a height of 1 mm recessed from the peripheral healthy cartilage (Fig. 5).
If the defect base is angled, then the PJAC cubes may shift and create an uneven graft layer. A layer of fibrin glue is then applied to the roof of the graft.
Fig. 5Successfully placed PJAC cubes, minced cubes are spaced 1 to 2 mm apart and recessed 1 mm below the adjacent healthy cartilage.
Alternatively, the graft can be molded to the custom shape of the defect on the back table. Foil, such as a suture wrapper, can be press-fit into the defect creating a concave mold. PJAC cubes can be placed into this mold up to the same 1 mm recessed level as the direct application method. Fibrin glue is then applied to the roof of the cubes. After the glue has hardened, the molded graft is removed from the foil, a new layer of fibrin glue is applied to the base of the graft, and it is applied into the defect before a final layer of fibrin glue is applied to the surface of the graft.
If the treated lesion is uncontained, a commercially available collagen I/III membrane can be sutured into place to cover the defect as a means of preventing PJAC graft dislodgement.
The postoperative protocol following PJAC is modeled after the MACI protocol described above. After closure, patients should remain in extension with a locking knee brace.
Patients receiving patellofemoral grafts are allowed to ambulate at full weight bearing when locked in knee extension if there was no concomitant procedure.
A concomitant osteotomy at time of PJAC will similarly indicate a patient to be nonweight-bearing for 2 weeks followed by PWB at 2 to 4 weeks. There is a fine balance between beginning PWB at an early stage to stimulate chondrocyte differentiation and prematurely returning to full weight-bearing, which could lead to graft delamination or dislodgement.
Is delayed weightbearing after matrix-associated autologous chondrocyte implantation in the knee associated with better outcomes? A systematic review of randomized controlled trials.
The hinged knee brace is generally unlocked 2 to 3 weeks postoperatively and can be used for daytime ambulation only.
A continuous passive motion machine should be used out of the brace for 6 hours daily, similarly aiming to achieve 90° flexion at 2 weeks and full range of motion by 7 to 9 weeks. Closed chain and gait training can start around 8 weeks, with activities like swimming and biking recommended after the 12-month mark. Patients generally return to full activities by 8 months postoperatively.
The majority of outcomes for PJAC described in the literature are from case series or case reports. A case series by Farr et al in 2014 demonstrated improved patient reported outcomes in the form of IKDC and KOOS scores over 2 years as well as histologic evidence of a mixture of hyaline and fibrocartilage with increased type II collagen compared to type I collagen, supporting successful graft incorporation.
A single center single arm prospective study of PJAC in 27 patients found significantly improved functional outcomes for patients treated for symptomatic patellofemoral articular cartilage defects. With a mean follow up of 3.84 years, no patients underwent revision surgery for graft-related issues. Additionally, nearly 70% of patients had the majority of their defect filled as identified by postoperative MRI at 2 years. Patients demonstrated statistically significant improvements in mean IKDC and KOOS Activities of Daily Living, with outcome scores not clearly affected by age, lesion location, or concomitant tibial tubercle osteotomy.
Patellofemoral cartilage lesions treated with particulated juvenile allograft cartilage: a prospective study with minimum 2-year clinical and magnetic resonance imaging outcomes.
As these procedures gain popularity, more robust long-term outcomes data for PJAC vs MACI would be necessary. Current evidence suggests that compared to MACI, PJAC has the potential to be more cost effective given it requires a single surgery instead of 2 as well as less costly graft material is utilized.
If results from studies on PJAC continue to be in favor of the procedure, we could expect to see PJAC one day surpass MACI with respect to volume of cases per year.
PJAC carries many of the same postoperative complications as those of cell-based therapies like ACI/MACI. The most common complications requiring revision surgery are graft hypertrophy and graft delamination.
Graft hypertrophy involves overgrowth of graft while delamination is the separation of the graft from the underlying subchondral bone, which can both lead to significant morbidity if not recognized and treated appropriately with revision.
Regarding the rates of graft hypertrophy seen after PJAC, the literature is sparse with only 2 small studies reporting on this complication. Tompkins et al found gross graft hypertrophy requiring debridement in just 2 patients out of 13 patients (15 knees), and two others exhibiting mild graft hypertrophy.
Preliminary results of a novel single-stage cartilage restoration technique: particulated juvenile articular cartilage allograft for chondral defects of the patella.
Another study in 2014 by Buckwalter et al reported on patients with high-grade patellar chondral with a mean size of 2.3 cm2. Of the 13 patients examined, there were no cases of graft hypertrophy reported. Of note, 6 of the patients underwent a concomitant tibial tubercle osteotomy to unload the lesion.
Although there is the autoimmune risk with the inherent allogeneic nature of allograft-based approaches, juvenile chondrocytes have not been shown to stimulate proliferation of allogeneic or xenogeneic lymphocytes or promote graft rejection immune responses.
Cell transplantation techniques such as MACI and PJAC offer treatment options that can effectively address large full-thickness chondral defects in TFJs or PFJs that may respond poorly to bone marrow stimulation or mosaicplasty. Both procedures have shown clinically significant improvements in outcome scores and low rates of complications. MACI has a handful of high-level studies reaching long-term follow-up, but most comparative studies use microfracture or earlier generation ACI procedure as its comparator. PJAC is still a relatively newer treatment option and is lacking high quality research with long-term follow up. RCTs involving PJAC with long-term follow up and further comparisons of MACI against other restoration procedures beyond microfracture and ACI will be needed to fully determine the extent that these procedures should be favored in different clinical settings involving chondral defects of the knee. Research in this field may ultimately lead to more successful treatment of articular cartilage lesions.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.
Ethics approval
No patients were involved in this research and, therefore, no informed consent was required.
Focal cartilage defects in the knee impair quality of life as much as severe osteoarthritis: a comparison of Knee injury and Osteoarthritis Outcome Score in 4 patient categories scheduled for knee surgery.
Articular cartilage treatment in high-level male soccer players: a prospective comparative study of arthroscopic second-generation autologous chondrocyte implantation versus microfracture.
Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: a randomized clinical trial.
Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study.
Arthroscopic treatment of patellar and trochlear cartilage lesions with matrix encapsulated chondrocyte implantation versus microfracture: quantitative assessment with MRI T2-mapping and MOCART at 4-year follow-up.
Consensus on rehabilitation guidelines among orthopedic surgeons in the United States following use of third-generation articular cartilage repair (MACI) for treatment of knee cartilage lesions.
Management of chondral lesions of the knee: analysis of trends and short-term complications using the national surgical quality improvement program database.
Minimum ten-year results of a prospective randomised study of autologous chondrocyte implantation versus mosaicplasty for symptomatic articular cartilage lesions of the knee.
Primary autologous chondrocyte implantation of the knee versus autologous chondrocyte implantation after failed marrow stimulation: a systematic review.
In vivo evaluation of autologous cartilage fragment-loaded scaffolds implanted into equine articular defects and compared with autologous chondrocyte implantation.
Is delayed weightbearing after matrix-associated autologous chondrocyte implantation in the knee associated with better outcomes? A systematic review of randomized controlled trials.
Patellofemoral cartilage lesions treated with particulated juvenile allograft cartilage: a prospective study with minimum 2-year clinical and magnetic resonance imaging outcomes.
Preliminary results of a novel single-stage cartilage restoration technique: particulated juvenile articular cartilage allograft for chondral defects of the patella.
A patellar chondral lesion after debridement to ensure vertical, stable walls perpendicular to the defect's base. Note that the subchondral bone has not been penetrated.
Focal articular chondral lesions are a common finding among patients presenting with knee pain. If symptomatic and unresponsive to conservative treatment, cell transplantation techniques offer a unique solution to address larger defects by engineering chondrocytes to integrate within the subchondral bone of the lesion and regenerate cartilage.
Objectives
The purpose of this article is to review the evaluation of, and clinical decision making for, patients being considered for cell transplantation and the available techniques an orthopaedic surgeon has at their disposal.
Methods
A review of recent literature regarding cartilage defects in the knee and cell transplantation techniques was performed to provide strategies for evaluating and treating chondral defects with matrix-induced autologous chondrocyte implantation (MACI) or particulated juvenile allograft cartilage (PJAC) procedures.
Results
Chondral defects in the knee can be treated with patients’ own chondrocytes embedded into a collagen membrane as a MACI procedure, or minced autologous donor cartilage that is then implanted onto a scaffold as a PJAC procedure. These cell transplantation techniques offer advantages compared to bone marrow stimulation or mosaicplasty, and have shown clinically significant improvements in outcome scores with low rates of complications.
Conclusion
Cell transplantation techniques such as MACI and PJAC offer treatment options that can effectively address large full-thickness chondral defects in the tibiofemoral joint or patellofemoral joint that may respond poorly to bone marrow stimulation or mosaicplasty.
Focal articular chondral lesions left untreated have been shown to progress to osteoarthritis (OA) given cartilage lacks an innate healing ability.1x1Gomoll, AH and Minas, T. The quality of healing: articular cartilage. Wound Repair Regen. 2014;
22: 30–38 Crossref | PubMed | Scopus (75) | Google ScholarSee all References This remains a prevalent issue, with one series of over 31,000 knees undergoing routine arthroscopy finding 63% to have at least 1 chondral defect.2x2Gomoll, AH, Yoshioka, H, Watanabe, A, Dunn, JC, and Minas, T. Preoperative measurement of cartilage defects by MRI underestimates lesion size. Cartilage. 2011;
2: 389–393 Crossref | PubMed | Scopus (54) | Google ScholarSee all References In athletes, prevalence of full-thickness chondral defects was 36%, although 14% of those with defects were asymptomatic upon presentation.3x3Flanigan, DC, Harris, JD, Trinh, TQ, Siston, RA, and Brophy, RH. Prevalence of chondral defects in athletes' knees: a systematic review. Med Sci Sports Exerc. 2010;
42: 1795–1801 Crossref | PubMed | Scopus (286) | Google ScholarSee all References While all cartilage defects are not symptomatic, they do have a propensity to cause pain, joint dysfunction, and interfere with a patient's quality of life to levels equivalent of those in a patient suffering from end stage OA awaiting knee arthroplasty.4x4Heir, S, Nerhus, TK, Røtterud, JH et al. Focal cartilage defects in the knee impair quality of life as much as severe osteoarthritis: a comparison of Knee injury and Osteoarthritis Outcome Score in 4 patient categories scheduled for knee surgery. Am J Sports Med. 2010;
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Cell transplantation techniques such as autologous chondrocyte implantation (ACI) and particulated juvenile allograft cartilage (PJAC) are treatment options with the goal of using healthy chondrocytes to restore the patient's knee cartilage surface congruity. Cartilage restoration surgery for focal osteochondral defects results in improved patient reported outcomes, delayed OA progression on advanced imaging, and delayed clinical need for total knee arthroplasty.5x5Gowd, AK, Weimer, AE, Rider, DE et al. Cartilage restoration of bipolar lesions within the patellofemoral joint delays need for arthroplasty: a systematic review of rates of failure. Arthroscopy. 2021;
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MACI is the third-generation of a cartilage restoration procedure aimed at treating symptomatic medium-to-large full-thickness chondral lesions by engineering patients’ own chondrocytes to integrate within the subchondral bone of the defect and regenerate cartilage.7x7Carey, JL, Remmers, AE, and Flanigan, DC. Use of MACI (autologous cultured chondrocytes on porcine collagen membrane) in the United States: preliminary experience. Orthop J Sports Med. 2020;
8: 2325967120941816 Crossref | Scopus (15) | Google ScholarSee all References The chondrocytes are embedded within a collagen matrix and have the ability to reproduce a hyaline-like layer similar to native cartilage, as opposed to an inferior fibrocartilage layer found following drilling, microfracture, or debridement.8x8Brittberg, M, Lindahl, A, Nilsson, A, Ohlsson, C, Isaksson, O, and Peterson, L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;
331: 889–895 Crossref | PubMed | Scopus (4648) | Google ScholarSee all References,9x9Friedman, MJ, Berasi, CC, Fox, JM, Del Pizzo, W, Snyder, SJ, and Ferkel, RD. Preliminary results with abrasion arthroplasty in the osteoarthritic knee. Clin Orthop Relat Res. 1984;
182: 200–205 Crossref | PubMed | Google ScholarSee all References ACI as a treatment has been shown to be a cost-effective option for patients resulting in clinically significant improvements.10x10Mistry, H, Connock, M, Pink, J et al. Autologous chondrocyte implantation in the knee: systematic review and economic evaluation. Health Technol Assess. 2017;
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Evolution
The first description of cell engineering used in a clinical setting was by Peterson et al in 1984, who pioneered the first generation periosteal patch ACI (p-ACI).11x11Peterson, L, Minas, T, Brittberg, M, and Lindahl, A. Treatment of osteochondritis dissecans of the knee with autologous chondrocyte transplantation: results at two to ten years. J Bone Joint Surg Am. 2003;
85: 17–24 Crossref | PubMed | Scopus (527) | Google ScholarSee all References This procedure involved harvesting chondrocytes from a healthy, lesser weight-bearing site of distal femur cartilage during first-look arthroscopy. The chondrocytes were cultured for 14-21 days before a second, open procedure during which the cells were injected into the defect. The filled defect was then covered with a periosteal flap harvested from the patient's tibia that was sutured into place.11x11Peterson, L, Minas, T, Brittberg, M, and Lindahl, A. Treatment of osteochondritis dissecans of the knee with autologous chondrocyte transplantation: results at two to ten years. J Bone Joint Surg Am. 2003;
85: 17–24 Crossref | PubMed | Scopus (527) | Google ScholarSee all References Results generally showed clinically significant improvements in pain and function over medium and long-term follow up, but there remained issues with the implants forming fibrous hyaline cartilage that contributed to worse clinical grades and reoperation.8x8Brittberg, M, Lindahl, A, Nilsson, A, Ohlsson, C, Isaksson, O, and Peterson, L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;
331: 889–895 Crossref | PubMed | Scopus (4648) | Google ScholarSee all References,12x12Gomoll, AH, Gillogly, SD, Cole, BJ, Farr, J, Arnold, R, Hussey, K, and Minas, T. Autologous chondrocyte implantation in the patella: a multicenter experience. Am J Sports Med. 2014;
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Issues found with this first-generation ACI include the need for a second surgical procedure to harvest the periosteal flap from the tibia, and then the process of suturing the periosteal flap into place over the treated defect.
To address some of the problems with harvesting a periosteal flap, a second-generation ACI procedure was designed to replace the periosteal flap with new cover consisting of porcine collagen I and III bi-layer membrane (c-ACI).13x13Haddo, O, Mahroof, S, Higgs, D et al. The use of chondrogide membrane in autologous chondrocyte implantation. Knee. 2004;
11: 51–55 Abstract | Full Text | Full Text PDF | PubMed | Scopus (199) | Google ScholarSee all References,14x14Kon, E, Delcogliano, M, Filardo, G, Montaperto, C, and Marcacci, M. Second generation issues in cartilage repair. Sports Med Arthrosc Rev. 2008;
16: 221–229 Crossref | PubMed | Scopus (56) | Google ScholarSee all References Kon et al15x15Kon, E, Filardo, G, Berruto, M et al. Articular cartilage treatment in high-level male soccer players: a prospective comparative study of arthroscopic second-generation autologous chondrocyte implantation versus microfracture. Am J Sports Med. 2011;
39: 2549–2557 Crossref | PubMed | Scopus (176) | Google ScholarSee all References followed 41 professional and semiprofessional male soccer players who received either microfracture or c-ACI over a minimum of 4 years (mean 7.5). The athletes who received microfracture returned to sport earlier (8.0 months vs 12.5 months) and both groups had a significantly improved International Cartilage Repair Society (ICRS) score at 2-year follow-up. However, the final percentage of athletes who returned to sport was not statistically different between groups. Additionally, those who received microfracture had a decrease in ICRS score from 2 year to final follow up while those with c-ACI had stable ICRS scores over that time, ending with significantly higher scores at final follow up.15x15Kon, E, Filardo, G, Berruto, M et al. Articular cartilage treatment in high-level male soccer players: a prospective comparative study of arthroscopic second-generation autologous chondrocyte implantation versus microfracture. Am J Sports Med. 2011;
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Despite changing the substance that would cover the filled defect, the second-generation procedure still had similar drawbacks. For both p-ACI and c-ACI, once the chondrocytes are injected into the defect, they are subject to gravity and thus may not integrate in a uniform pattern across the articular lesion.16x16Sohn, DH, Lottman, LM, Lum, LY et al. Effect of gravity on localization of chondrocytes implanted in cartilage defects. Clin Orthop Relat Res. 2002;
394: 254–262 Crossref | PubMed | Scopus (77) | Google ScholarSee all References Despite the covering material, these chondrocytes may still be expelled from the defect and thus exists the possibility of graft hypertrophy, delamination, or failure.17x17Smith, GD, Knutsen, G, and Richardson, JB. A clinical review of cartilage repair techniques. J Bone Joint Surg Br. 2005;
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As a therapeutic option aimed at avoiding the complications associated with the first two generations of ACI and simplifying the procedure, a third-generation procedure was conceived and met United States Food and Drug Administration approval in 2016. For MACI, chondrocytes harvested in an initial arthroscopic procedure are expanded in a laboratory setting and then suspended in a resorbable Type I/III collagen membrane scaffold before being implanted into the chondral defect and covered with fibrin glue.20x20Behrens, P, Bitter, T, Kurz, B, and Russlies, M. Matrix-associated autologous chondrocyte transplantation/implantation (MACT/MACI)–5-year follow-up. Knee. 2006;
13: 194–202 Abstract | Full Text | Full Text PDF | PubMed | Scopus (388) | Google ScholarSee all References,21x21Steinwachs, M. New technique for cell-seeded collagen-matrix-supported autologous chondrocyte transplantation. Arthroscopy. 2009;
25: 208–211 Abstract | Full Text | Full Text PDF | PubMed | Scopus (82) | Google ScholarSee all References This eliminates the need for a native periosteal patch, and because the chondrocytes are embedded within the matrix, they can uniformly fill the defect and withstand the influence of gravity.
Evaluating candidates for MACI
Evaluation of a patient who presents with a chondral defect who may be a candidate for MACI starts with the history and physical examination. While not specific nor sensitive for focal cartilage lesions vs other intra-articular etiologies, a history and clinical examination are important to determine the timeframe of symptoms, prior treatment, malalignment, instability, or concurrent pathologies.22x22Dekker, TJ, Aman, ZS, DePhillipo, NN, Dickens, JF, Anz, AW, and LaPrade, RF. Chondral lesions of the knee: an evidence-based approach. J Bone Joint Surg Am. 2021;
103: 629–645 Crossref | PubMed | Scopus (19) | Google ScholarSee all References,23x23Hinckel, BB and Gomoll, AH. Autologous chondrocytes and next-generation matrix-based autologous chondrocyte implantation. Clin Sports Med. 2017;
36: 525–548 Abstract | Full Text | Full Text PDF | PubMed | Scopus (48) | Google ScholarSee all References Cartilage lesions may present after an acute traumatic injury, such as a fall or twisting injury that may be accompanied by an ACL rupture, meniscus tear, or patellar dislocation. Alternatively, patients may have an insidious onset of pain associated with recurrent microtraumas causing degeneration of the cartilage. Physical examination can be the first line of detecting lower extremity malalignment such as genu valgum/varum, malrotation, or patellofemoral maltracking.22x22Dekker, TJ, Aman, ZS, DePhillipo, NN, Dickens, JF, Anz, AW, and LaPrade, RF. Chondral lesions of the knee: an evidence-based approach. J Bone Joint Surg Am. 2021;
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Routine radiographic imaging of the symptomatic knee should be ordered with the following views: Anteroposterior, perfect lateral, merchant, 45-degree flexion posteroanterior weight-bearing, and full-length standing limb length. These radiographs may reveal loose bodies or fracture because of a traumatic cartilage injury, skeletal malalignment, patella alta, trochlear dysplasia, or evidence of more widespread osteoarthritic joint changes.
Advanced imaging with computed tomography or magnetic resonance imaging (MRI) allows for better characterization of the lesion to best counsel the patient and guide treatment.24x24Gorbachova, T, Melenevsky, Y, Cohen, M, and Cerniglia, BW. Osteochondral lesions of the knee: differentiating the most common entities at MRI. Radiographics. 2018;
38: 1478–1495 Crossref | PubMed | Scopus (66) | Google ScholarSee all References Absent or insignificant subchondral edema on MRI suggests a stable lesion, while fragmentation of the defect may signify an unstable lesion.24x24Gorbachova, T, Melenevsky, Y, Cohen, M, and Cerniglia, BW. Osteochondral lesions of the knee: differentiating the most common entities at MRI. Radiographics. 2018;
38: 1478–1495 Crossref | PubMed | Scopus (66) | Google ScholarSee all References However, caution should be taken when estimating lesion size as preoperative MRI has been shown to underestimate total lesion size by 65% compared to measurements taken at time of open cartilage repair.2x2Gomoll, AH, Yoshioka, H, Watanabe, A, Dunn, JC, and Minas, T. Preoperative measurement of cartilage defects by MRI underestimates lesion size. Cartilage. 2011;
2: 389–393 Crossref | PubMed | Scopus (54) | Google ScholarSee all References MRI will also help reveal an accompanying meniscal or other ligamentous injury that should be considered with surgical decision making.
Indications
MACI is indicated as first line treatment for patients less than 55 years of age with single or multiple Outerbridge Grade III or IV full-thickness chondral lesions ≥2 cm2, traditionally without bony involvement although MACI has been Food and Drug Administration-approved for symptomatic defects both with and without bony involvement in adults.22x22Dekker, TJ, Aman, ZS, DePhillipo, NN, Dickens, JF, Anz, AW, and LaPrade, RF. Chondral lesions of the knee: an evidence-based approach. J Bone Joint Surg Am. 2021;
103: 629–645 Crossref | PubMed | Scopus (19) | Google ScholarSee all References,23x23Hinckel, BB and Gomoll, AH. Autologous chondrocytes and next-generation matrix-based autologous chondrocyte implantation. Clin Sports Med. 2017;
36: 525–548 Abstract | Full Text | Full Text PDF | PubMed | Scopus (48) | Google ScholarSee all References,25x25Hinckel, BB and Gomoll, AH. Patellofemoral cartilage restoration: indications, techniques, and outcomes of autologous chondrocytes implantation, matrix-induced chondrocyte implantation, and particulated juvenile allograft cartilage. J Knee Surg. 2018;
31: 212–226 Crossref | PubMed | Scopus (12) | Google ScholarSee all References,26x26Slattery, C and Kweon, CY. Classifications in brief: outerbridge classification of chondral lesions. Clin Orthop Relat Res. 2018;
476: 2101–2104 Crossref | PubMed | Scopus (98) | Google ScholarSee all References MACI is also a viable option as second line treatment for lesions ≤2 cm2 in size.23x23Hinckel, BB and Gomoll, AH. Autologous chondrocytes and next-generation matrix-based autologous chondrocyte implantation. Clin Sports Med. 2017;
36: 525–548 Abstract | Full Text | Full Text PDF | PubMed | Scopus (48) | Google ScholarSee all References,27x27Bartlett, W, Skinner, JA, Gooding, CR et al. Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study. J Bone Joint Sur Br. 2005;
87: 640–645 Crossref | PubMed | Scopus (610) | Google ScholarSee all References Because of the ability to cut the MACI scaffolding to the defect's exact dimensions and nature of the cells being embedded into the matrix, this technique is more easily performed in both patellofemoral joint (PFJ) and tibiofemoral joint (TFJ) spaces. Along with this, outcomes of MACI in the PFJ have been reported to be superior to those in the TFJ.
Contraindications
Absolute contraindications to MACI include inflammatory arthritis, a recent or active infection, uncorrected congenital blood coagulopathies, diffuse joint OA, allergy to porcine or bovine products or aminoglycosides such as gentamicin, and any inability to adhere to the strict postoperative rehabilitation protocol. Because chondral defects can be caused by musculoskeletal comorbidities such as genu valgum/varum, recurrent patellar instability, or meniscal/ligamentous insufficiency, these pathologies left uncorrected are risk factors for failure following isolated cartilage repair and, therefore, are contraindications to MACI unless addressed before or at the time of the MACI procedure.23x23Hinckel, BB and Gomoll, AH. Autologous chondrocytes and next-generation matrix-based autologous chondrocyte implantation. Clin Sports Med. 2017;
36: 525–548 Abstract | Full Text | Full Text PDF | PubMed | Scopus (48) | Google ScholarSee all References,28x28Andrade, R, Nunes, J, Hinckel, BB et al. Cartilage restoration of patellofemoral lesions: a systematic review. Cartilage. 2021;
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Surgical technique of MACI
Stage 1—Diagnostic arthroscopy and cartilage biopsy
Most patients presenting with a symptomatic chondral lesion should first trial a period of conservative treatment consisting of activity modification and physical therapy. This nonoperative period should generally be 3 to 6 months, though it can be less in younger patients presenting with traumatic etiology.23x23Hinckel, BB and Gomoll, AH. Autologous chondrocytes and next-generation matrix-based autologous chondrocyte implantation. Clin Sports Med. 2017;
36: 525–548 Abstract | Full Text | Full Text PDF | PubMed | Scopus (48) | Google ScholarSee all References In those who fail conservative therapy, the next step should be a diagnostic arthroscopy. This allows the surgeon to better visualize the location and extent of cartilage damage along with any concurrent intra-articular injury. This stage should be performed as a standard knee arthroscopy using medial and lateral portals while patient is supine. The medial and lateral tibiofemoral compartments along with PFJ should be visualized to identify the chondral damage and presence of loose bodies and meniscal or ligamentous pathology. Once identified, the edges of the chondral defect can be debrided until the lesion's rims are stabilized.
If the defect is determined to be amenable to MACI treatment, a biopsy should be taken from a healthy region of nonweight-bearing cartilage. This can usually be taken from the superolateral region of the intercondylar notch using a curette. The biopsied cartilage should total 200 to 300 mg which will then be sent for chondrocyte isolation and expansion.
This process of chondrocyte culturing takes approximately 6 weeks. During this time, many patients may experience symptomatic relief due to arthroscopic debridement of their defect and thus may not require the second-stage chondrocyte implantation.29x29Dozin, B, Malpeli, M, Cancedda, R et al. Comparative evaluation of autologous chondrocyte implantation and mosaicplasty: a multicentered randomized clinical trial. Clin J Sports Med. 2005;
15: 220–226 Crossref | PubMed | Scopus (30) | Google ScholarSee all References,30x30Wood, JJ, Malek, MA, Frassica, FJ et al. Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration. J Bone Joint Surg Am. 2006;
88: 503–507 Crossref | PubMed | Scopus (171) | Google ScholarSee all References Cultured cells are able to be kept in a cryopreserved state for up to 5 years, so a patient who initially experiences symptomatic relief after debridement but has recurrence or progression of symptoms within this 5-year window will not require a repeat cartilage biopsy.
Stage 2—Implantation of the MACI graft
The second stage of MACI treatment was originally described as an open procedure, though arthroscopic implantation has proven to be a safe alternative offering a significantly shorter hospital stay and faster recovery with improvements in clinical and radiologic scores at short- and mid-term follow-up.31x31Ebert, JR, Fallon, M, Ackland, TR, Wood, DJ, and Janes, GC. Arthroscopic matrix-induced autologous chondrocyte implantation: 2-year outcomes. Arthroscopy. 2012;
28: 952–964.e1-2 Abstract | Full Text | Full Text PDF | PubMed | Scopus (52) | Google ScholarSee all References,32x32Edwards, PK, Ebert, JR, Janes, GC, Wood, D, Fallon, M, and Ackland, T. Arthroscopic versus open matrix-induced autologous chondrocyte implantation: results and implications for rehabilitation. J Sport Rehab. 2014;
23: 203–215 Crossref | PubMed | Google ScholarSee all References,33x33Olivos Meza, A, Cortés González, S, Ferniza Garza, JJ, Pérez Jiménez, FJ, Enrique, VC, and Ibarra, C. Arthroscopic treatment of patellar and trochlear cartilage lesions with matrix encapsulated chondrocyte implantation versus microfracture: quantitative assessment with MRI T2-mapping and MOCART at 4-year follow-up. Cartilage. 2021;
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Arthroscopic implantation may be done through the standard medial and lateral arthroscopic portals for most defect locations. The arthrotomy technique depends on location of the defect—preferred approach for patellofemoral lesions is via a lateral parapatellar approach to maintain the integrity of the medial patellofemoral ligament and avoid the vastus medialis as well as iatrogenic patellofemoral instability. The same approach should be taken for lesions of the lateral femoral condyle. Lesions of the medial femoral condyle may necessitate a medial parapatellar approach to allow for adequate visualization of the condyle, but again care should be taken to avoid iatrogenic damage to the medial patellofemoral ligament or to the menisci and healthy regions of cartilage.34x34Brittberg, M, Recker, D, Ilgenfritz, J, and Saris, DBF. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: five-year follow-up of a prospective randomized trial. Am J Sports Med. 2018;
46: 1343–1351 Crossref | PubMed | Scopus (136) | Google ScholarSee all References,35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
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After visualization has been achieved with arthrotomy or arthroscopy, all damaged and fibrous tissue in the defect is debrided to the level of subchondral bone, making sure to remove the calcified cartilage layer so that the implanted cell sheet has contact with the subchondral bone. It is important to ensure the defect has stable, vertical walls and that you do not penetrate the subchondral bone (Fig. 1Fig. 1). It may be helpful to deflate the tourniquet after debridement has finished to test if the lesion's base experiences significant bleeding. This should be controlled prior to moving on to graft implantation, as significant bleeding may displace the MACI graft.35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
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Fig. 1
A patellar chondral lesion after debridement to ensure vertical, stable walls perpendicular to the defect's base. Note that the subchondral bone has not been penetrated.
The MACI kit comes with a template sheet that can be cut to the proper dimensions of the defect. The MACI implant is packaged as a 3 cm × 5 cm cellular sheets of a resorbable porcine Type I/III collagen membrane that has a rougher side that has been seeded with the chondrocytes that will face the subchondral bone. The density of these MACI implants are 500,000 cells/cm2 to 1,000,000 cells/cm2. The opposite, smoother side of the matrix will face the articular surface. The sheet should remain cell-side facing up and hydrated with the accompanying media. The modified template is placed underneath the MACI sheet, only coming into contact with the smooth side, and the MACI implant is cut to the dimensions of the template (Fig. 2Fig. 2).34x34Brittberg, M, Recker, D, Ilgenfritz, J, and Saris, DBF. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: five-year follow-up of a prospective randomized trial. Am J Sports Med. 2018;
46: 1343–1351 Crossref | PubMed | Scopus (136) | Google ScholarSee all References,36x36Saris, D, Price, A, Widuchowski, W et al. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: two-year follow-up of a prospective randomized trial. Am J Sports Med. 2014;
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Fig. 2
A MACI implant cut from the 3 cm × 5 cm MACI cellular sheet to fit the dimensions of the templated chondral defect.
Before the MACI implant is placed into the defect, care should be taken to ensure there is no active bleeding at the subchondral bed before a very thin layer of fibrin glue is applied to the defect base (Fig. 3Fig. 3). The MACI implant is then placed with the correct orientation ensuring that the rough, cell-embedded side is face down. Light pressure is held on the implant for 3 minutes, before a layer of fibrin glue is applied to the edges of the MACI implant (Fig. 4Fig. 4). Chondrocytes will translocate from the fibrin glue matrix to subchondral bone following the procedure.34x34Brittberg, M, Recker, D, Ilgenfritz, J, and Saris, DBF. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: five-year follow-up of a prospective randomized trial. Am J Sports Med. 2018;
46: 1343–1351 Crossref | PubMed | Scopus (136) | Google ScholarSee all References,36x36Saris, D, Price, A, Widuchowski, W et al. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: two-year follow-up of a prospective randomized trial. Am J Sports Med. 2014;
42: 1384–1394 Crossref | PubMed | Scopus (213) | Google ScholarSee all References Interrupted, resorbable sutures are indicated for lesions with unstable rims or lesions >10 cm2.
Fig. 3
Application of a thin fibrin glue layer to the base of the chondral defect prior to placing the MACI graft.
A consensus for postoperative rehabilitation protocol was established among a panel of U.S. surgeons performing at least 10 MACI procedures per year.37x37Flanigan, DC, Sherman, SL, Chilelli, B et al. Consensus on rehabilitation guidelines among orthopedic surgeons in the United States following use of third-generation articular cartilage repair (MACI) for treatment of knee cartilage lesions. Cartilage. 2021;
13: 1782S–1790S Crossref | PubMed | Scopus (3) | Google ScholarSee all References According to this consensus, patients with a contained lesion of the PFJ can initiate full weight bearing immediately postoperatively and can be released to unrestricted activities of daily living as early as 3 months, with release to running at 7 to 9 months. Conversely, poorly contained lesions require partial weight bearing (PWB) no more than 20% body weight with longer time before progression. Additionally, patients who receive concomitant osteotomy require a period of nonweight bearing for 2 weeks, then PWB at 2 to 4 weeks so long as they have improved pain and are gaining a normal gait pattern.37x37Flanigan, DC, Sherman, SL, Chilelli, B et al. Consensus on rehabilitation guidelines among orthopedic surgeons in the United States following use of third-generation articular cartilage repair (MACI) for treatment of knee cartilage lesions. Cartilage. 2021;
13: 1782S–1790S Crossref | PubMed | Scopus (3) | Google ScholarSee all References
For patients receiving tibiofemoral treatment, they should expect to be PWB for 2 weeks if the treated lesion was small, and 6 weeks PWB for patients with larger lesions. Gait training along with closed chain strengthening exercises can begin at 8 weeks postoperatively. Return to full activities should be expected around 8 months postoperatively.38x38Farr, J, Cole, BJ, Sherman, S, and Karas, V. Particulated articular cartilage: CAIS and DeNovo NT. J Knee Surg. 2012;
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All patients, regardless of defect location or concomitant osteotomy, should immediately start continuous passive motion from 0° to 45° and increase by 15° each week with the goal of achieving full range of motion at 7 to 9 weeks on average.37x37Flanigan, DC, Sherman, SL, Chilelli, B et al. Consensus on rehabilitation guidelines among orthopedic surgeons in the United States following use of third-generation articular cartilage repair (MACI) for treatment of knee cartilage lesions. Cartilage. 2021;
13: 1782S–1790S Crossref | PubMed | Scopus (3) | Google ScholarSee all References
Patients with a single patellofemoral or tibiofemoral defect may return to low-intensity stationary cycling as early as 3 to 4 weeks postoperatively.37x37Flanigan, DC, Sherman, SL, Chilelli, B et al. Consensus on rehabilitation guidelines among orthopedic surgeons in the United States following use of third-generation articular cartilage repair (MACI) for treatment of knee cartilage lesions. Cartilage. 2021;
13: 1782S–1790S Crossref | PubMed | Scopus (3) | Google ScholarSee all References Those with multiple defects treated or concomitant procedures may require a slower return to activity personalized to their case and progress.
Outcomes of MACI
A total of 15,609 cartilage procedures were performed from 2010-2016, with a linear increase over this period. ACI was performed 2.6 ± 1.7 per 100,000 procedures and overall increased by 626.6% in this span.39x39Gowd, AK, Cvetanovich, GL, Liu, JN et al. Management of chondral lesions of the knee: analysis of trends and short-term complications using the national surgical quality improvement program database. Arthroscopy. 2019;
35: 138–146 Abstract | Full Text | Full Text PDF | PubMed | Scopus (37) | Google ScholarSee all References In examining the data from the first 1000 consecutive patients to receive MACI (Vericel), Carey et al found an evenly split ratio of male-to-female (49.6%-to-50.4%) recipients with a mean age of 34.0 years.7x7Carey, JL, Remmers, AE, and Flanigan, DC. Use of MACI (autologous cultured chondrocytes on porcine collagen membrane) in the United States: preliminary experience. Orthop J Sports Med. 2020;
8: 2325967120941816 Crossref | Scopus (15) | Google ScholarSee all References The mean treated defect size was 4.7 cm2, the same as mean MACI-treated defect size found on meta-analysis by Hinckel et al.40x40Hinckel, BB, Pratte, EL, Baumann, CA et al. Patellofemoral cartilage restoration: a systematic review and meta-analysis of clinical outcomes. Am J Sports Med. 2020;
48: 1756–1772 Crossref | PubMed | Scopus (28) | Google ScholarSee all References
The same meta-analysis compared outcomes of cartilage restoration techniques within the PFJ but grouped all generations of ACI/MACI together as the chondrocyte cell–based therapy group. This group consisted of 38 studies and was compared to pooled results of osteochondral allograft transplantation (OCA), osteochondral autograft transfer, bone marrow stimulation therapy, and scaffold treatment. Chondrocyte cell-based therapy had an overall failure rate of 5.7% [95% CI 3.9%-8.2%], which was not statistically different than the overall pooled failure rate of all cartilage treatments studied (6.8%; 95% CI, 4.7%-9.5%). 83% of ACI/MACI studies had significant improvement in clinical outcome scores.40x40Hinckel, BB, Pratte, EL, Baumann, CA et al. Patellofemoral cartilage restoration: a systematic review and meta-analysis of clinical outcomes. Am J Sports Med. 2020;
48: 1756–1772 Crossref | PubMed | Scopus (28) | Google ScholarSee all References
Third-generation MACI outcomes have been reported across numerous case series, comparative cohort studies, and randomized controlled trials (RCTs), with significantly improved clinical and patient reported scores from baseline for both tibiofemoral and patellofemoral defects at short-, mid-, and long-term follow up out to 10 years postoperatively.19x19Zeifang, F, Oberle, D, Nierhoff, C, Richter, W, Moradi, B, and Schmitt, H. Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: a randomized clinical trial. Am J Sports Med. 2010;
38: 924–933 Crossref | PubMed | Scopus (190) | Google ScholarSee all References,27x27Bartlett, W, Skinner, JA, Gooding, CR et al. Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study. J Bone Joint Sur Br. 2005;
87: 640–645 Crossref | PubMed | Scopus (610) | Google ScholarSee all References,28x28Andrade, R, Nunes, J, Hinckel, BB et al. Cartilage restoration of patellofemoral lesions: a systematic review. Cartilage. 2021;
13: 57S–73S Crossref | PubMed | Scopus (11) | Google ScholarSee all References,40x40Hinckel, BB, Pratte, EL, Baumann, CA et al. Patellofemoral cartilage restoration: a systematic review and meta-analysis of clinical outcomes. Am J Sports Med. 2020;
48: 1756–1772 Crossref | PubMed | Scopus (28) | Google ScholarSee all References,41x41Ebert, JR, Fallon, M, Wood, DJ, and Janes, GC. A prospective clinical and radiological evaluation at 5 years after arthroscopic matrix-induced autologous chondrocyte implantation. Am J Sports Med. 2017;
45: 59–69 Crossref | PubMed | Scopus (57) | Google ScholarSee all References,42x42Filardo, G, Kon, E, Andriolo, L, Di Matteo, B, Balboni, F, and Marcacci, M. Clinical profiling in cartilage regeneration: prognostic factors for midterm results of matrix-assisted autologous chondrocyte transplantation. Am J Sports Med. 2014;
42: 898–905 Crossref | PubMed | Scopus (58) | Google ScholarSee all References,43x43Kon, E, Filardo, G, Gobbi, A et al. Long-term results after hyaluronan-based MACT for the treatment of cartilage lesions of the patellofemoral joint. Am J Sports Med. 2016;
44: 602–608 Crossref | PubMed | Scopus (37) | Google ScholarSee all References,44x44Müller, PE, Gallik, D, Hammerschmid, F et al. Third-generation autologous chondrocyte implantation after failed bone marrow stimulation leads to inferior clinical results. Knee Surg Sports Traumatol Arthrosc. 2020;
28: 470–477 Crossref | PubMed | Scopus (22) | Google ScholarSee all References,45x45Schuette, HB, Kraeutler, MJ, and McCarty, EC. Matrix-assisted autologous chondrocyte transplantation in the knee: a systematic review of mid- to long-term clinical outcomes. Orthop J Sports Med. 2017;
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Kon et al followed 32 patients treated with MACI to the PFJ over 10 years and found their International Knee Documentation Committee (IKDC) subjective scores, EuroQol visual analog scale scores, and Tegner scores all significantly improved from baseline and remained stable through final follow up.43x43Kon, E, Filardo, G, Gobbi, A et al. Long-term results after hyaluronan-based MACT for the treatment of cartilage lesions of the patellofemoral joint. Am J Sports Med. 2016;
44: 602–608 Crossref | PubMed | Scopus (37) | Google ScholarSee all References One patient progressed to total knee arthroplasty due to persistent pain and swelling, and there was a total failure rate of 12.5% when including patients who did not achieve a clinically significant improvement.43x43Kon, E, Filardo, G, Gobbi, A et al. Long-term results after hyaluronan-based MACT for the treatment of cartilage lesions of the patellofemoral joint. Am J Sports Med. 2016;
44: 602–608 Crossref | PubMed | Scopus (37) | Google ScholarSee all References Of note, in analyzing the influence of other variables on the final outcomes, the authors found that women with patellar lesions who required an additional realignment procedure had worse IKDC subjective outcome at the 10-year follow-up.43x43Kon, E, Filardo, G, Gobbi, A et al. Long-term results after hyaluronan-based MACT for the treatment of cartilage lesions of the patellofemoral joint. Am J Sports Med. 2016;
44: 602–608 Crossref | PubMed | Scopus (37) | Google ScholarSee all References
In a prospective RCT evaluating clinical outcome measures following MACI vs microfracture over 24 months, MACI was found to be significantly more effective than microfracture in terms of Lysholm (P = .005), Tegner (P = .04), ICRS patient (P = .03), and ICRS surgeon (P = .02) scores at final follow up.46x46Basad, E, Ishaque, B, Bachmann, G, Stürz, H, and Steinmeyer, J. Matrix-induced autologous chondrocyte implantation versus microfracture in the treatment of cartilage defects of the knee: a 2-year randomised study. Knee Surg Sports Traumatol Arthrosc. 2010;
18: 519–527 Crossref | PubMed | Scopus (319) | Google ScholarSee all References
The Superiority of MACI implant to Microfracture Treatment, or SUMMIT, trial prospectively randomized patients to receive MACI or microfracture for symptomatic chondral defects >3 cm2 on the femoral condyles or trochlea.34x34Brittberg, M, Recker, D, Ilgenfritz, J, and Saris, DBF. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: five-year follow-up of a prospective randomized trial. Am J Sports Med. 2018;
46: 1343–1351 Crossref | PubMed | Scopus (136) | Google ScholarSee all References,36x36Saris, D, Price, A, Widuchowski, W et al. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: two-year follow-up of a prospective randomized trial. Am J Sports Med. 2014;
42: 1384–1394 Crossref | PubMed | Scopus (213) | Google ScholarSee all References The study group found mean Knee injury and Osteoarthritis Outcome Score (KOOS) pain, function, activities of daily living, knee-related quality of life, and other symptoms subscores to be significantly more improved from baseline to 2-year follow-up in MACI patients compared to those receiving microfracture.36x36Saris, D, Price, A, Widuchowski, W et al. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: two-year follow-up of a prospective randomized trial. Am J Sports Med. 2014;
42: 1384–1394 Crossref | PubMed | Scopus (213) | Google ScholarSee all References At 5-year follow-up, KOOS pain, function, and activities of daily living subscores remained significantly more improved from baseline in the MACI group compared to microfracture.34x34Brittberg, M, Recker, D, Ilgenfritz, J, and Saris, DBF. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: five-year follow-up of a prospective randomized trial. Am J Sports Med. 2018;
46: 1343–1351 Crossref | PubMed | Scopus (136) | Google ScholarSee all References Improvements in KOOS quality of life and other symptoms subscores were nonsignificantly greater in the MACI group at the 5-year timepoint. At both 2- and 5-year follow-up, the degree of defect fill seen on MRI (measured by the scale of Whole Organ MRI Score) was nonsignificantly greater in the MACI group. There were no significant adverse events with either group through final follow-up.34x34Brittberg, M, Recker, D, Ilgenfritz, J, and Saris, DBF. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: five-year follow-up of a prospective randomized trial. Am J Sports Med. 2018;
46: 1343–1351 Crossref | PubMed | Scopus (136) | Google ScholarSee all References
There is a paucity of research comparing MACI directly to other cartilage restoration procedures such as OCA. In a 2012 prospective RCT with minimum 10-year results published by Bentley et al, 100 consecutive patients with symptomatic cartilage defects in the knee were randomized to receive either second-generation ACI or OCA mosaicplasty.47x47Bentley, G, Biant, LC, Vijayan, S, Macmull, S, Skinner, JA, and Carrington, RW. Minimum ten-year results of a prospective randomised study of autologous chondrocyte implantation versus mosaicplasty for symptomatic articular cartilage lesions of the knee. J Bone Joint Surg Br. 2012;
94: 504–509 Crossref | PubMed | Scopus (218) | Google ScholarSee all References Patients receiving ACI had significantly greater improvements in the modified Cincinnati knee score (P = .02) and better Stanmore-Bentley functional rating scores, though this did not reach significance (P = .27). The failure rate for ACI (17%) was significantly less than seen with mosaicplasty (55%; P < .001), displaying the advantage that even older generations of ACI have over OCA mosaicplasty when treating large articular cartilage defects (mean size 4.41 cm2 in the ACI group and 4.0 cm2 in the mosaicplasty group).47x47Bentley, G, Biant, LC, Vijayan, S, Macmull, S, Skinner, JA, and Carrington, RW. Minimum ten-year results of a prospective randomised study of autologous chondrocyte implantation versus mosaicplasty for symptomatic articular cartilage lesions of the knee. J Bone Joint Surg Br. 2012;
94: 504–509 Crossref | PubMed | Scopus (218) | Google ScholarSee all References
Andrade et al completed a systematic review including 25 studies evaluating ACI/MACI in the PFJ. This analysis found clinically significant improvements in all studies measuring IKDC and Kujala for ACI/MACI patients. Only 2 studies did not achieve the minimum clinically important difference for Lysholm score and 1 for the KOOS score. ACI/MACI had a weighted mean patient satisfaction of 84% and weighted failure rate of 5%.28x28Andrade, R, Nunes, J, Hinckel, BB et al. Cartilage restoration of patellofemoral lesions: a systematic review. Cartilage. 2021;
13: 57S–73S Crossref | PubMed | Scopus (11) | Google ScholarSee all References The low rates of failure within the PFJ suggest that ACI/MACI is well adept at reconstituting the native articular topography in a region that may be difficult to otherwise match congruity with other cartilage restoration procedures.
Another factor to consider when evaluating a patient who may need MACI is any prior history of microfracture or other marrow stimulation procedure. Schuette et al48x48Schuette, HB, Kraeutler, MJ, Schrock, JB, and McCarty, EC. Primary autologous chondrocyte implantation of the knee versus autologous chondrocyte implantation after failed marrow stimulation: a systematic review. Am J Sports Med. 2021;
49: 2536–2541 Crossref | PubMed | Scopus (15) | Google ScholarSee all References performed a systematic review of 7 studies including a total of 1335 patients comparing outcomes in primary ACI vs secondary ACI after failed bone marrow stimulation for large chondral lesions (mean 5.43 cm2). The authors found improvement in patient reported outcomes for both groups, but patients who received ACI after a failed primary marrow stimulation procedure tended to have worse subjective outcome scores and higher incidence of ACI failure, potentially due to the compromise of the subchondral plate from initial marrow stimulation.48x48Schuette, HB, Kraeutler, MJ, Schrock, JB, and McCarty, EC. Primary autologous chondrocyte implantation of the knee versus autologous chondrocyte implantation after failed marrow stimulation: a systematic review. Am J Sports Med. 2021;
49: 2536–2541 Crossref | PubMed | Scopus (15) | Google ScholarSee all References
PJAC
Background
PJAC is a cartilage restoration procedure in which autologous donor cartilage is minced and implanted on a scaffold which is placed into a chondral defect, either arthroscopically or through an open approach, in a single-stage procedure. While early applications of particulated cartilage were allograft, there are distinct biological benefits of juvenile articular cartilage that make it superior. Animal and preclinical models have shown the reproduction of hyaline-like tissue following implantation.49x49McCormick, F, Yanke, A, Provencher, MT, and Cole, BJ. Minced articular cartilage–basic science, surgical technique, and clinical application. Sports Med Arthrosc Rev. 2008;
16: 217–220 Crossref | PubMed | Scopus (73) | Google ScholarSee all References Pro cartilage repair gene expression profiles are increased in juvenile chondrocytes compared to adults. Specifically, juvenile chondrocytes demonstrate increased proteoglycan content and exhibit increased gene expression of collagen type II and type IX, factors that direct cartilage growth and expansion.50x50Adkisson, HD, Martin, JA, Amendola, RL et al. The potential of human allogeneic juvenile chondrocytes for restoration of articular cartilage. Am J Sports Med. 2010;
38: 1324–1333 Crossref | PubMed | Scopus (204) | Google ScholarSee all References In vitro, juvenile chondrocytes are found to have low immunogenicity, as well as increased metabolic activity, cellular density, and proliferation rate compared to adult chondrocytes.50x50Adkisson, HD, Martin, JA, Amendola, RL et al. The potential of human allogeneic juvenile chondrocytes for restoration of articular cartilage. Am J Sports Med. 2010;
38: 1324–1333 Crossref | PubMed | Scopus (204) | Google ScholarSee all References,51x51Adkisson, HD, Gillis, MP, Davis, EC, Maloney, W, and Hruska, KA. In vitro generation of scaffold independent neocartilage. Clin Orthop Relat Res. 2001;
391: S280–S294 Crossref | PubMed | Scopus (98) | Google ScholarSee all References,52x52Bonasia, DE, Martin, JA, Marmotti, A et al. Cocultures of adult and juvenile chondrocytes compared with adult and juvenile chondral fragments: in vitro matrix production. Am J Sports Med. 2011;
39: 2355–2361 Crossref | PubMed | Scopus (63) | Google ScholarSee all References Mincing the graft tissue allows for liberation of the chondrocytes from their native extracellular matrix and allows them to construct new matrix and hyaline-like cartilage.53x53Lu, Y, Dhanaraj, S, Wang, Z et al. Minced cartilage without cell culture serves as an effective intraoperative cell source for cartilage repair. J Orthop Res. 2006;
24: 1261–1270 Crossref | PubMed | Scopus (188) | Google ScholarSee all References
Evolution
The first published use of particulated cartilage grafts was in 1983 out of Germany.54x54Albrecht, F, Roessner, A, and Zimmermann, E. Closure of osteochondral lesions using chondral fragments and fibrin adhesive. Arch Orthop Trauma Surg. 1983;
101: 213–217 Crossref | PubMed | Scopus (52) | Google ScholarSee all References Following this model, several studies were published in the early 2000s where animal models demonstrated the efficacy of transplantation of minced cartilage pieces in the repair of chondral defects.38x38Farr, J, Cole, BJ, Sherman, S, and Karas, V. Particulated articular cartilage: CAIS and DeNovo NT. J Knee Surg. 2012;
25: 23–29 Crossref | PubMed | Scopus (97) | Google ScholarSee all References,53x53Lu, Y, Dhanaraj, S, Wang, Z et al. Minced cartilage without cell culture serves as an effective intraoperative cell source for cartilage repair. J Orthop Res. 2006;
24: 1261–1270 Crossref | PubMed | Scopus (188) | Google ScholarSee all References,55x55Frisbie, DD, Lu, Y, Kawcak, CE, DiCarlo, EF, Binette, F, and McIlwraith, CW. In vivo evaluation of autologous cartilage fragment-loaded scaffolds implanted into equine articular defects and compared with autologous chondrocyte implantation. Am J Sports Med. 2009;
37: 71S–80S Crossref | PubMed | Scopus (108) | Google ScholarSee all References Since around 2010, increasing evidence of successful use of particulated cartilage grafts in humans has been published.56x56Cole, BJ, Farr, J, Winalski, CS et al. Outcomes after a single-stage procedure for cell-based cartilage repair: a prospective clinical safety trial with 2-year follow-up. Am J Sports Med. 2011;
39: 1170–1179 Crossref | PubMed | Scopus (196) | Google ScholarSee all References,57x57Farr, J and Yao, JQ. Chondral defect repair with particulated juvenile cartilage allograft. Cartilage. 2011;
2: 346–353 Crossref | PubMed | Scopus (78) | Google ScholarSee all References The first commercialized iteration of particulated cartilage grafts in the US was the Cartilage Autograft Implantation System (CAIS) from Depuy Mitek that utilized autograft cartilage from the patient. In a randomized trial vs microfracture, CAIS demonstrated significantly higher patient reported outcomes over 2 years of follow up.56x56Cole, BJ, Farr, J, Winalski, CS et al. Outcomes after a single-stage procedure for cell-based cartilage repair: a prospective clinical safety trial with 2-year follow-up. Am J Sports Med. 2011;
39: 1170–1179 Crossref | PubMed | Scopus (196) | Google ScholarSee all References Around the same time that CAIS was being developed and tested, Zimmer introduced their version of particulated cartilage graft, DeNovo NT, a cartilage repair system utilizing deceased juvenile donor chondrocytes which had been shown to improve extracellular matrix production compared to autologous adult chondrocytes and demonstrated positive early outcomes.52x52Bonasia, DE, Martin, JA, Marmotti, A et al. Cocultures of adult and juvenile chondrocytes compared with adult and juvenile chondral fragments: in vitro matrix production. Am J Sports Med. 2011;
39: 2355–2361 Crossref | PubMed | Scopus (63) | Google ScholarSee all References,57x57Farr, J and Yao, JQ. Chondral defect repair with particulated juvenile cartilage allograft. Cartilage. 2011;
2: 346–353 Crossref | PubMed | Scopus (78) | Google ScholarSee all References DeNovo NT, still commercially available, is harvested from femoral condyles of pediatric donors aged 0 to 13. Like other fresh allografts, the tissue has a shelf-life of 45 days from harvest for which it must be implanted to avoid substantial loss of chondrocyte viability. Each package of DeNovo NT contains graft from a single donor capable of treating defects up to 2.5 cm2 where larger lesions can be treated with multiple packages. It is currently marketed for use in the knee, ankle, hip and shoulder.
Indications
Indications for PJAC can be considered similar to those for a MACI with regards to patient age, location of the lesion, and the size of the chondral lesion being treated. Currently, PJAC use is limited to the treatment of patellofemoral and tibiofemoral chondral lesions in active patients 55 or younger with BMI <35 kg/m2. These are general guidelines, as case by case exceptions can be made based on physiologic age and other contributing factors such as quality of healthy cartilage and overall arthritic burden. Chondral defects treated with PJAC should be at least a grade 3 or higher on the ICRS scale and range from 1 to 6 cm2 following debridement.35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
8: 429–435 Crossref | PubMed | Scopus (42) | Google ScholarSee all References
Contraindications
Main contraindications to the use of PJAC include ICRS grade 1 or 2 lesions, extensive subchondral bone edema, uncorrected ligamentous instability that can risk damage to the graft, anatomical malalignment, meniscal deficiency, and osteochondritis dissecans lesions with >6 mm of subchondral bone loss.52x52Bonasia, DE, Martin, JA, Marmotti, A et al. Cocultures of adult and juvenile chondrocytes compared with adult and juvenile chondral fragments: in vitro matrix production. Am J Sports Med. 2011;
39: 2355–2361 Crossref | PubMed | Scopus (63) | Google ScholarSee all References,54x54Albrecht, F, Roessner, A, and Zimmermann, E. Closure of osteochondral lesions using chondral fragments and fibrin adhesive. Arch Orthop Trauma Surg. 1983;
101: 213–217 Crossref | PubMed | Scopus (52) | Google ScholarSee all References Relative contraindications include bipolar lesions as well as uncontained lesions and those with subchondral insufficiency as adjuncts such as collagen membranes and bone grafting have been used successfully with PJAC.35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
8: 429–435 Crossref | PubMed | Scopus (42) | Google ScholarSee all References Although not a consensus contraindication, there is evidence that prior microfracture results in inferior outcomes.44x44Müller, PE, Gallik, D, Hammerschmid, F et al. Third-generation autologous chondrocyte implantation after failed bone marrow stimulation leads to inferior clinical results. Knee Surg Sports Traumatol Arthrosc. 2020;
28: 470–477 Crossref | PubMed | Scopus (22) | Google ScholarSee all References,58x58Minas, T, Gomoll, AH, Rosenberger, R, Royce, RO, and Bryant, T. Increased failure rate of autologous chondrocyte implantation after previous treatment with marrow stimulation techniques. Am J Sports Med. 2009;
37: 902–908 Crossref | PubMed | Scopus (344) | Google ScholarSee all References,59x59Pestka, JM, Bode, G, Salzmann, G, Südkamp, NP, and Niemeyer, P. Clinical outcome of autologous chondrocyte implantation for failed microfracture treatment of full-thickness cartilage defects of the knee joint. Am J Sports Med. 2012;
40: 325–331 Crossref | PubMed | Scopus (131) | Google ScholarSee all References
Surgical technique of PJAC
Much of the surgical technique of PJAC is similar to that of MACI, up until the transplantation of the cellular agent. PJAC should also be preceded by a diagnostic knee arthroscopy to further characterize the cartilage defect and identify other potential pathologies that might indicate or contraindicate the use of PJAC.54x54Albrecht, F, Roessner, A, and Zimmermann, E. Closure of osteochondral lesions using chondral fragments and fibrin adhesive. Arch Orthop Trauma Surg. 1983;
101: 213–217 Crossref | PubMed | Scopus (52) | Google ScholarSee all References
However, in the case of PJAC, there is no biopsy and culture of native cartilage so the procedure itself can be done at the same time as diagnostic arthroscopy if indicated. After arthroscopic evaluation and debridement of the chondral lesion(s) to attain stable edges, PJAC can be performed.
Arthrotomy incisions will again depend on defect location as described in the MACI technique section. The lesion should be debrided to the level of subchondral bone and the lesion's rims should have stable, vertical walls.38x38Farr, J, Cole, BJ, Sherman, S, and Karas, V. Particulated articular cartilage: CAIS and DeNovo NT. J Knee Surg. 2012;
25: 23–29 Crossref | PubMed | Scopus (97) | Google ScholarSee all References,60x60Hevesi, M, Krych, AJ, and Saris, DBF. Treatment of cartilage defects with the matrix-induced autologous chondrocyte implantation cookie cutter technique. Arthroscopy Tech. 2019;
8: e591–e596 Abstract | Full Text | Full Text PDF | PubMed | Scopus (6) | Google ScholarSee all References
Once the defect has been prepared for PJAC application, the graft material may be applied directly into the chondral defect. The knee should be positioned so that the defect base is parallel to the floor so that the PJAC cubes can be positioned in a uniform manner across the entire base of the defect to a height of 1 mm recessed from the peripheral healthy cartilage (Fig. 5Fig. 5).35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
8: 429–435 Crossref | PubMed | Scopus (42) | Google ScholarSee all References,38x38Farr, J, Cole, BJ, Sherman, S, and Karas, V. Particulated articular cartilage: CAIS and DeNovo NT. J Knee Surg. 2012;
25: 23–29 Crossref | PubMed | Scopus (97) | Google ScholarSee all References If the defect base is angled, then the PJAC cubes may shift and create an uneven graft layer. A layer of fibrin glue is then applied to the roof of the graft.
Fig. 5
Successfully placed PJAC cubes, minced cubes are spaced 1 to 2 mm apart and recessed 1 mm below the adjacent healthy cartilage.
Alternatively, the graft can be molded to the custom shape of the defect on the back table. Foil, such as a suture wrapper, can be press-fit into the defect creating a concave mold. PJAC cubes can be placed into this mold up to the same 1 mm recessed level as the direct application method. Fibrin glue is then applied to the roof of the cubes. After the glue has hardened, the molded graft is removed from the foil, a new layer of fibrin glue is applied to the base of the graft, and it is applied into the defect before a final layer of fibrin glue is applied to the surface of the graft.38x38Farr, J, Cole, BJ, Sherman, S, and Karas, V. Particulated articular cartilage: CAIS and DeNovo NT. J Knee Surg. 2012;
25: 23–29 Crossref | PubMed | Scopus (97) | Google ScholarSee all References
If the treated lesion is uncontained, a commercially available collagen I/III membrane can be sutured into place to cover the defect as a means of preventing PJAC graft dislodgement.61x61Gomoll, AH, Probst, C, Farr, J, Cole, BJ, and Minas, T. Use of a type I/III bilayer collagen membrane decreases reoperation rates for symptomatic hypertrophy after autologous chondrocyte implantation. Am J Sports Med. 2009;
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Postoperative recovery following PJAC
The postoperative protocol following PJAC is modeled after the MACI protocol described above. After closure, patients should remain in extension with a locking knee brace.35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
8: 429–435 Crossref | PubMed | Scopus (42) | Google ScholarSee all References Patients receiving patellofemoral grafts are allowed to ambulate at full weight bearing when locked in knee extension if there was no concomitant procedure.35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
8: 429–435 Crossref | PubMed | Scopus (42) | Google ScholarSee all References
A concomitant osteotomy at time of PJAC will similarly indicate a patient to be nonweight-bearing for 2 weeks followed by PWB at 2 to 4 weeks. There is a fine balance between beginning PWB at an early stage to stimulate chondrocyte differentiation and prematurely returning to full weight-bearing, which could lead to graft delamination or dislodgement.62x62Kraeutler, MJ, Belk, JW, Carver, TJ, and McCarty, EC. Is delayed weightbearing after matrix-associated autologous chondrocyte implantation in the knee associated with better outcomes? A systematic review of randomized controlled trials. Orthop J Sports Med. 2018;
6: 2325967118770986 Crossref | Scopus (8) | Google ScholarSee all References The hinged knee brace is generally unlocked 2 to 3 weeks postoperatively and can be used for daytime ambulation only.
A continuous passive motion machine should be used out of the brace for 6 hours daily, similarly aiming to achieve 90° flexion at 2 weeks and full range of motion by 7 to 9 weeks. Closed chain and gait training can start around 8 weeks, with activities like swimming and biking recommended after the 12-month mark. Patients generally return to full activities by 8 months postoperatively.35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
8: 429–435 Crossref | PubMed | Scopus (42) | Google ScholarSee all References
Outcomes of PJAC
The majority of outcomes for PJAC described in the literature are from case series or case reports. A case series by Farr et al in 2014 demonstrated improved patient reported outcomes in the form of IKDC and KOOS scores over 2 years as well as histologic evidence of a mixture of hyaline and fibrocartilage with increased type II collagen compared to type I collagen, supporting successful graft incorporation.63x63Farr, J, Tabet, SK, Margerrison, E, and Cole, BJ. Clinical, radiographic, and histological outcomes after cartilage repair with particulated juvenile articular cartilage: a 2-year prospective study. Am J Sports Med. 2014;
42: 1417–1425 Crossref | PubMed | Scopus (141) | Google ScholarSee all References A single center single arm prospective study of PJAC in 27 patients found significantly improved functional outcomes for patients treated for symptomatic patellofemoral articular cartilage defects. With a mean follow up of 3.84 years, no patients underwent revision surgery for graft-related issues. Additionally, nearly 70% of patients had the majority of their defect filled as identified by postoperative MRI at 2 years. Patients demonstrated statistically significant improvements in mean IKDC and KOOS Activities of Daily Living, with outcome scores not clearly affected by age, lesion location, or concomitant tibial tubercle osteotomy.64x64Wang, T, Belkin, NS, Burge, AJ et al. Patellofemoral cartilage lesions treated with particulated juvenile allograft cartilage: a prospective study with minimum 2-year clinical and magnetic resonance imaging outcomes. Arthroscopy. 2018;
34: 1498–1505 Abstract | Full Text | Full Text PDF | PubMed | Scopus (31) | Google ScholarSee all References
As these procedures gain popularity, more robust long-term outcomes data for PJAC vs MACI would be necessary. Current evidence suggests that compared to MACI, PJAC has the potential to be more cost effective given it requires a single surgery instead of 2 as well as less costly graft material is utilized.65x65LeBrun, DG, Nwachukwu, BU, Buza, SS et al. Particulated juvenile articular cartilage and matrix-induced autologous chondrocyte implantation are cost-effective for patellar chondral lesions. Arthroscopy. 2022;
38: 1252–1263.e3 Abstract | Full Text | Full Text PDF | PubMed | Scopus (2) | Google ScholarSee all References If results from studies on PJAC continue to be in favor of the procedure, we could expect to see PJAC one day surpass MACI with respect to volume of cases per year.
PJAC carries many of the same postoperative complications as those of cell-based therapies like ACI/MACI. The most common complications requiring revision surgery are graft hypertrophy and graft delamination.35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
8: 429–435 Crossref | PubMed | Scopus (42) | Google ScholarSee all References Graft hypertrophy involves overgrowth of graft while delamination is the separation of the graft from the underlying subchondral bone, which can both lead to significant morbidity if not recognized and treated appropriately with revision.35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
8: 429–435 Crossref | PubMed | Scopus (42) | Google ScholarSee all References,66x66White, CL, Chauvin, NA, Waryasz, GR, March, BT, and Francavilla, ML. MRI of native knee cartilage delamination injuries. AJR Am J Roentgenol. 2017;
209: W317–W321 Crossref | PubMed | Scopus (10) | Google ScholarSee all References However, the most commonly reported adverse events overall are joint effusion and stiffness.35x35Riboh, JC, Cole, BJ, and Farr, J. Particulated articular cartilage for symptomatic chondral defects of the knee. Curr Rev Musculoskelet Med. 2015;
8: 429–435 Crossref | PubMed | Scopus (42) | Google ScholarSee all References
Regarding the rates of graft hypertrophy seen after PJAC, the literature is sparse with only 2 small studies reporting on this complication. Tompkins et al found gross graft hypertrophy requiring debridement in just 2 patients out of 13 patients (15 knees), and two others exhibiting mild graft hypertrophy.67x67Tompkins, M, Hamann, JC, Diduch, DR et al. Preliminary results of a novel single-stage cartilage restoration technique: particulated juvenile articular cartilage allograft for chondral defects of the patella. Arthroscopy. 2013;
29: 1661–1670 Abstract | Full Text | Full Text PDF | PubMed | Scopus (86) | Google ScholarSee all References Another study in 2014 by Buckwalter et al reported on patients with high-grade patellar chondral with a mean size of 2.3 cm2. Of the 13 patients examined, there were no cases of graft hypertrophy reported. Of note, 6 of the patients underwent a concomitant tibial tubercle osteotomy to unload the lesion.68x68Buckwalter, JA, Bowman, GN, Albright, JP, Wolf, BR, and Bollier, M. Clinical outcomes of patellar chondral lesions treated with juvenile particulated cartilage allografts. Iowa Orthop J. 2014;
34: 44–49 PubMed | Google ScholarSee all References
Although there is the autoimmune risk with the inherent allogeneic nature of allograft-based approaches, juvenile chondrocytes have not been shown to stimulate proliferation of allogeneic or xenogeneic lymphocytes or promote graft rejection immune responses.50x50Adkisson, HD, Martin, JA, Amendola, RL et al. The potential of human allogeneic juvenile chondrocytes for restoration of articular cartilage. Am J Sports Med. 2010;
38: 1324–1333 Crossref | PubMed | Scopus (204) | Google ScholarSee all References,69x69Adkisson, HD, Milliman, C, Zhang, X, Mauch, K, Maziarz, RT, and Streeter, PR. Immune evasion by neocartilage-derived chondrocytes: Implications for biologic repair of joint articular cartilage. Stem Cell Res. 2010;
4: 57–68 Crossref | PubMed | Scopus (99) | Google ScholarSee all References
Conclusion
Cell transplantation techniques such as MACI and PJAC offer treatment options that can effectively address large full-thickness chondral defects in TFJs or PFJs that may respond poorly to bone marrow stimulation or mosaicplasty. Both procedures have shown clinically significant improvements in outcome scores and low rates of complications. MACI has a handful of high-level studies reaching long-term follow-up, but most comparative studies use microfracture or earlier generation ACI procedure as its comparator. PJAC is still a relatively newer treatment option and is lacking high quality research with long-term follow up. RCTs involving PJAC with long-term follow up and further comparisons of MACI against other restoration procedures beyond microfracture and ACI will be needed to fully determine the extent that these procedures should be favored in different clinical settings involving chondral defects of the knee. Research in this field may ultimately lead to more successful treatment of articular cartilage lesions.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.
Ethics approval
No patients were involved in this research and, therefore, no informed consent was required.
References
1Gomoll, AH and Minas, T. The quality of healing: articular cartilage. Wound Repair Regen. 2014;
22: 30–38
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