Autologous Chondrocyte Implantation
J. Winslow Alford MD
Brian J. Cole MD, MBA
History of the Technique
Historically, the initial treatment of chondral injury included arthroscopic debridement to smooth the surface and remove debris that might promote an inflammatory response. Reparative techniques such as marrow stimulation offer another option that involves penetration of the subchondral bone to stimulate bleeding and recruitment of pluripotent mesenchymal marrow stem cells that differentiate and form fibrocartilage.1 Restorative options used to replace the damaged cartilage include osteochondral autograft and allograft transplantation. Finally, autologous chondrocyte implantation (ACI), the subject of this chapter, involves the biologic replacement of articular cartilage. First reported clinically by Brittberg et al.2 in 1994 and subsequently by several other authors,3,5 ACI has become an acceptable treatment option in appropriately indicated patients with symptomatic chondral defects.
The procedure involves an arthroscopically performed biopsy of articular cartilage followed by implantation of cultured chondrocytes beneath a periosteal patch. At this juncture, ACI is considered a first-generation technology and advances in biologic carriers, cell-seeded scaffolds, and single-stage biological techniques are sure to replace ACI within the next 5 to 10 years depending upon regulatory pathways. Although the vast majority of the clinical experience with these technologies is with the treatment of chondral injuries of the knee, our experience is beginning to include other weight-bearing diarthrodial joints as well.
Preclinical Experience
In the 1980s, several groups reported the results of ACI performed in rabbit articular cartilage defects.6,7 In shallow defects, an average of 82% of the surface area of the defect was covered by reformed cartilage. More recently, Brittberg et al.8 placed periosteal patches on rabbit patellar defects with and without implanting chondrocytes. After 1 year, the periosteal grafts with chondrocytes had resulted in an average repair area of 87% of the total area of the defect compared to 31% in the animals treated without chondrocytes. In addition, the tissue produced by the chondrocytes and periosteal flap had a hyalinelike appearance compared to a fibrous appearance in the group without chondrocytes.
In contrast, Breinan et al.9 found no difference at 12 or 18 months in coverage area or histologic appearance of defects repaired with either empty periosteal patches or chondrocyte-filled patches. In this study, a substantial number of defects involved violation of the subchondral bone, resulting in the creation and evaluation of osteochondral defects. Since this work, the importance of avoiding violation of the subchondral bone and antecedent bleeding has been implicated as a key feature of the ACI procedure. With respect to the longevity of the chondrocytes, studies monitoring the fate of labeled chondrocytes have demonstrated that implanted chondrocytes contribute to the formation of repair tissue and are integrated into surrounding normal articular cartilage up to 18 months following implantation.10
Indications and Contraindications
Overview
Traumatic focal chondral lesions are rarely found in isolation. A thorough evaluation of the involved extremity is essential. Assessment of associated ligament injuries, meniscal
deficiency, and coexisting mechanical axis malalignment or patellofemoral maltracking must be identified with a strategy for correction incorporated into the overall surgical plan and postoperative rehabilitation.
deficiency, and coexisting mechanical axis malalignment or patellofemoral maltracking must be identified with a strategy for correction incorporated into the overall surgical plan and postoperative rehabilitation.
Patient evaluation and identification of candidates for ACI treatment remain challenging. This is in part due to the fact that the natural history of commonly found asymptomatic lesions is unclear. In general, incidentally discovered articular cartilage lesions are well tolerated and rarely become symptomatic.11 It is generally accepted that a symptomatic cartilage lesion that fails to respond to conservative care or initial arthroscopic measures is likely to persist or worsen without treatment.12,13,14 Alternatively, the likelihood of a cartilage lesion detected incidentally on magnetic resonance imaging (MRI) or at arthroscopy becoming symptomatic depends on its location, depth, geographic configuration, the physical demands of the patient, subjective pain tolerances, and the presence of co-morbidities. Added to the unpredictable nature of the incidental lesion, the tendency for articular cartilage to respond to injury with a disordered and often incomplete repair response is likely to be related to the variability of symptoms that patients demonstrate following cartilage injury.1,2,15
Obtaining a history of the mechanism of injury, the onset and pattern of symptoms, prior treatments and the response to these treatments, as well as a thorough review of previous operative reports, arthroscopic images, and video is an important part of the initial patient evaluation. For example, Peterson et al.16 demonstrated that the typical patient indicated for ACI had an average of 2.1 previous treatments. The senior author (BJC) has had a similar experience in more than 120 ACI procedures, and we have learned that direct verbal or written communication with the most recent treating physician is extremely useful.
The etiology of chondral lesions is variable and includes blunt trauma, focal wear, or chronic conditions (i.e., osteochondritis dissecans). Variable etiology and associated biology are further affected by prior treatments rendered, functional expectations of the patient, and unique patient personality characteristics. For these reasons, identifying candidates for ACI remains challenging. For a specific patient at a particular point in time there may be several reasonable treatment options. A central tenant of cartilage restoration is that a selected treatment must not “burn bridges” but rather allow for further treatments should they prove necessary. It is essential to avoid “linear reasoning” when evaluating a particular patient. There are often several potential etiologies that lead to patient complaints of knee pain, and, thus, incidental defects must not be inappropriately labeled as responsible for a patient’s symptoms.
In addition to lesion characteristics, an evaluation of the relative severity of commonly occurring co-morbidities such as ligament and meniscal insufficiency and malalignment of the patellofemoral or tibiofemoral joints must also occur. This coexisting pathology must be addressed in conjunction with the articular cartilage pathology or in an appropriately staged fashion. Left untreated, coexisting pathology remains a contraindication to ACI. Ligament reconstruction, corrective osteotomies, or meniscal transplants are frequently required in addition to an ACI procedure. A comprehensive plan to address all features of the patient’s joint pathology must be devised and discussed at length with the patient before proceeding. Treating co-morbidities greatly enhances a patient’s possibility of achieving a good outcome by providing a symbiosis of two or more mutually beneficial procedures. The decision to perform multiple procedures concomitantly or in a staged manner requires the judgment of an experienced articular cartilage surgeon.
Imaging
Radiographic evaluation should include standing anterior to posterior, non–weight-bearing 45-degree flexion lateral, patellar skyline (i.e., Merchant), 45-degree flexion posterior-anterior (PA) weight bearing, full-length alignment views. The PA weight bearing 45-degree (tunnel or Rosenberg) view is essential because it brings the posterior femoral condyle into a tangential position relative to the tibial plateau and x-ray beam. A normal appearing joint in a standing AP x-ray may reveal severe articular cartilage loss in the region of the posterior femoral condyle when viewed with the knee in 45 degrees of flexion.
Recent advancements in cartilage-specific MRI technology permit precise diagnosis and measurement of articular cartilage pathology. High-resolution fast spin echo sequencing techniques provide a high level of accuracy in predicting defect location, size, and depth.17 Techniques using fat saturation in T2 protocols or fat suppression in T1 protocols combined with ionic gadolinium diethylene triamine penta-acetic acid (Gd-DTPA) contrast allow for inferences of biomechanical and biochemical changes involved in matrix degradation and formation.18,19 Improvements in MRI technology allow for a more accurate preoperative determination of lesion characteristics and also may allow for the postoperative assessment of actual glycosaminoglycan content and an assessment of the overall biochemical quality of the healing tissue.
Animal studies investigating the utility of ultrasound technology in the evaluation of articular surfaces were modeled to evaluate degenerative lesions, and the reliability of ultrasound for the evaluation of focal chondral lesions is unproven at this time.20 Nuclear medicine studies are of limited value due to the nonspecific nature of the information it provides. However, in the presence of osteochondritis dissecans (OCD), a completely different pathophysiology exists and a bone scan can provide information about biologic activity and healing potential.
Arthroscopy
An examination under anesthesia will allow for an assessment of co-morbidities that may need to be addressed. A
thorough arthroscopic evaluation is valuable to determine the location, topical geography, surface area, and depth of a defect in addition to providing a formal assessment of co-morbidities such as the condition of the opposing articular surface, ligament and meniscus status, and an evaluation for other unsuspected defects. Grading of articular cartilage lesions depends on direct visual assessment and has inter- and intraobserver variability. In addition to the rating systems of Outerbridge,21 Insall,22 Baur,23 and Noyes and Stabler,24 which are frequently cited in the literature, the International Cartilage Repair Society (ICRS) has offered a grading system to be used as a universal language when surgeons are communicating about cartilage lesions.25 Verbal or written grading of articular surfaces should specify which grading system is being used and should be accompanied by a written and diagrammatic description of the lesion.
thorough arthroscopic evaluation is valuable to determine the location, topical geography, surface area, and depth of a defect in addition to providing a formal assessment of co-morbidities such as the condition of the opposing articular surface, ligament and meniscus status, and an evaluation for other unsuspected defects. Grading of articular cartilage lesions depends on direct visual assessment and has inter- and intraobserver variability. In addition to the rating systems of Outerbridge,21 Insall,22 Baur,23 and Noyes and Stabler,24 which are frequently cited in the literature, the International Cartilage Repair Society (ICRS) has offered a grading system to be used as a universal language when surgeons are communicating about cartilage lesions.25 Verbal or written grading of articular surfaces should specify which grading system is being used and should be accompanied by a written and diagrammatic description of the lesion.
If the lesion is located in the patellofemoral joint, careful arthroscopic analysis of patellofemoral tracking and mechanical alignment is important because a combined anteromedialization of the tibial tubercle is generally recommended in conjunction with ACI of the patellofemoral joint.
Indications
The overall assumption is that identified defects are at least in part responsible for the patient’s signs and symptoms at the time of clinical evaluation. Smaller acute defects (i.e., less than 3 cm2) are typically treated initially with other modalities, whereby ACI is employed when these treatments fail to improve upon the patient’s clinical presentation following adequate time for recovery and response. ACI is ideal for symptomatic, unipolar, full thickness, or nearly full thickness chondral or shallow osteochondral defects. Commonly, patients have failed previous treatments. Occasionally, larger symptomatic lesions in high demand patients are indicated for ACI as a first line treatment. ACI is traditionally indicated for treatment of focal defects in the knee, but its off-label use has recently been expanded to include the treatment of chondral defects in the ankle, shoulder, elbow, wrist, and hip.26,27,28,29,30 In the knee, off-label usage for the patella and tibia has also met with success rates that parallel the femoral condyle and trochlea. Bipolar lesions (greater than grade II changes on the opposing surface) are a relative contraindication to ACI. As already discussed, malalignment, ligament instability, and meniscus deficiency are not considered contraindications to ACI as long as they are addressed concomitantly or in a staged fashion.
Patellofemoral lesions are commonly treated with simultaneously performed anteromedialization of the tibial tubercle. It is important to determine the desired ratio of anteriorization to medialization required from the distal realignment as this will determine the angle of the tubercle osteotomy performed at the time of implantation.
OCD is not a contraindication for ACI provided that bone loss is less than 6 to 8 mm. Greater degrees of bone loss are corrected with bone grafting in a single- or two-stage procedure. A “sandwich technique” where the cells are injected between two opposing layers of periosteum placed over a bone graft to re-establish the subchondral bed has been utilized in a single stage, but the senior author (BJC) prefers to first graft the lesion and biopsy at that time only to return if necessary to perform the ACI procedure no sooner than 6 months following the index treatment.
Surgical Techniques
Stage I
Prior to biopsy, we make every effort to obtain insurance approval for both phases of the ACI procedure. We rarely will biopsy a patient without the explicit intention to definitively treat the defect with ACI. The first stage involves an arthroscopic evaluation of the focal chodral lesion to assess containment, depth, and potential bone loss (Fig. 59-1). A biopsy of normal hyaline cartilage is obtained from either the superomedial edge of the trochlea,31 or our preferred site, the lateral side of the intercondylar notch (i.e., where bone is removed for an ACL notchplasty) using a curved bone-graft harvesting gouge (Fig. 59-2). If the biopsy is obtained from the trochlear ridge, it is recommended that a ring curette be used to allow for visualization of the biopsy process. The total volume of the biopsy should be approximately 200 to 300 mg preferably in three “Tic-Tac-sized” fragments. It is preferable to penetrate to the subchondral bone to ensure that the deep chondrocytes are included in the biopsy. The prepared shipping container has a collection vial that is clearly
marked to indicate adequate biopsy volume (Fig. 59-3). As when performing an ACL notchplasty, it is important not to violate the weight-bearing articular cartilage. The biopsy is sent to Genzyme Biosurgery Corp (Cambridge, Mass) for processing and cellular expansion.
marked to indicate adequate biopsy volume (Fig. 59-3). As when performing an ACL notchplasty, it is important not to violate the weight-bearing articular cartilage. The biopsy is sent to Genzyme Biosurgery Corp (Cambridge, Mass) for processing and cellular expansion.