Articular Cartilage Injury and Autologous Chondrocyte Implantation
Which Patients Might Benefit?
Randall R. Wroble, MD
THE PHYSICIAN AND SPORTSMEDICINE - VOL 28 - NO. 11 - NOVEMBER 2021
In Brief: Injuries to the knee articular cartilage are extremely common, and, until recently, methods for treatment did not produce good long-term results. A better understanding of how articular cartilage responds to injury has produced various techniques that hold promise for long-term success. Among such techniques is autologous chondrocyte implantation, in which a patient's own cartilage cells are harvested, grown ex vivo, and reimplanted in a full-thickness articular surface defect. Results are available with up to 10 years' follow-up, and more than 80% of patients have shown improvement with relatively few complications.
Knee injuries are exceedingly common and often result in surgery. According to computer procedural terminology (CPT)-4 code data, more than 1 million procedures for soft-tissue knee injuries are performed in the United States each year (1). A large number of these injuries are to knee menisci and ligaments. Over time, successful treatment strategies have been developed for treating these disorders. Long-term results of meniscal repair and ligament reconstruction have shown improved quality of life and activity level (2,3).
Advances in imaging and in diagnostic arthroscopic techniques have increased our knowledge of the frequency of articular cartilage injuries. Isolated full-thickness femoral condyle defects due to trauma have been found in large numbers: As many as 4% of knees undergoing arthroscopy have them (figure 1) (4). If left untreated, such lesions may progress and become symptomatic. Additionally, bone bruises, found in up to 80% of patients with anterior cruciate ligament (ACL) tears, may result in articular surface degeneration (5,6). Biopsy and arthroscopic evaluation have revealed early surface damage to the articular cartilage and underlying tissue, but treatment for articular cartilage injuries has not proved to be as effective as that for meniscal and ligament injuries. Even though tens of thousands of articular cartilage procedures are performed every year, no form of treatment has demonstrated long-term effectiveness (7-10).
Extensive investigation has provided substantial insight into the anatomy of articular cartilage and its response to injury. Furthermore, basic science discoveries have led to potentially significant advances in treating full-thickness articular cartilage defects. If these treatments could prevent progression to osteoarthritis, the need for total knee replacement—which is now performed more than 150,000 times per year in the United States alone—might be delayed or even eliminated.
Articular cartilage performs an impressive variety of feats. Although the knee articular cartilage is only a few millimeters thick, it distributes the load between the femur and tibia to avoid high stresses on small load-bearing areas within the joint. It also must provide a low-friction bearing surface for the gliding and rolling of joint surfaces against one another. In fact, its coefficient of friction is calculated to be lower than that of ice gliding on ice (9).
Cushioning the joint. Articular cartilage must be able to withstand repetitive compressive loads for a lifetime. With each step, articular cartilage withstands forces of 1.2 megapascals (11). Nelson and Wagner (12) describe these forces as being equivalent to the "amount of compression that would be exerted on the skin if a 300-lb person were to hang from a ledge by a fingertip," and emphasize that for the average person this activity occurs about one million times per year.
Composition. To accomplish these varied and difficult functions, articular cartilage has a unique composition and organization. It is composed of cells, water, and matrix. The cells are known as chondrocytes and account for about 1% of the tissue volume. The chondrocytes are completely surrounded by the matrix. They are isolated from other cells and obtain nutrients and substrates needed for various metabolic processes from the synovial fluid that diffuses through the matrix. In turn, chondrocytes produce and maintain a healthy articular cartilage matrix.
Structure. The matrix grossly appears homogeneous, but it actually has an elaborate structure (13,14). Sixty percent to 80% of the matrix is water, the rest being the structural macromolecules: collagens, proteoglycans, and glycoproteins (figure 2) (9). Collagen provides the tensile strength of the matrix, and in hyaline, or articular cartilage, it is 90% to 95% type 2 collagen (13). Type 1 collagen is the primary collagen in fibrocartilage.
Proteoglycans interact with tissue fluid to give cartilage stiffness, resilience, and resistance to compression. They are macromolecules made up of polysaccharide chains bound to protein cores and consist of multiple monomers that form large aggregates. Proteoglycans have many negatively charged side chains that bind water and positively charged ions. Compression forces the negatively charged chains together and forces fluid out; release of pressure allows expansion. The collagen network restrains the proteoglycans, and, if the network is disrupted, water content increases and proteoglycan content decreases. Glycoproteins help organize and maintain the structure of the matrix and the relationship between the cells and the matrix.
Response to Injury
The remarkable functional properties of articular cartilage are tempered by its sole serious weakness: It is unable to heal from even minor injuries. Injury occurs through prolonged, repetitive joint loading or through a single high-shear load (13).
Cartilage and injury. Articular cartilage responds differently to injury than other tissues (14). Unlike other tissues, cartilage has no direct blood supply, lymphatic drainage, or innervation. In addition, articular cartilage has a slow regeneration rate, and chondrocytes can't migrate within the matrix to the site of injury as do cells in other tissues. In partial-thickness cartilage injury, the response is limited or nonexistent. When the collagen framework is disrupted, cells directly adjacent to the injury have only a limited ability to respond. The lack of a vascular supply prevents a true inflammatory or cellular response. Thus, the defect is not repaired. In articular cartilage defects that penetrate the subchondral bone, a reparative response is generated. Initial granulation tissue is converted into fibrocartilage or a mixture of hyaline cartilage and fibrocartilage (15).
Full-thickness injury and repair. The precise natural history of full-thickness articular surface defects has not been elucidated. From a clinical point of view, however, most large, full-thickness defects in articular cartilage are symptomatic (10,16,17). Symptoms include pain, swelling, and catching, particularly in patients such as runners, whose activities include repetitive high-impact loads. Many but not all of these defects, especially the bigger ones, tend to enlarge (18). Also, symptoms tend to worsen with time.
Many techniques have been advocated for facilitating articular cartilage healing (10). Treatments include debridement or simple removal of cartilage and meniscal fragments. Arthroscopic washing out of loose fragments and joint fluid containing degradative enzymes has been used since the early 120210s with good short-term but poor long-term results (19). Other techniques such as drilling, abrasion, and microfracture all work by penetrating the subchondral bone and stimulating the local cells. These pluripotential mesenchymal cells do produce a reparative response. Unfortunately, the reparative response produced is one that synthesizes primarily fibrocartilage (7,15).
Fibrocartilage is not as effective in maintaining joint function as hyaline cartilage. It has weaker mechanical properties, cannot distribute forces as well, and, over time, is prone to fibrillation and breakdown.
Assessing outcomes. The literature concerning outcomes of articular cartilage procedures is difficult to assess (9,18). The ages of patients treated and type of defects vary widely. The methodology, techniques, and evaluation processes have not been standardized for different patient groups. But for most procedures, such as debridement, chondroplasty, abrasion arthroplasty, or microfracture, up to 80% of patients have improved pain relief and function in the short term. After 4 or 5 years, however, these results deteriorate (9,15,18). In fact, in a physician survey, it was estimated that 10 years after the initial arthroscopic surgery, nearly 60% of patients would require additional surgical intervention (20).
Autologous Chondrocyte Implantation
The fact that the damaged articular cartilage appears to have little ability to regenerate functional tissue has led to attempts at transplanting cells of various types into chondral defects. Transplants have included autologous rib perichondrial cells, autologous periosteum, and, more recently, autologous chondrocytes. In 1994, Swedish investigators reported a new technique for treating full-thickness articular cartilage defects in the knee (21). In their group (23 patients with 2- to 7- year follow-up and lesion sizes ranging from 1.5 to 6.5 cm2), all prior treatment had failed. After autologous chondrocyte implantation (ACI), 88% of the patients with femoral lesions had good or excellent results. These results have been extended in Sweden and replicated in the United States in several centers in follow-ups of intermediate range (up to 10 years) (8,19,22-24).
Implantation procedure. The basic premise is that the techniques available for growing healthy in vitro chondrocytes can be employed clinically by harvesting cells from the patient, culturing the chondrocytes, and reimplanting them. The procedure involves two steps (figure 3) (8,21). The first step is an arthroscopic evaluation and biopsy. The defect, which can be located on the femoral condyle in a load-bearing area or the trochlea, is assessed. A biopsy of healthy articular cartilage is then taken from the medial or lateral femoral condylar ridge in a non-weight-bearing area. The biopsy specimen is used for laboratory culture of additional chondrocytes.
Once chondrocytes have grown to about 2.6 million to 5 million cells, they are ready for implantation, typically 11 to 21 days later. At a second surgical procedure, an arthrotomy of the knee is performed. The edges of the defect are trimmed to provide a healthy cartilage edge. The base of the lesion is also debrided so that only bone (no cartilage) is present. Next, a periosteal patch the same size as the defect is harvested from the anteromedial proximal tibia. The patch is then sutured onto the defect and the edge sealed with fibrin glue. Finally, the cells are injected under the patch and the injection point sealed.
Chondrocyte proliferation. Over time, the implanted cells begin to produce articular cartilage (21,25,26). Initially, the transplanted chondrocytes proliferate rapidly. A maturation phase follows with increased formation of matrix. At 2 to 6 months, the cartilage in the subchondral region forms an orderly transition into bone, resulting in an articular surface that closely resembles the host hyaline cartilage. Biopsies taken 1 to 2 years after implantation have revealed tissue described as "hyaline-like" (8,27). Clinical results have shown approximately 80% good and excellent results at 5- to 10-year follow-up, with a complication rate of about 5% (9,19,23,24,28). Most often, these complications have been adhesions or arthrofibrosis. In about 2% of patients, the graft failed (8,9).
A recent economic and quality-of-life analysis has also confirmed the efficacy of ACI (29). Quality of life was improved significantly during the first 2 years after surgery. ACI was also judged to be cost effective compared with other therapies for chronic illnesses. Readers desiring more details of the complex cost analysis should consult the article by Minas (29).
Indications for implantation. Currently, this procedure is for patients who have full-thickness articular cartilage defects on the load-bearing surface of the medial or lateral femoral condyle or the femoral trochlea. The lesion must be contained, that is, have normal articular cartilage at its borders, and be less than 10 cm2. Lesions smaller than 2 cm2 can probably be treated effectively using microfracture or similar techniques. The patient's symptoms should correlate with the location of the defect. If a drilling or microfracture procedure has been done previously, ACI must take place at least 9 to 12 months later so that the subchondral bone is healed. Patient criteria include ages 15 to 50 years, no inflammatory arthritis, and willingness to follow and comprehension of the need to comply with the rehabilitation program. The patient's knee must be stable, and tibiofemoral and patellofemoral alignment must be corrected prior to ACI.
Post-ACI rehabilitation. The rehabilitation program is lengthy. The goal is to provide stimulus for cartilage regeneration without overstressing the area being repaired. Early motion in the form of continuous passive motion is recommended. The graft is protected from full weight bearing by use of crutches or a cane for up to 12 weeks. Early on, physical therapy emphasizes patellar mobility, quadriceps strength, and range of motion. Effusion is controlled with compression, cryotherapy, and anti-inflammatory medication. Progressive strength training and agility exercises increase gradually as the graft matures. It takes about 6 months to return to light-impact training and jogging. Return to high-level sports takes about a year.
While ACI has shown promise and good intermediate-term results, long-term efficacy remains to be determined. Another unanswered question is whether this or any procedure can lessen the frequency of total knee replacement. Thus, it is not surprising that several other procedures are being investigated. A variety of methods can stimulate formation of new cartilage and may be options.
Allografts. Allograft transplantation of articular cartilage has been performed for many years but is limited by tissue availability, possibility of disease transmission, and chondrocyte viability within preserved specimens (30). Allografts are osteochondral composites, and the bone in these grafts can provoke an immunogenic response. Thus, rejection is also possible.
Other techniques. Other types of autologous chondrocyte transplantation such as osteochondral autograft transfer or mosaicplasty are also available. In these techniques, osteochondral plugs are placed within the patient's knee (31,32). Plugs are harvested from non-load-bearing areas and sutured into the defect. These may be either multiple small plugs or a single larger plug that can fill the entire defect. Early results appear promising. One limitation is the relatively small amount of "noncritical" (non-load-bearing) cartilage available for harvesting. Another problem is the somewhat destructive nature of the transplantation as the subchondral bone is, by nature of the procedure, disrupted at the time of implantation.
Other modalities still in the early stages of development are the use of natural and synthetic polymer replacement for articular surfaces and injection of growth factors or therapy with gene-bearing vectors (7,33). Artificial matrices may permit delivery and stabilization of cells or growth factor into a defect. In addition, they may stimulate growth of cells and improve matrix function. Growth factors affect chondrocytes and may upregulate physiologic functions of new articular cartilage matrix. These procedures may also be options for the patient with articular cartilage damage.
It should be emphasized that none of these therapies, including ACI, has produced tissue that precisely duplicates the biochemical properties, structure, and durability of articular hyaline cartilage. Future treatment methods must include correction of malalignment and instability, joint debridement, and implantation of cells or growth factors within a compatible matrix that optimizes stability, protects from immune response, and allows cell proliferation. Additionally, there should be minimal adverse reactions. The outcomes of these procedures must be evaluated in terms of long-term improvement in quality of life and cost effectiveness.
Patients should be aware that in conjunction with these procedures, they should engage in muscle strengthening exercise programs, maintain or reduce body weight to appropriate levels, and modify activities to avoid repetitive impact loading. Even though intermediate results may appear good, Brody said, "it takes many studies that examine an issue from many angles" (34), and these words should be heeded before changing our approach to treatment.
Dr Wroble is a staff physician at Sports Medicine Grant in Columbus, Ohio, and an editorial board member of The Physician and Sportsmedicine. Address correspondence to Randall R. Wroble, MD, 323 E Town St, Columbus, OH 43215; e-mail to [email protected].