Chondrocyte Transplantation Techniques

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CHAPTER 18 Chondrocyte Transplantation Techniques

Developing concepts and methods that can restore hyaline articular cartilage has been the goal of researchers and clinicians for centuries.¹ In 1994, Brittberg and coworkers² reported on the first successful use of autologous chondrocytes in human subjects with full-thickness articular cartilage lesions of the knee using a two-step implantation technique. Since its first description, chondrocyte transplantation has been performed in more than 15,000 patients worldwide and many research studies have clinically validated this surgical technique as a reliable method for biologic restoration of hyaline-like articular cartilage.³^–¹³ Based on the evolution and better understanding of the treatment of articular cartilage defects and cell-based implantation techniques in recent years, this demanding surgical technique has undergone several technical modifications. These recent developments can help reduce patient morbidity and technique-specific complications. Chondrocyte implantation techniques continue to evolve using modern tissue engineering technologies.

PATIENT EVALUATION

History

Obtaining a thorough history in patients with chondral defects presents a critical first step in the treatment process and selection of patients who are appropriate candidates for chondrocyte implantation. Patients with articular cartilage defects typically present with a spectrum of mechanical symptoms from the defect. Symptoms from cartilage defects are usually nonspecific and can mimic other forms of knee pathology, such as meniscal tears. Pain with weight bearing is usually present with impact activities. Cartilage defects of the femoral condyles often produce point tenderness over the femoral condyle rather than the joint line. Catching and locking sensations can occur from cartilage flaps or larger defects. Joint effusion is frequently reported, particularly after demanding impact activities. Defects of the patella or trochlea usually lead to pain when ambulating stairs, driving a car, getting out of a chair, or assuming a squatting position. Symptoms of patellar instability may be reported. Articular cartilage defects may present acutely after joint trauma such as knee ligament tears or chronically. Patients considered for chondrocyte transplantation techniques may have undergone prior cartilage repair procedures and a detailed evaluation of the prior surgical procedures should be performed. The time since the initial injury, as well as the types of previous surgeries, should be recorded because these factors have been shown to affect the outcome after chondrocyte implantation.

Physical Examination

Physical examination includes evaluation of gait pattern and lower extremity alignment. Hip, knee, and ankle range of motion should be assessed and any joint effusion noted. Because articular cartilage lesions are frequently found in patients with acute hemarthrosis, acute or chronic ligamentous instability, patellar dislocation or maltracking, or lower extremity malalignment, these factors should be routinely evaluated. Depending on defect location and size, mechanical symptoms may or may not be present and may overlap with meniscal tests. The patient’s body mass index (BMI) should be assessed because it has been shown to correlate with functional outcome after articular cartilage repair.

Diagnostic Imaging

Plain radiographs, including weight-bearing anteroposterior (AP) and lateral views, Rosenberg and tunnel views, long-leg films, and Merchant views, can help identify osteochondral lesions, joint space narrowing, patellar maltracking, or lower extremity malalignment. Cartilage-sensitive magnetic resonance imaging (MRI) presents a sensitive, specific, and accurate tool for noninvasive diagnosis of articular cartilage injury.¹⁴^,¹⁵ Images should be obtained in three planes; using fast spin-echo imaging with a repetition time (TR) of 3500 to 5000 msec and moderate echo time (TE) provides high contrast resolution among articular cartilage, subchondral bone, and joint fluid. Cartilage-sensitive MRI provides useful information about meniscal and ligamentous status, subchondral bone, lesion size, and depth Because of the pathologic changes in the surrounding cartilage, the final size of the defect intraoperatively is usually larger than the defect size measured on preoperative MRI. In addition to its use for preoperative diagnosis, cartilage-sensitive MRI can be helpful for postoperative evaluation of cartilage repair. Routine postoperative MRI is recommended to evaluate the cartilage repair tissue and detect potential complications, such as graft hypertrophy. If available, newer technologies, such as T2 mapping, delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), and T1 rho relaxation mapping, can be used to obtain additional details about cartilage morphology pre- and postoperatively.¹⁵

Preoperative Planning and Counseling

Based on the history, physical examination, and radiologic information, the indication for autologous chondrocyte transplantation or adjuvant procedures is discussed with the patient. In-depth preoperative patient counseling is critically important to determine the patient’s demands, assess his or her ability to comply with the postoperative rehabilitation protocol, and create realistic expectations and goals for postoperative knee function and activity level.

TREATMENT

Indications and Contraindications

Chondrocyte implantation is indicated for symptomatic, high-grade chondral and osteochondral defects of the knee in active patients who are physiologically too young for arthroplasty. This technique can be successfully used as a first-line treatment of femoral condylar, trochlear, and patellar lesions larger than 2 cm², or used as a revision technique for failed prior cartilage repair procedures.⁸^,¹¹^–¹³ The technique can be successfully used for isolated, multiple, and kissing cartilage defects. Prerequisites for successful autologous chondrocyte transplantation include adequate range of motion, appropriate axial alignment or patellar tracking, ligamentous stability, and the ability to comply with the postoperative rehabilitation protocol. Adjuvant procedures may be indicated to correct coexisting knee pathology; these can be performed simultaneously with chondrocyte transplantation without negative effects of the complex procedures on the postoperative functional outcome and activity level.

Absolute contraindications for autologous chondrocyte transplantation include generalized osteoarthritis, inflammatory arthropathies, and joint sepsis. Patients unable to comply with the postoperative rehabilitation and weight-bearing protocols should also not be treated with this technique. A body mass index (BMI) more than 30 kg/m² has been associated with limited improvement after knee articular cartilage repair and presents a relative contraindication. Patients with severe meniscal deficiency should be considered for meniscal allograft transplantation at the time of chondrocyte transplantation.

Arthroscopic Technique

Autologous chondrocyte transplantation of the knee is carried out as a two-stage procedure.

Stage 1: Chondrocyte Harvest

Step 1. Arthroscopic Evaluation.

The first stage involves a thorough diagnostic arthroscopy. In addition to identification of the known articular cartilage defect, the meniscal and ligamentous status is evaluated and the entire articular cartilage is inspected to rule out any additional cartilage defects. Partial meniscectomy or meniscal repair can be performed at the time of this arthroscopy because it minimally affects the course after the initial arthroscopy and can decrease operative time during the second-stage procedure. However, surgical treatment of meniscal deficiency or ligamentous pathology should be performed simultaneously with autologous chondrocyte implantation to avoid repetitive operative joint trauma and prolonged rehabilitation. During the first-stage arthroscopy, the cartilage defect is identified and existing cartilage flaps are débrided back to a stable and healthy peripheral margin. Following thorough débridement, the size of the articular cartilage lesion is measured and its containment documented. The knee is taken through a full range of motion and the arc of motion during which the lesion articulates with the opposing joint surface is carefully recorded (Fig. 18-1). The opposing joint surface should always be carefully inspected for the presence of a kissing lesion or signs of low grade cartilage injury.

FIGURE 18-1 The exact location and range of articulation of the defect are noted carefully to facilitate postoperative rehabilitation in the nonloading safe zone.

Step 2. Chondrocyte Harvesting.

Following initial arthroscopic evaluation, chondrocyte graft harvesting of 200 to 300 mg of normal articular cartilage is obtained from a lesser weight-bearing area of the injured knee, generally the medial or lateral superior ridge of the femoral condyle or intercondylar notch. The intercondylar notch is preferred for patellofemoral lesions. Using cartilage that has been débrided from the cartilage defect as graft is not recommended because chondrocyte quality from this area has been shown to be inferior. Graft procurement is done best with an angled or ring curette. The grafted cartilage tissue is sent for standardized commercial isolation and culturing of chondrocytes. Implantation of cultured chondrocytes is performed after 2 to 4 weeks when a sufficient number of cells has been obtained for the size of the defect (range, 4 to 12 million cells). Chondrocyte viability is routinely tested and should be more than 95% before implantation.

Stage 2: Chondrocyte Implantation

Step 1. Addressing Concomitant Pathology.

Malalignment, ligamentous instability, and/or meniscal injury and deficiency are known to contribute to the development of articular cartilage lesions and surgically addressing these concomitant pathologies is critical for an effective and durable articular cartilage repair.¹¹^–¹³ Concomitant ligament reconstruction, meniscal allograft, or osteotomy should be performed before autologous chondrocyte implantation. Isolated or combined adjuvant procedures, including anterior cruciate ligament (ACL) reconstruction, high tibial osteotomy, or meniscal allograft and repair do not negatively affect postoperative activity levels after autologous chondrocyte transplantation.⁹ Simultaneous rather than staged adjuvant procedures avoid prolonged rehabilitation, promote postoperative activity, and provide a significant cost benefit.

Step 2. Chondrocyte Implantation.

Chondrocyte implantation is performed using a parapatellar arthrotomy in a tourniquet-controlled bloodless field. The cartilage defect is again débrided back to a healthy cartilage margin and the calcified cartilage is carefully débrided without violating the subchondral bone using a ring curette (Fig. 18-2A). If bleeding is encountered, hemostasis of the defect bed can be achieved by application of thrombin or fibrin glue. Intralesional osteophytes can be débrided using a 4-mm burr without compromising the subchondral bone. A template of the defect is created with sterile aluminum foil or paper and then used to harvest an appropriately sized periosteal flap from the proximal medial border of the tibia. When using periosteum, the tissue patch should be slightly larger than the defect because of a tendency of the periosteum to contract. Any adherent fatty or connective tissue needs to be carefully removed to minimize the potential for graft hypertrophy. The periosteal flap is then sutured flush to the articular cartilage defect using interrupted 6-0 Vicryl sutures (Ethicon; Somerville, NJ), with the cambium layer facing into the defect (see Fig. 18-2B). As an alternative to the periosteum, a type I or III collagen membrane can be used to cover the defect (Fig. 18-3). This allows for smaller incisions, reduces patient morbidity, and minimizes the potential for graft hypertrophy. The rim of the periosteal flap or collagen membrane is sealed watertight with fibrin glue (Tisseel; Baxter; Deerfield, Ill) except for one corner, where the implanted chondrocytes are injected into the defect. Following cell injection, the remaining corner of the periosteal flap is secured with sutures and sealed with fibrin glue. If a tourniquet was used, it should be released and meticulous hemostasis should be obtained. Drains are not normally used so as to avoid injury to the periosteal cover or fibrin seal of the defect from direct abrasion by the drain during postoperative joint mobilization. A compression dressing is placed and cryotherapy used routinely. Bracing is not necessary for isolated chondrocyte transplantations but may be used if simultaneous adjuvant procedures require postoperative protection.

FIGURE 18-2 A, Articular cartilage defect of the femoral condyle before implantation. B, Cartilage defect after coverage with periosteum. C, Cartilage-sensitive MRI scan at 36 months postoperatively.

FIGURE 18-3 A, Cartilage defect of femoral condyle. B, Collagen membrane shaped to the contour of the defect. C, Collagen membrane covering the defect

Deep Chondral or Osteochondral Defects

In patients with lesions deeper than 1 cm, autologous bone grafting should be performed in combination with autologous chondrocyte implantation (ACI). Implantation of chondrocytes in these cases is performed using the sandwich technique. The os seous defect is filled with cancellous bone graft from the iliac crest or proximal tibia to the level of the subchondral plate. One periosteal flap or collagen membrane sized for the defect is then anchored with the facing toward the joint using fibrin glue applied between the patch and bone graft. A second sized periosteal flap or membrane is then placed facing into the defect and secured to the surrounding cartilage with interrupted 6-0 Vicryl sutures. The rim is again sealed with fibrin glue and the cultured chondrocytes are implanted between the two periosteal flaps or collagen membranes (sandwich technique; Fig. 18-4).

FIGURE 18-4 Stepwise description of the sandwich technique of autologous chondrocyte transplantation for deep osteochondral defects. A, The defect is débrided to stable chondral and bony margins and the bony base is drilled to facilitate bony healing. Bone grafting of the defect to the level of the subchondral bone plate is then performed. B, The bone graft is covered with the first periosteal patch placed with the cambium layer facing into the defect and sealed with fibrin glue. C, The second periosteal patch is sutured to the cartilage margin and the chondrocyte cell suspension is injected between the periosteal patches.

(Adapted from Mandelbaum BR, Gerhardt MB, Peterson L. Autologous chondrocyte implantation of the talus. Arthroscopy. 2003;19(suppl 1):129-37).

PEARLS& PITFALLS

PEARLS

1. Assess for and address concomitant joint pathology (e.g., alignment, instability, meniscal pathology).

2. Avoid staging adjuvant procedures to reduce prolonged rehabilitation and facilitate return to activity.

3. Record the location and articulation of defect to facilitate postoperative rehabilitation in a safe zone.

4. Substituting periosteum with collagen membrane or matrix-associated chondrocyte implantation (MACI) can reduce invasiveness and the risk for graft hypertrophy.

5. The sandwich technique is useful for deep chondral and osteochondral defects.

6. An accelerated postoperative weight-bearing protocol can help promote postoperative function.

PITFALLS

1. Failure to recognize and treat concomitant joint pathology can be problematic.

2. There is a limited success rate for tibial defects and kissing lesions.

3. Avoid exercising through pain and effusion during rehabilitation.

4. Graft delamination from failure to treat symptomatic graft hypertrophy can occur.

Postoperative Rehabilitation Protocol

Postoperative management varies, depending on the lesion location, size, and concomitant procedures. Rehabilitation is based on the biology of the cartilage repair tissue. During the initial proliferation phase (0 to 4 weeks), the developing repair cartilage tissue requires protection and weight bearing is avoided in tibiofemoral defects. Patients with patellofemoral cartilage lesions immediately start weight bearing in a knee brace locked in full extension. Continuous passive motion (CPM) used for 6 hours/day for 4 weeks should be implemented. Closed kinetic chain exercises such as stationary biking are allowed at 2 weeks; limited arc-strengthening exercises are initiated with range of motion modifications based on the location of the lesion and patellar contact pattern observed at the time of surgery. In the second matrix production phase (4 to 8 weeks), weight bearing is advanced by 25% per week depending on lesion size, location, and the patient’s symptoms. Pain and swelling indicate too rapid progression of rehabilitative exercises and should be reduced. The third maturation phase is characterized by low-impact activities and advanced based on the patient’s symptoms. Running is usually allowed at about 6 to 8 months after chondrocyte transplantation while cutting and pivoting exercises are avoided until 8 to 10 months postoperatively. Early weight bearing has been shown to promote postoperative function.¹⁸ Magnetic resonance imaging (MRI) is recommended before return to high-impact pivoting activities (see Fig. 18-2C).

COMPLICATIONS

Complications after chondrocyte transplantation include stiffness and adhesions in up to 10% of patients. Graft hypertrophy is seen in 25% to 63% of postoperative MRI images but has been described as clinically symptomatic in only 13% to 15%.²^–¹⁵ Symptomatic hypertrophy can be effectively treated by arthroscopic chondroplasty. Hypertrophy may lead to partial detachment or graft delamination. Substituting the periosteum with collagen membranes or second-generation MACI effectively reduces the risk for periosteal hypertrophy.¹⁹^,²⁰ Graft failure has been described in 6% to 7% of patients. Grafts usually fail between 12 and 24 months after surgery and frequently show central degeneration. Treatment with revision chondrocyte implantation has been shown to be effective in many cases.¹³ All patients with graft failure should be carefully evaluated for the presence of subtle instability, axial malalignment, or patellar maltracking, which have been shown to lead to lower success rates after autologous chondrocyte transplantation.

OUTCOMES

Autologous chondrocyte transplantation has been successfully used for hyaline-like restoration of full-thickness articular cartilage lesions in the knee with long-term durability of functional improvement of up to 11 years.¹¹^,¹² Good to excellent results were found in 92% of isolated femoral condyle lesions, 89% of osteochondritis dissecans, 75% of femoral condyle lesions with concomitant anterior cruciate ligament reconstruction, 67% of patients with multiple lesions, and 65% of patellar lesions.²^–¹³ Return to sport is possible in 33% to 96% of patients, with the best return rates in competitive and adolescent athletes. Patients with single lesions, younger age, and short preoperative intervals have the best results.⁹^,¹⁰ Accelerated weight bearing can improve long-term functional results.¹⁸ Correcting axial malalignment, patellar maltracking, and ligamentous laxity is critical for the functional improvement.

CONCLUSIONS

Limitations of this technique include its invasiveness, long postoperative rehabilitation, and periosteal hypertrophy, which may lead to acute graft delamination. This cartilage repair technique provides significant functional improvement with high return rates to demanding sports and excellent durability, even under high athletic demands in primary and revision settings.

Scaffold-associated second-generation autologous cartilage transplantation techniques use three-dimensional biodegradable scaffolds to support the chondrocytes temporarily until they are replaced by matrix components synthesized from the implanted cells. MACI has been used with promising results in Europe and Australia but is not yet routinely available in the United States.¹⁹^,²⁰ The use of the biomatrix seeded with chondrocytes reduces surgical invasiveness and has the theoretic advantages of less chondrocyte leakage, more homogeneous chondrocyte distribution, and less graft hypertrophy. Arthroscopic MACI has been described, with improvement of knee function in up to 90% (Fig. 18-5).

FIGURE 18-5 Arthroscopic image showing matrix-associated cartilage implant (MACI, Hyalograft C; Fidia Advanced Biopolymers; Abano Terme, Italy) following arthroscopic placement.

(From Kon E, Gobbi A, Filardo G, et al. Arthroscopic second-generation autologous chondrocyte implantation compared with microfracture for chondral lesions of the knee. Prospective nonrandomized study at 5 years. Am J Sports Med. 2009;37:33-41).

Future developments are aimed at improving cellular matrix production by using more productive characterized chondrocytes with more sophisticated bioactive scaffolds that include growth factors and stimulate a more natural spatial distribution of chondrocytes within the repair cartilage.²¹^–²³ Other promising future approaches include identification and selective expansion of specific chondrocytes subpopulations capable of producing more hyaline-like repair cartilage tissue and implantation of neocartilage tissue produced in specifically designed bioreactors.²⁴

REFERENCES

1. Mandelbaum BT, Browne JE, Fu F, et al. Articular cartilage lesions of the knee. Am J Sports Med. 2000;26:853-861.

2. Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331:889-895.

3. Bentley G, Biant LC, Carrington RW, et al. A prospective, randomised comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg Br. 2003;85:223-230.

4. Fu F, Zurakowski D, Browne, et al. Autologous chondrocyte implantation versus debridement for treatment of full-thickness chondral defects of the knee: an observational cohort study with 3-year follow-up. Am J Sports Med. 2005;33:1658-1666.

5. Horas U, Pelinkovic D, Aigner T. Autologous chondrocyte implantation and osteochondral cylinder transplantation in cartilage repair of the knee joint: A prospective comparative trial. J Bone Joint Surg Am. 2003;85:185-192.

6. Knutsen G, Drogset JO, Engebertson L, et al. A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am. 2007;89:2105-2112.

7. Knutsen, G, Engebretsen L, Ludvigsen TC, et al. Autologous chrondrocyte implantation compared with microfracture in the knee. J Bone Joint Surg Am. 2004;86:455-464.

8. Mandelbaum B, Browne JE, Fu F, et al. Treatment outcomes of autologous chondrocyte transplantation for full-thickness articular cartilage defects of the trochlea. Am J Sports Med. 2007;35:915-921.

9. Mithöfer K, Peterson L, Mandelbaum BR, Minas T. Articular cartilage repair in soccer players with autologous chondrocyte transplantation: functional outcome and return to competition. Am J Sports Med. 2005;33:1639-1646.

10. Mithöfer K, Minas T, Peterson L, et al. Functional outcome of articular cartilage repair in adolescent athletes. Am J Sports Med. 2005;33:1147-1153.