Chapter 10. Cartilage repair of the knee. Junji Iwasa 1, Lars Engebretsen 2. Shimane University School of Medicine, Shimane, Japan.

Transcription

1 Chapter 10 Cartilage repair of the knee Junji Iwasa 1, Lars Engebretsen 2 1 Department of Orthopaedic Surgery, Shimane University School of Medicine, Shimane, Japan 2 Orthopedic Center, Ullevaal University Hospital and Faculty of Medicine, Oslo, Norway

2 Introduction Articular cartilage defects in the knee of young or active individuals remain a problem in orthopaedic practice. These defects have limited ability to heal and may progress to osteoarthritis. These may be symptomatic and cause pain, swelling and catching. Several different surgical procedures have been applied to treat cartilage injuries, but no method has been judged superior. One such attempt was the method of autologous chondrocyte implantation (ACI), described by Brittberg et al. in 1994 (1). This represented the start of in vitro cell based tissue engineering in clinical orthopedics. At present, more than 4,000 Medline citations are available on surgical cartilage treatment, but only five randomized clinical trials have been published (2-6). Three of these studies show that cell transplantation produces similar results as two other much used and less expensive techniques; microfracture and mosaicplasty. In approximately 75% of the patients, these three techniques improve symptoms assessed using patient-centered global outcome scores. This paper reviews current surgical strategies in the treatment of cartilage injuries. Keep in mind that the methods discussed are used for cartilage injuries only and not for osteoarthritis. How common are cartilage injuries? In a study of 993 consecutive arthroscopies done in patients with knee pain from Norway (7), articular cartilage changes were noted in 66% of the knees and isolated, localized cartilage lesions in about 20% of the cases. Full thickness cartilage lesions were found in 11% of the knees. An acute traumatic symptom onset was reported in 59% of the cases and a more gradual onset with no history of trauma in 41%. Sports

3 participation was the most commonly reported activity (49%), with team sports such as soccer and European team handball as the most frequent. Most of the patients with localized cartilage lesions were in the younger age groups (median age: 30 years). The most serious cartilage injuries grade III and IV were commonly located at the medial femoral condyle followed by the patella. A single full-thickness area of more than 2 cm 2 was observed in 6% of all knees, and half of these patients had a cartilage lesion as their only pathology. Fifty percent of these larger lesions (grade III-IV and >2 cm 2 ) were localized in the medial femoral condyle and 13% in the femoral trochlea. Another review, of 31,000 arthoscopic procedures, found articular cartilage lesions in 63% (8) and yet another reported the incidence of localized chondral and osteochondral lesions in 1,000 consecutive arthroscopies to 19% (9). Treatment goals The ultimate aim of cartilage treatment is the restoration of normal knee function by regeneration of hyaline cartilage in the defect, and to achieve a complete integration of the new cartilage to the surrounding cartilage and underlying bone. Recent years have seen several new surgical procedures emerge with the aim to improve function to create normal cartilage. Unfortunately, this effort has not been followed by appropriate studies to assess these new methods or compare them with available procedures. Marrowstimulating procedures have been widely used, directed at the recruitment of bone marrow cells. These methods penetrate the subchondral bone to allow fibrin clot formation within the defect and create repair tissue. Pridie drilling has been used for decades (10). More recent marrow-stimulating procedure is microfracture where an awl

4 instead of drilling is used to penetrate the subchondral plate (11-14). Other approaches to the treatment of full-thickness cartilage defects include methods of resurfacing with periosteum (15,16), perichondrium (17-19), osteochondral plugs (mosaicplasty) (20,21) and allografts (22-24). ACI was first described in 1994 (1). Encouraging primary results were reported, and further research was promoted. (25-27). Newer techniques combining scaffolds, cells and growth factors have also been developed (28-33). Biotechnology and nanotechnology have already opened new doors in orthopedics and will be important tools in the future. What are we treating? Cartilage injuries can be acute or chronic. In the Norwegian arthroscopy study described above, three main patterns of cartilage injury were detected (7). Cartilage injuries were seen in conjunction with bone bruises and osteochondral fractures, both caused by a traumatic incident. In addition, cartilage injuries were caused by bone disease, such as the typical osteochondritis dissecans (OCD), genetic and metabolic diseases (e.g. hemophilia, acromegaly, Paget s disease and the Stickler syndrome). The so-called bone bruise which may lead to secondary cartilage damage occurs in as many as 90% of rotational injuries to the knee (34). Recent basic science and clinical studies suggest that bruising of the subchondral bone changes the environment for the cartilage in the area. Follow-up MRI studies of patients with bone bruises suggest that this may lead to degeneration of the cartilage and early arthritis (34). In addition it has been shown that isolated cartilage injuries may lead to degeneration of the adjacent cartilage (35). These changes may be caused by the abnormally high stresses acting on

5 the rim of the defect. The cartilage surface opposing an isolated cartilage injury often shows fibrillation caused by mechanical irritation (36). Thus, it is suggested that rotational injury to the knee with a bone bruise and subsequent cartilage changes may progress into degenerative arthritis. Because the natural history in human is not well documented, a treatment protocol based on science is unavailable. Currently, the consensus seems to be that defects less than 2cm 2 can be treated conservatively, even when they are located on weightbearing surfaces. This is based on retrospective studies, which show that these patients to do reasonably well in the short term. In patients with defects larger than 2cm 2 on the weight-bearing surface of the femur, a high number of well-proven and new techniques are currently undergoing follow-up studies. In adults, articular cartilage possesses neither a blood supply nor lymphatic drainage. Although the cells continue to produce new extracellular matrix throughout life, they are ineffective in responding to injury. Not until the subchondral bone is penetrated, is the usual inflammatory wound healing response observed. Cells recruited from the bone marrow then attempt to fill the defect with new tissue, in some cases resulting in fibrocartilage. Of the numerous techniques available today, no method has yet been able to consistently reproduce normal hyaline cartilage. In the following an overview of the current status in this field is presented. It is important to keep in mind that the surgical procedures are carried out to eliminate or reduce stiffness, pain and swelling and allow the patient to return to the former activity level. So far, no evidence exists to indicate that surgical treatment prevents osteoarthritis later in life.

6 Microfracture Microfracture technique, as a low cost and minimally invasive procedure, is currently being used as the first choice in patients with previously untreated cartilage defects. This technique has in common the goal of recruiting pluripotential stem cells from the marrow by penetrating the subchondral bone. According to Steadman (11), the penetration must be done with specific awls to avoid the heating that occurs with drilling. The Steadman technique has been shown to produce hyaline-like cartilage in small defects in rabbits and in larger defects in horses. Only two controlled, randomized clinical studies exists (4, 6). Knutsen et al. (4) have found good pain relief after 2 years of follow-up in 70-80% of the patients althogh Gudas et al. (6) found superiority of the osteochondral autologous transplantation over microfracture at 1, 2 and 3 years timepoints. Further, the Norwegian study comparing ACIs with microfracture did not see a deterioration in the clinical results even 5 years after surgery (37). Salter introduced and investigated the biological concept of CPM for the postoperative treatment of articular cartilage injuries (38). His group found good effect of CPM in rabbits with small cartilage defects, but much less effect in larger defects. CPM has subsequently been used by Steadman after his microfracture technique with good success. The present use of CPM after several of the new cartilage repair techniques is controversial and no good studies are available. Microfracture is reported to result in up to 75% improvement after five years (11, 38). It has been suggested based on animal data, that traditional drilling and debridement lead to good and excellent results up to five years and that the results will then decline. Histological analysis of repair tissue after these operations shows mainly fibrocartilage

7 (3). Steadman and others have suggested, however, that the microfracture technique results in a more durable repair than traditional drilling and that the repair tissue may be a hybrid of hyaline cartilage and fibrocartilage (11). Younger and more active patients have a better clinical outcome and repair tissue (13, 16). Steadman found that at seven years after surgery 80% of the patients rated themselves as improved (12). All these patients were less than 45 years of age at inclusion and the mean size of the defects was smaller (2.77 cm²), and they also included some acute defects. Recently Kreuz et al. (14) reported good short term results following microfracture, although, they observed a deterioration starting 18 months after surgery. There is an obvious need for longer follow-up studies. Periosteal transplant Periosteum has been used alone for biological resurfacing arthroplasty in humans for more than a decade. In Scandinavia, the Umeå group has published long-term results of their technique for resurfacing patellar cartilage defects (15). Their clinical use of periosteum is based on animal data, predominantly from rabbits. The short-term results are encouraging, showing a majority of hyaline-like cartilage. O Driscoll has published extensively on the animal side and has reported encouraging clinical results (16). As he and the Umeå group points out, the technique is demanding and relies on a meticulous surgical procedure (see figure 1 from Lorentzon and co-workers). The injured area is cleaned, drilled or microfractured and covered by a periosteal flap harvested from the tibia or the femur. The periosteal flap is anchored to the patella with sutures through frill holes as well as with glue. No controlled clinical studies are currently available. There is an obvious need for good follow-up studies.

8 Perichondrial transplant This technique, which was described by Homminga et al, (17) uses autologous strips of perichondrium fixed to the subchondral bone with fibrin glue. The long term results for 88 patients with a mean follow-up of 52 months showed good results in only 38 % using the Hospital for Special Surgery score(18). In a histological analysis of 22 biopsies taken after perichondral grafting (19), tissue with a hyaline morphology of over 50 % was found in only six biopsies (27%). Autologous chondrocyte implantation (ACI) Autologous chondrocytes for cell transplantation to regenerate cartilage have been elected by many investigators (1, 25-27). Other possibilities include undifferentiated stem cells or even allogenic cells. Bone marrow, as well as periosteum, can be used as sources for such cells. The fully differentiated chondrocytes have the capacity to produce cartilage matrix and may be suitable for chondral defects only. However, most defects involve a bony part as well, and chondrocytes can not produce bone. Periosteal and bone marrow cells, on the other hand, do have the capacity to regenerate both cartilage and subchondral bone. In many instances the osteochondral defects are several millimeters deep and isolated chondrocyte transplantation will not be able to fill the gap. Many clinicians have therefore moved to a combination of bone graft followed by chondrocytes transplantation or use periosteal transplantation alone. A problem remaining is the incomplete incorporation of the healing tissue into the cartilage defect. On the experimental side much research remains to confirm the

9 scientific validity of transplantation of chondrocytes using the currently advocated techniques. Several clinical studies have reported promising results with chondrocytes transplantation in femoral cartilage defects (1, 25-27). The procedure involves the patient having to undergo harvesting through an arthroscopic procedure, followed 2-8 weeks later by an arthrotomy, where the cells are injected under a cover of periosteum. Clinical results from femoral defects have ranged from 60% to 90% excellent and good. So far the results of four controlled studies have been published. Bentley et al. (2) showed that after 19 months, 88% of the patients in the cell group versus 69% in the mosaic group had good to excellent results based on two non-validated scoring systems. Horas et al. (3) found no differences between cells and mosaicplasty after two years. Dozin et al. (5) also concluded that ACI and mosaicplasty were clinically equivalent and similar in performance although compliance with follow-up was rather unsatisfactory, with a median follow-up duration of less than 1 year. The Norwegian study (4) found no difference between cell transplantation and microfractures both leading to improvement in more than 75% of the patients after two years. The microfracture group had significantly more improvement in the SF-36 physical component score in the first two years than did the autologous chondrocyte implantation group. There was no significant difference in macroscopic or histological results between the two treatment groups and no association between the histological findings and the clinical outcome at the two-year time-point. Further, the Norwegian study comparing ACIs with microfracture, did not see a deterioration in the clinical results even 5 years after surgery (37). In the Norwegian study, they had 22% failures in each treatment group at the five

10 year time point. In contrast to their findings, Peterson et al reported a failure rate of 11% after ACI on the femoral condyles, with most of the failures occurring less than two years postoperatively(27). They also concluded that graft survival after two years is close to 100%. Their clinical success has been quoted to be from 80-90% and they concluded that a graft surviving for two years is likely to remain viable three to eight years later. Recently, the clinical outcome of ACI at five years in US subjects (Carticel prospective cartilage repair registry) was published (39). Eighty-seven percent (87 of 100) completed a 5-year follow-up. Thirteen patients (15%) had treatment failure and overall 62 patients had improved scores at follow-up. Hypertrophy of tissue seemed to be the major cause for re-operations after ACI (40). Using collagen membranes instead of periosteum could possibly reduce the requirement for re-operations (31). According to Steinwachs et al. (32), there was no patient with a symptomatic graft hypertrophy 36 months after ACI with a type I/III collagen membrane. In conclusion, the surgeon can expect that 75-90% of the patients will show improvement. The improvement will peak at approximately 2 years, and it does not seem to deteriorate up to 8 years. At the present time, the cost of the procedure in Britain is approximately At the moment the procedure is reserved for patients with large defects on the weightbearing surface of the knee joint. The defects should not be deeper than approximately 5 millimeters without being bone grafted. ACI may be preferred as a second-line treatment for large defects. Recently microfracture was found to have less favorable results in treating patellofemoral lesions and ACI may be a better option for trochlear defects (14). Matrix guided autologous chondrocyte implantation (MACI)

11 The original ACI technique involved the injection of a suspension of cultured chondrocytes into a debrided chondral defect beneath a periosteal cover. Periosteum was the favoured cover material since it was thought to have a chondrogenic action, either by providing growth factors or mesenchymal stem cells with the potential to develop into chondrocytes. There have, however, been complications associated with the use of periosteum as a cover material, including hypertrophy of the graft and, less commonly, calcification and delamination. Besides, the implantation of cultured chondrocytes in suspension has led to concerns about the uneven distribution of chondrocytes within the defect and the potential for cell leakage. In order to overcome such problems, researchers have initiated the use of carriers that is a scaffolds or matrices upon which the cells are grown. A further advantage of this method of cell delivery is that the scaffold may act as a barrier to invasion of the graft by fibroblasts, which may otherwise induce fibrous repair. The ideal matrix material has not been identified, and to date biodegradable matrices such as hyaluronan, collagen, or fibrin glue seem to have the most promise. Already carriers have been marketed and promising development is underway also with regards to growth factors attached to the scaffolds. According to a prospective, randomized study by Bartlett et al. (28), no differences were found in the clinical, arthroscopic and histological outcomes between ACI on the use of a cover manufactured from porcine-derived type I/type III collagen and MACI after one year. Other positive clinical results (29, 30) have been published, but so far none of these methods have been judged to be better and they have not been able to prove a complete healing with normal hyaline articular cartilage.

12 Mosaicplasty and osteochondral autologous grafts An alternative to biological regeneration of a defect is to replace it with a substitute. This can be done either partly through special available equipment or completely with a matched osteochondral transplant. Several orthopedic companies have produced coring drills, which will harvest plug from areas with relatively less weightbearing such as the intercondylar notch or the most lateral part of the femoral condyle. The plugs are then placed in the defect in predrilled cylinders. Advantages of this technique are that defects can be filled immediately with mature, hyaline articular cartilage and that both chondral and osteochondral defects can be treated in the same way. However, donor site morbidity is a concern and studies have shown that no part of the femoral condyle is non-weightbearing and the long-term results of the harvesting procedure are not known. So far there is limited animal data on the procedure. The clinical data was first published first by Hangody and Bobic (20, 21) and the results match those after chondrocyte transplantation by Brittberg et al (1). The recent study by Bentley et al. (2) shows less encouraging results for this technique, while the Horas study (3) and the Dozin (5) study report more optimistic results. Further, the study by Gudas et al. (6) has shown significant superiority of this technique over microfracture procedures. There is an obvious need for longer follow-up studies. The use of the technique is limited only by the size of the defect due to the necessity of harvesting from relatively less weight bearing areas. Osteochondral allograft Osteochondral allograft transplantation is appealing because it provides the ability to resurface larger and deeper defects with mature hyaline articular cartilage and addresses

13 the underlying bone deficit in a single procedure. So far, the use of osteochondral allografts has primarily been after fracture sequela of the femur or tibial plateau or large OCD lesions. The viability of chondrocytes has been demonstrated both after refrigerated allografts and in retrieved specimens after as long as 12 years. Fresh osteochondral allograft transplantation has a long clinical history with good to excellent results at ten to fifteen years (22, 23). Recently, Gross et al. (23) have reported Kaplan- Meier survivorship scores of 95 % at 5 years and 85 % at 10 years for femoral grafts, and those of 95 % at 5 years, 80 % at 10 years, and 65 % at 15 years for tibial grafts. Recent advances in allograft procurement, screening, and storage have made fresh osteochondral allografts commercially available. And now it seems that these grafts can safely be prolonged up to several weeks, which is an option that offers numerous benefits (24). The use of the technique is currently only limited by allograft availability. The quality of cartilage repair studies (Summary) Although it is currently unknown how many of cartilage injuries will need surgery, and the natural history of cartilage lesions in general is unknown, a number of new surgical techniques to treat these injuries have been developed over the last 15 years. However, the methodological level of the clinical papers is in general low. Jacobsen (41) showed very low methodological quality of most studies on cartilage repair. So far, only five controlled, randomized studies have been published in this field. The generally low methodological quality of many studies shows that caution is required when interpreting results after surgical cartilage repair. Firm recommendations on which cartilage repair procedure to choose cannot be given at this time on the basis of these studies. Surgeons should pay more attention when designing, conducting, and reporting trials, to improve

14 the methodological quality. Journals could include a detailed methodology score in their submission process to further encourage surgeons to focus on sound methodology. Most scientists and surgeons will agree upon the statement that a complete repair with normal hyaline cartilage is not achievable today with any method. A major objective for cartilage repair is to have complete healing of the defects, i.e. restoration of normal articular cartilage in the knee-joint. Clearly, cell based techniques have a big potential, probably in combination with scaffolds enabling minimal invasive surgery, growth factors and possibly gene therapy. More animal studies using scaffolds, growth factors and stem cells needs to be carried out and these should be followed by controlled clinical studies financed through public research grants and not through industry. Valid clinical answers in this field will only be the results of a combination of randomized control trials (RCTs). Further, long term follow up is needed to determine if one method is better than the other. References 1. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, and Peterson L (1994): Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N. Engl. J. Med. 331: Bentely G, Biant LC, Carrington RWT, Akmal M, Goldberg A, Williams AM, Skinner JA, Pringle J (2003): A prospective, randomized comparison of autologous chondrocyte implantation versus mosaicplasty for ostechondral defects of the knee. J Bone Joint Surg 85-B,

15 3. Horas U, Pelinkovic D, Herr G, Aigner T, Schnettler R (2003): Autologous chondrocyte implantation and osteochondral cylinder transplantation in cartilage repair of the knee joint. J Bone Joint Surg 85-A; Knutsen G, Engebretsen L, Ludvigsen TC, Drogset JO, Grøntvedt T, Solheim E, Strand T, Roberts S, Isaksen V, Johansen O (2004): Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg 86-A; Dozin B, Malpeli M, Cancedda R, Bruzzi P, Calcagno S, Molfetta L, Priano F, Kon E, Marcacci M (2005): Comparative evaluation of autologous chondrocyte implantation and mosaicplasty. A multicentered randomized clinical trial. Clin J Sport Med 15: Gudas R, Stankevicius E, Monastyreckiene E, Pranys D, Kalesinskas RJ (2006): Osteochondral autologous transplantation versus microfracture for the treatment of articular cartilage defects in the knee joint in athletes. Knee Surg Sports Traumatol Arthrosc. 14: Aroen A, Loken S, Heir S, Alvik E, Ekeland A, Granlund OG, and Engebretsen L (2004): Articular cartilage lesions in 993 consecutive knee arthroscopies Am. J. Sports Med. 32: Curl WW, Krome J, Gordon ES, et al (1999): Cartilage injuries: a review of 31,516 knee arthroscopies. Arthroscopy 13: Hjelle K, Solheim E, Strand T, Muri R, and Brittberg M (2002): Articular cartilage defects in 1,000 knee arthroscopies. Arthroscopy. 18:

16 10. Pridie KW. (1959): A method of resurfacing osteoarthritic knee joints. J Bone Joint Surg. 41B: Steadman JR, Rodkey WG, Briggs KK, and Rodrigo JJ (1999): The microfracture technic in the management of complete cartilage defects in the knee joint. Orthopade. 28: Steadman JR., Briggs KK, Rodrigo JJ, Kocher MS, Gill TJ, and Rodkey WG. (2003): Outcomes of microfracture for traumatic chondral defects of the knee: Average 11-year follow-up. Arthroscopy. 19: Mithoefer K, Williams 3 rd RJ, Warren RF, Wickiewicz TL, Marx RG (2005): Highimpact athletics after knee articular cartilage repair. A prospective evaluation of the microfracture technique. Am. J. Sports Med. 34: Kreuz PC, Steinwachs MR, Erggelet C, Krause SJ, Konrad G, Uhl M, and Sudkamp N (2006): Results after microfracture of full-thickness chondral defects in different compartments in the knee. Osteoarthritis. Cartilage. 15. Lorentzon R, Alfredson H, and Hildingsson C (1998): Treatment of deep cartilage defects of the patella with periosteal transplantation. Knee. Surg. Sports Traumatol. Arthrosc. 6: O'Driscoll SW and Fitzsimmons JS (2001): The role of periosteum in cartilage repair. Clin. Orthop.S190-S Homminga GN, Bulstra SK, Bouwmeester PS, van der Linden A J (1990): Perichondral grafting for cartilage lesions of the knee. J Bone Joint Surg. 72B:

17 18. Bouwmeester SJ, Beckers JM, Kuijer R, van der Linden, A J, Bulstra SK (1997): Long-term results of rib perichondrial grafts for repair of cartilage defects in the human knee. Int Orthop.21: Bouwmeester P, Kuijer R, Terwindt-Rouwenhorst E, van der Linden, T, Bulstra S (1999): Histological and biochemical evaluation of perichondrial transplants in human articular cartilage defects. J Orthop Res. 17: Bobic V (1996): Arthroscopic osteochondral autograft transplantation in anterior cruciate ligament reconstruction: a preliminary clinical study. Knee. Surg. Sports Traumatol. Arthrosc. 3: Hangody L, Feczko P, Bartha L, Bodo G, and Kish G (2000): Mosaicplasty for the treatment of articular defects of the knee and ankle. Clin. Orthop.S328-S Aubin PP, Cheah HK, Davis AM, Gross AE (2001): Long term followup of fresh femoral osteochondral allografts for posttraumatic knee defects. Clin Orthop Relat Res. 391: S Gross AE, Shasha N, Aubin P (2005): Long-term followup of the use of fresh osteochondral allografts for posttraumatic knee defects. Clin Orthop Relat Res. 435: Williams RJ 3 rd, Ranawat AS, Potter HG, Carter T, Warren RF (2007): Fresh stored allografts for the treatment of osteochondral defects of the knee. J Bone Joint Surg. 89A: Peterson L, Minas T, Brittberg M, Nilsson A, Sjogren-Jansson E, and Lindahl A (2000): Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin. Orthop

18 26. Minas T (2001): Autologous chondrocyte implantation for focal chondral defects of the knee. Clinical Orthopaedics & Related Research.S349-S Peterson L, Brittberg M, Kiviranta I, Akerlund EL, and Lindahl A (2002): Autologous chondrocyte transplantation. Biomechanics and long-term durability. Am. J. Sports Med. 30: Bartlett W, Skinner JA., Gooding CR, Carrington RW, Flanagan AM, Briggs TW, and Bentley G (2005): Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study. J Bone Joint Surg Br. 87: Nehrer S, Domayer S, Dorotka R, Schatz K, Bindreiter U, and Kotz R (2006): Threeyear clinical outcome after chondrocyte transplantation using a hyaluronan matrix for cartilage repair. Eur. J. Radiol. 57: Behrens P, Bitter T, Kurz B, Russlies M (2006): Matrix-associated autologous chondrocyte transplantation/implantation (MACT/MACI)-5-year follow-up. Knee. 13: Krishnan SP, Skinner JA, Carrington RW, Flanagan AM, Briggs TW, and Bentley G (2006): Collagen-covered autologous chondrocyte implantation for osteochondritis dissecans of the knee: two- to seven-year results. J Bone Joint Surg Br. 88: Steinwachs M, Kreuz PC (2007): Autologous chondrocyte implantation in chondral defects of the knee with a type I/III collagen membrane: a prospective study with a 3-year follow-up. Arthroscopy. 23:

19 33. van den Berg, WB, van der Kraan PM, Scharstuhl A, and van Beuningen, HM (2001): Growth factors and cartilage repair. Clin. Orthop. Relat Res.S244-S Engebretsen L, Arendt E, Fritts H (1993). Osseous lesions in acute ACL injuries. Acta Ortho Scand 64: Wei XC, Messner C (1999). Maturation dependent durability of spontaneous cartilage repair in rabbit knee joint. J Biomed Mater Res 46: Twyman RS, Desai K, Aicroth PM (1991) Osteochondritis dissecans of the knee. A long-term study. J Bone Joint Surg Br. 73(3): Engebretsen L (2007 in press): A randomized trial of autologous chondrocyte implantation versus microfracture. The picture at five years. J. Bone Joint Surg. Am. in press. 38. O'Driscoll SW, Giori NJ (2000): Continuous passive motion (CPM): a theory and principles of application. J Rehabil Res Dev. 37: Browne JE, Anderson AF, Arciero R, Mandelbaum B, Moseley JB, Jr, Micheli LJ, Fu F, and Erggelet, C (2005): Clinical outcome of autologous chondrocyte implantation at 5 years in US subjects. Clin. Orthop. Relat Res , 40. Muellner T, Knopp A, Ludvigsen TC, and Engebretsen L (2001): Failed autologous chondrocyte implantation. Complete atraumatic graft delamination after two years. Am. J. Sports Med. 29: Jakobsen RB, Engebretsen L, and Slauterbeck JR (2005): An analysis of the quality of cartilage repair studies. J. Bone Joint Surg. Am. 87:

20 Correspondence: Lars Engebretsen Orthopaedic Center Ullevaal University Hospital 0407 Oslo, Norway telephone: fax:

21 Figures Figure 1. Periosteal transplantation (modified from Ronny Lorentzon, Umeå University, Sweden). Merknad: her tror jeg det er nødvendig med en skikkelig gjennomgang Merknad: Skriv en mer fyldestgjørende figurtekst som forklarer gangen i teknikken. Sett inn referanse til originalfiguren.

22 Figure 2. Chondrocyte transplantation to the medial femoral epicondyle. Merknad: her trengs det en mer beskrivende figurtekst og referanse til originalarbeidet. Merknad: finnes det en bedre figure?

23 Figure year old patient treated with mosaic plasty due to major cartilage trauma during skiing. These figures show a autologous transplant at 6 months, 3b at 21 months 3c the retrieved implant at 22 months and 3d the following mosaicplasty at 22 months in the same patient. Merknad: figurteksten stemmer ikke med figurine. skriv om