– Written by Steffano Zaffagnini, Francesco Perdisa and Giuseppe Filardo, Italy

Knee articular cartilage defects greater than 4 cm² can be considered large defects. Smaller lesions can also be symptomatic, degenerate and increase in size due to increased stress at the lesion edges, leading to osteoarthritis (OA). However, there is no consensus of opinion on the benefit provided by different treatment options for these types of lesions. Indications for larger  defects are less controversial, large defects are usually symptomatic and may have a bigger impact on joint homeostasis. Treatment of large articular defects is therefore mandatory to relieve symptoms and improve knee function, as well as to prevent or delay further joint degeneration.

The peculiar structure of articular cartilage explains its very limited self-repair potential, as well as the challenge in obtaining good results with the biological options currently available^1,2. Although cartilage repair procedures have traditionally had limited indication in large defects or OA, they are becoming the focus of increased interest for the provision of pain relief and altering the progression of degenerative diseases. In addition to lesion size, several key factors should be considered for the treatment indication, including lesion depth, joint environment, duration of symptoms, body mass index (BMI), presence of ligament instability, malalignment or general comorbidities. The treatment indication, however, is mainly dictated by the patient’s age. In fact, adolescent patients can obtain satisfactory results with traditional reparative procedures, such as simple fragment refixation or marrow stimulation procedures, whereas more invasive reparative techniques or scaffold-based regenerative procedures are mainly indicated for adult patients. Finally, the chance of a successful procedure decreases in those over 40 years old³ and patients older than 60 years are precluded from cartilage repair due to their limited self-repair ability and the degenerative environment – both conditions strongly affecting the expected outcomes⁴. Non-operative options are usually the first-choice treatments for maintaining quality of life, whereas knee replacement (preferably unicompartmental) is the most common surgical indication for these patients⁵. This article discusses the specific treatments available according to their indications for large cartilage defects in different age populations.

CHILDREN AND YOUNG ADULTS (<20 YEARS OLD)

Since large cartilage lesions in this group of patients are mainly due to trauma or osteochondritis dissecans (OCD), the presence of a detached fragment is relatively common. The high regenerative potential of young patients makes attempts to preserve a detached fragment mandatory, if feasible. The choice between fragment refixation or removal and marrow stimulation relies on its integrity and vitality.

Fragment refixation

Acute cases require careful curettage of the blood clots and any fibrous tissue, in order to avoid any damage to the subchondral bone at the base of the lesion⁶. In chronic lesions, a more extensive curettage is required to debride the fibrous tissue covering the lesion and the sclerotic subchondral bone; then, it may be necessary to pack cancellous bone at the level of the surrounding osteochondral junction to favour the integration of the refixed fragment.

The fragment can be refixed using different fixation devices (bone pegs^7,8, K-wire^9,10, pins¹¹, compression screws^12,13, biodegradable pins^6,14-16). The most superficial part of the fixation device should be kept 2 mm below the level of the cartilage surface in order to avoid mechanical damage on the opposite cartilage surface. In case part of the fragment is severely damaged, this part can be removed and the fragment refixed through an additional autologous osteochondral transplant^6,17.

Good clinical results have been reported using these different devices. Moreover, some studies have analysed the histology of refixed fragments. Chondral fragments resulting from acute delamination showed healing into the subchondral bed, with no evidence of fibrous tissue and a normal transitional area with hyaline cartilage at 12 months after surgery¹⁵. OCD cases also showed normal features of the refixed cartilage and the development of new bone trabeculae at 12 months after surgery⁶.

Marrow stimulation

Even though in older patients marrow stimulation procedures (microfracture or drilling) are usually recommended only for small lesions, in younger patients these techniques may be indicated when a detached fragment is severely damaged or not refixable. Good results can be expected, even for larger articular defects, thanks to the high intrinsic activity of resident bone marrow cells in this patient group. Moreover, these procedures represent a minimally invasive, relatively cheap and technically easy option to perform.

This surgical approach can be performed arthroscopically, taking care to accurately prepare the damaged area, especially in case of chronic lesions^18,19. Steadman et al treated a group of 26 patients (average age of 16.6 years, maximum 18 years) with microfracture. They observed good results at 5 years follow-up, with recovery of function and return to high levels of sports activity²⁰. More generally, positive outcomes for microfracture have been reported to be correlated with younger age²¹, even in high-level athletes²². However, despite these satisfactory findings, there is agreement about the limitations in terms of the tissue quality produced by marrow stimulation: 90% of the biopsies after microfractures showed predominant fibrocartilage²³. Since fibrocartilage has inferior mechanical properties compared to hyaline cartilage, poor results are generally expected when treating large defects, with a rapid worsening of outcomes reported at mid-term follow-up^24,25. Thus, the indication is mainly limited to small cartilage defects (<2 cm²), with a higher chance of success in children or adolescent patients²⁶.

ADULT PATIENTS (20 TO 60 YEARS OLD)

The aetiology of articular cartilage defects in patients aged between 20 and 60 years old can be heterogeneous, ranging from traumatic, to degenerative/microtraumatic, OCD sequelae or osteonecrosis, reflecting the clinical history of the patient, different presentation, symptom modality and duration.

Regenerative procedures are the preferred method in this age group, in order to maximise the body's self-regenerative potential and restore the defect with a tissue resembling as closely as possible the original one, aiming to obtain durable clinical benefits.

Autologous chondrocyte implantation (ACI)

ACI is the most documented regenerative method for the surgical treatment of large articular defects in young to middle-aged patients. However, ACI has notable disadvantages due to the need for two different surgeries – the first operation for the arthroscopic harvest of articular cartilage and, after cell isolation and culture, the second for the implantation of cultured chondrocytes.

The first generation ACI technique involved the injection of a cell suspension under an autologous periosteal flap that had been previously sutured to the edge of the surrounding cartilage to cover the defect²⁷. Beris et al treated a group of 42 patients for large symptomatic chondral defects of the knee (mean size 5.3 cm²), showing significantly improved clinical and functional scores at 8-year follow-up²⁸. Minas et al reported the results of over 200 patients treated for very large lesions (mean size 8.4 cm²) and observed durable outcomes at long-term follow-up and a 71% graft survivorship at 10 years follow-up. Interestingly, the authors reported an increased risk of failure in patients with larger lesions and in those previously treated with microfracture for the same defect²⁹. Moreover, level one studies reported no clear difference in outcomesbetween ACI and microfractures at 60 months follow-up for the treatment of large lesions^23,30.

Despite these good and durable clinical results using first generation ACI, a relatively high rate of graft hypertrophy³¹, together with the need for an open and technically demanding surgery prompted the use of newer techniques in which the cultured cells are seeded into three-dimensional matrices (mainly type I/III collagen or hyaluronan). Some of these second generation techniques simplified the overall approach and even allowed for arthroscopic implantation³². Further modifications include combination with autologous bone implants to address deeper lesions that are very frequently associated with large size defects or OCDs³³. These matrix-assisted ACI (MACI) procedures have also been successfully used for the treatment of large lesions, with positive results at long-term follow-up³². Bigger focal defects can be treated up to 12 cm² in size; however, large lesions often occur in a degenerative joint environment, which is a relative contraindication for MACI procedures. In fact, MACI did not show superior mid-term results to those of microfracture when the onset of symptoms was more than 3 years before the operation³⁴. Saris et al showed in a level one study that MACI produced superior results and a lower failure rate at 24 months follow-up in 137 patients treated for large lesions of the knee (mean size 4.8 cm²). This superiority, however, was not reflected by MRI appearance of the repair tissue³⁵.

Finally, some findings also highlighted poorer but still effective and durable results in patients older than 40 years, suggesting the possibility to extend the treatment indication to this age group, where the regenerative approach has traditionally been excluded³.

Beside some controversial findings, ACI procedures seem to produce better tissue repair quality and longer-lasting results than microfracture and currently there is an overall consensus for the treatment of large lesions with such a biological approach.

Osteochondral autograft transfer (OAT)

OAT techniques, including mosaicplasty, rely on viable osteochondral grafts to fill an articular defect through a single-step surgery³⁶. Despite being reported to offer overall good and durable clinical results at long-term follow-up, their use for the treatment of large lesions is questionable, due to technical limitations, graft availability and issues related to donor site morbidity³⁷. Thus, while OATs represent an affordable choice for the treatment of small size defects (usually not larger than 2.5 cm²) requiring a limited number of plugs, autologous one-step procedures are not indicated for large lesions³⁸.

The mega-OATS technique was proposed as a salvage procedure for large osteochondral lesions of the knee. It involves the harvest of a significant part of the posterior knee condyle as a source of osteochondral graft, which is then prepared with a specific device³⁹. The few available studies show this technique has produced a significant clinical improvement at mid-term follow-up, with satisfactory outcomes in terms of knee function^40,41. Paired with this, in a few cases positive MRI features were reported in terms of vitality of the graft and also partial remodelling of the posterior condyle. However, the loss of the posterior femoral condyle makes a certain degree of donor site morbidity unavoidable and the use of this procedure should be restricted to salvage procedures in young patients with large knee osteochondral defects and limited treatment alternatives⁴⁰.

Osteochondral allograft transplantation (OCA)

Osteochondral allografting allows the replacement of a damaged osteochondral unit with viable tissue, while avoiding the issues related to donor-site morbidity; thus, it is a suitable option for the treatment of a large surface area. The different storage methods (fresh, fresh-frozen and cryopreserved) are important factors, since chondrocyte viability directly correlates with the clinical success of OCA transplantation^5,35 and it has been shown that fresh OCAs stored at physiological temperatures have the highest chondrocyte viability⁴². Fresh osteochondral grafts can be harvested and implanted through free-hand technique or as described above for Mega-OATS implantation⁴³.

This procedure is common in the United States, where the use of allografts is widespread. Excellent results have been reported in 122 patients by Levy et al with 82% survivorship at 10 years, decreasing to 66% at 20 years follow-up. Patients over 30 years old who had two or more previous surgeries were associated with graft failure⁴⁴. On the other hand Gracitelli et al showed that, while previous bone marrow stimulation was correlated to a higher re-operation rate after osteochondral allografting, no influence was observed on graft survivorship or functional outcomes⁴⁵. Raz et al also confirmed the benefits of OCA after up to 22 years follow-up, with an acceptable survival rate of 59% at final-follow-up⁴⁶. Finally, limited and controversial data are available on more active patients, in terms of their return to previous sports or physical activity^7,19.

While the outcomes for OCA are good and durable, this procedure is still difficult to implement in most countries due to high costs and difficulty in finding fresh donors⁴⁷. Thus, in many countries it is mainly restricted to salvage procedures in young patients with no other options.

Bi-layered scaffolds

In recent years, advances in the field of biomaterials have enabled the introduction of new strategies for the treatment of large articular defects. Some of the biopolymers, applied as scaffold, have been used ‘cell-free’, using the properties of the biomaterial itself to improve marrow stimulation-induced reparative processes in a single operation⁴⁸. While some of them have also been tested seeded with bone marrow concentrate.

Improved knowledge of the primary role of subchondral bone in large articular defects has led to the development of bi-layered scaffolds which mimic the biological and functional requirements for the growth of both bone and cartilage. In fact, the results of the previously-mentioned cartilage regenerative techniques were limited when applied to more complex articular lesions, where the subchondral bone is frequently involved⁴⁹. Among the few osteochondral scaffolds approved for clinical use, one is more specifically targeted for the treatment of large osteochondral defects.

MaioRegen™ (Fin-ceramica, Faenza, Italy) is the most widely documented osteochondral scaffold, a nanostructured implant consisting of different ratios of collagen and hydroxyapatite organised in three layers. After promising preliminary findings, the positive results offered by this biomaterial have been confirmed up to a mid-term follow-up. Twenty-seven patients were evaluated at 5 years’ follow-up, confirming that the improvement in clinical scores was stable over time. MRI evaluation revealed some abnormalities, but ongoing improvement. However, no correlation was found with the clinical outcome⁵⁰. Several studies further confirmed the effectiveness and versatility of this approach for the treatment of different kinds of articular defects of the knee. Among these, Delcogliano et al published a study on 19 patients affected by large (5.2±1.6 cm²) cartilage defects, showing encouraging results after 2 years⁵¹. Comparable results at short-term follow-up were also reported by Berruto et al in a larger group of 49 patients affected by large (4.4±1.3 cm²) lesions and treated by this scaffold implantation – a significant improvement was observed in all clinical scores, paired with encouraging MRI findings of the regenerating tissue. Interestingly, lower activity levels and older age were significantly correlated with worse outcomes, suggesting that this regenerative approach is less effective in older patients, with limited regenerative potential⁵². Similar age limitations were shown, despite the overall benefit offered by this procedure, in the treatment of unicompartmental OA in relatively young patients, where the osteochondral scaffold implantation was applied as a salvage procedure alternative to metal resurfacing. This study also underlined the importance of addressing all comorbidities in order to obtain the best clinical result⁵³.

Even though some issues have been raised on the quality of the repair tissue offered by this approach⁵⁴, it still represents a viable option for the treatment of large osteochondral defects in a young population, where limited options are suitable⁴⁸. However, the indication should be planned carefully and an age limit has been highlighted. Future studies should focus on a possible improvement with different cell types to ameliorate the regenerative potential and possibly favour healing of more difficult cases such as larger lesions in older patients.

In this regard, encouraging findings have been recently documented in a one-step surgical procedure in which multi-potent stem cells in a bone marrow concentrate are used to treat large full-thickness chondral defects. The procedure looks promising, even for less favourable cases which would otherwise be doomed to a metal resurfacing procedure.

OLDER PATIENTS (>60 YEARS OLD)

Large defects of the articular surface in patients of older age are usually part of a more complex degenerative environment, likely to be encompassed by the definition of OA, which is a primary cause of chronic disability in the elderly.  As discussed above, most cartilage repair surgical options present decreased effectiveness when applied to degenerated joints and lower outcomes are correlated with ageing. In fact, these patients present with an already altered homeostasis that strongly impairs the regenerative processes.

Thus, only conservative choices are indicated in this patient group, which is characterised by a low regenerative potential, with the aim of improving quality of life by reducing temporary symptoms and improving joint function. This can be considered the first-line approach either in the early or more advanced OA phases, in order to delay metal resurfacing procedures that may be too demanding for the patient both from a physical and psychological point of view.

Physical therapies

Non-pharmacological therapies, such as exercise and rehabilitation, have been reported to have beneficial effects in the short-term for pain reduction and physical function improvement, even though data from the literature are limited and there is no clear evidence for any particular method of exercise. Physical therapy has also been shown to be effective in OA patients⁵⁶ and, despite very few studies being available, this approach has been included into the Osteoarthritis Research Society International recommendations for the management of knee and hip OA⁵⁷. The optimal physical strategy, as well as its dosage in terms of intensity, frequency and duration, however, still has to be determined.

Injective therapies

Injective treatments are very popular among patients and physicians. Classic and new substances can be applied directly into the affected joint. Some of them act as biomechanically active spacers or via their immunomodulatory properties.

Corticosteroids are well-known for their strong anti-inflammatory properties, able to interrupt the immune cascade at different levels. Intra-articular injections of corticosteroids were originally described in 1951 by Hollander et al, with the rationale of maintaining a prolonged concentration of drug in the synovial space⁵⁸, thus maximising the anti-inflammatory effect with minimal risks of systemic side-effects⁵⁹. This approach was reported to be effective in the short-term on pain reduction and global assessment versus placebo^30,58, but its benefit seemed to decrease after the fourth week of follow-up, while hyaluronian (HA) had longer-lasting effects. Since the prolonged use of corticosteroids might accelerate tissue atrophy and joint degeneration and since the long-term benefits seem to be limited, their use as chronic treatment is questionable.

Viscosupplementation is based on the rationale that HA concentration highly decreases in the OA knee⁶⁰, therefore HA intra-articular injections have been proposed to provide lubrication and shock absorbency to the joint⁶⁰, some evidence even suggests biologic disease-modifying properties⁶¹. Among the many HA preparations available on the market, they can be broadly classified into low and high molecular weight HA. The correlation between molecular weight and clinical efficacy is still controversial⁶², but HA lower than 500 kilodalton was reported as ineffective in improving pain and function⁶³. While clinical findings suggest that HA injections may be an effective treatment for OA⁶², randomised studies failed to show superiority of any product. As a result, American Academy of Orthopaedic Surgeons does not recommend viscosupplementation for the treatment of mild-to-moderate OA.

Platelet-rich plasma (PRP) is a blood derivative that has recently garnered much interest for its supposed anabolic and anti-inflammatory properties. Pre-clinical studies showed promising findings, with positive effects on the entire joint homeostasis⁶⁴ and there is an overall support among the published clinical literature on PRP intra-articular administration. However, the superiority of PRP versus HA injections has not clearly been proven yet and the best formulation and application modalities are still under investigation in order to optimise the treatment of joints affected by OA⁶⁵.

CONCLUSIONS

The treatment of large articular lesions in young knees remains a challenge for surgeons, with patients subjected to pain and at risk for further join degeneration. Several procedures have been proposed to address large defects in order to improve symptoms and prevent OA-related changes. The indication for the right technique is driven by some key factors including patient age, but also by the availability of the procedure due to legal and economical issues. In this respect, cell-free scaffold-based procedures or one-step cell-based procedures are emerging as promising options for restoring a biologically and functionally effective tissue even for challenging large osteochondral lesions.

References

1. Buckwalter JA. Articular cartilage: injuries and potential for healing. J Orthop Sports Phys Ther 1998; 28:192-202.
2. Buckwalter JA, Mankin HJ. Articular cartilage repair and transplantation. Arthritis Rheum 1998; 41:1331-1342.
3. Kon E, Filardo G, Condello V, Collarile M, Di Martino A, Zorzi C et al. Second-generation autologous chondrocyte implantation: results in patients older than 40 years. Am J Sports Med 2011; 39:1668-1675.
4. Filardo G, Kon E, Di Martino A, Patella S, Altadonna G, Balboni F et al. Second-generation arthroscopic autologous chondrocyte implantation for the treatment of degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc 2012; 20:1704-1713.
5. Saccomanni B. Unicompartmental knee arthroplasty: a review of literature. Clin Rheumatol 2010; 29:339-346.
6. Yonetani Y, Matsuo T, Nakamura N, Natsuume T, Tanaka Y, Shiozaki Y et al. Fixation of detached osteochondritis dissecans lesions with bioabsorbable pins: clinical and histologic evaluation. Arthroscopy 2010; 26:782-789.
7. Lindholm TS, Osterman K. Long-term results after transfixation of an osteochondritis dissecans fragment to the femoral condyle using autologous bone transplants in adolescent and adult patients. Arch Orthop Trauma Surg 1980; 97:225-230.
8. Slough JA, Noto AM, Schmidt TL. Tibial cortical bone peg fixation in osteochondritis dissecans of the knee. Clin Orthop Relat Res 1991:122-127.
9. Jaberi FM. Osteochondritis dissecans of the weight-bearing surface of the medial femoral condyle in adults. Knee. 2002; 9:201-207.
10. Lipscomb PR Jr., Lipscomb PR Sr., Bryan RS. Osteochondritis dissecans of the knee with loose fragments. Treatment by replacement and fixation with readily removed pins. J Bone Joint Surg Am 1978; 60:235-240.
11. Jakob RP, Miniaci A. A compression pinning system for osteochondritis dissecans of the knee. Acta Orthop Scand 1989; 60:319-321.
12. Johnson LL, Uitvlugt G, Austin MD, Detrisac DA, Johnson C. Osteochondritis dissecans of the knee: arthroscopic compression screw fixation. Arthroscopy 1990; 6:179-189.
13. Magnussen RA, Carey JL, Spindler KP. Does operative fixation of an osteochondritis dissecans loose body result in healing and long-term maintenance of knee function? Am J Sports Med 2009; 37:754-759.
14. Nakagawa T, Kurosawa H, Ikeda H, Nozawa M, Kawakami A. Internal fixation for osteochondritis dissecans of the knee. Knee Surg Sports Traumatol Arthrosc 2005; 13:317-322.
15. Nakamura N, Horibe S, Iwahashi T, Kawano K, Shino K, Yoshikawa H. Healing of a chondral fragment of the knee in an adolescent after internal fixation. A case report. J Bone Joint Surg Am 2004; 86-A:2741-2746.
16. Weckstrom M, Parviainen M, Kiuru MJ, Mattila VM, Pihlajamaki HK. Comparison of bioabsorbable pins and nails in the fixation of adult osteochondritis dissecans fragments of the knee: an outcome of 30 knees. Am J Sports Med 2007; 35:1467-1476.
17. Miura K, Ishibashi Y, Tsuda E, Sato H, Toh S. Results of arthroscopic fixation of osteochondritis dissecans lesion of the knee with cylindrical autogenous osteochondral plugs. Am J Sports Med 2007; 35:216-222.
18. Drobnic M, Radosavljevic D, Cor A, Brittberg M, Strazar K. Debridement of cartilage lesions before autologous chondrocyte implantation by open or transarthroscopic techniques: a comparative study using post-mortem materials. J Bone Joint Surg Br 2010; 92:602-608.
19. Steadman JR, Rodkey WG, Briggs KK. Microfracture to treat full-thickness chondral defects: surgical technique, rehabilitation, and outcomes. J Knee Surg 2002; 15:170-176.
20. Steadman J. Outcomes of microfractures in pediatric patients. American Orthopaedic Society for Sports Medicine - Specialty Day. San Diego; 2011.
21. Steadman JR, Briggs KK, Rodrigo JJ, Kocher MS, Gill TJ, Rodkey WG. Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up. Arthroscopy 2003; 19:477-484.
22. Steadman JR, Miller BS, Karas SG, Schlegel TF, Briggs KK, Hawkins RJ. The microfracture technique in the treatment of full-thickness chondral lesions of the knee in National Football League players. J Knee Surg 2003; 16:83-86.
23. Knutsen G, Engebretsen L, Ludvigsen TC, Drogset JO, Grontvedt T, Solheim E et al. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg Am 2004; 86-A:455-464.
24. Goyal D, Keyhani S, Lee EH, Hui JH, . Evidence-based status of microfracture technique: a systematic review of level I and II studies. Arthroscopy 2013; 29:1579-1588.
25. Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am J Sports Med 2009; 37:2053-2063.
26. Niemeyer P, Kostler W, Salzmann GM, Lenz P, Kreuz PC, Sudkamp NP. Autologous chondrocyte implantation for treatment of focal cartilage defects in patients age 40 years and older: A matched-pair analysis with 2-year follow-up. Am J Sports Med 2010; 38:2410-2416.
27. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994; 331:889-895.
28. Beris AE, Lykissas MG, Kostas-Agnantis I, Manoudis GN. Treatment of full-thickness chondral defects of the knee with autologous chondrocyte implantation: a functional evaluation with long-term follow-up. Am J Sports Med 2012; 40:562-567.
29. Minas T, Von Keudell A, Bryant T, Gomoll AH. The John Insall Award: A minimum 10-year outcome study of autologous chondrocyte implantation. Clin Orthop Relat Res 2014; 472:41-51.
30. Basad E, Ishaque B, Bachmann G, Sturz H, 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.
31. Niemeyer P, Uhl M, Salzmann GM, Morscheid YP, Sudkamp NP, Madry H. Evaluation and analysis of graft hypertrophy by means of arthroscopy, biochemical MRI and osteochondral biopsies in a patient following autologous chondrocyte implantation for treatment of a full-thickness-cartilage defect of the knee. Arch Orthop Trauma Surg 2015; 135:819-830.
32. Kon E, Filardo G, Di Martino A, Marcacci M. ACI and MACI. J Knee Surg 2012; 25:17-22.
33. Filardo G, Kon E, Berruto M, Di Martino A, Patella S, Marcheggiani Muccioli GM et al. Arthroscopic second generation autologous chondrocytes implantation associated with bone grafting for the treatment of knee osteochondritis dissecans: Results at 6 years. Knee. 2012; 19:658-663.
34. Vanlauwe J, Saris DB, Victor J, Almqvist KF, Bellemans J, Luyten FP. Five-year outcome of characterized chondrocyte implantation versus microfracture for symptomatic cartilage defects of the knee: early treatment matters. Am J Sports Med 2011; 39:2566-2574.
35. Saris D, Price A, Widuchowski W, Bertrand-Marchand M, Caron J, Drogset JP 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.
36. Filardo G, Kon E, Di Matteo B, Di Martino A, Marcacci M. Single-plug autologous osteochondral transplantation: results at minimum 16 years' follow-up. Orthopedics 2014; 37:e761-767.
37. Filardo G, Kon E, Perdisa F, Balboni F, Marcacci M. Autologous osteochondral transplantation for the treatment of knee lesions: results and limitations at two years' follow-up. Int Orthop 2014; 38:1905-1912.
38. Filardo G, Kon E, Perdisa F, Tetta C, Di Martino A, Marcacci M. Arthroscopic mosaicplasty: long-term outcome and joint degeneration progression. Knee 2015; 22:36-40.
39. Agneskirchner JD, Brucker P, Burkart A, Imhoff AB. Large osteochondral defects of the femoral condyle: press-fit transplantation of the posterior femoral condyle (MEGA-OATS). Knee Surg Sports Traumatol Arthrosc 2002; 10:160-168.
40. Braun S, Minzlaff P, Hollweck R, Wortler K, Imhoff AB. The 5.5-year results of MegaOATS--autologous transfer of the posterior femoral condyle: a case-series study. Arthritis Res Ther 2008; 10:R68.
41. Brucker P, Agneskirchner JD, Burkart A, Imhoff AB. [Mega-OATS. Technique and outcome]. Unfallchirurg 2002; 105:443-449.
42. Bugbee WD, Convery FR. Osteochondral allograft transplantation. Clin Sports Med 1999; 18:67-75.
43. Chui K, Jeys L, Snow M. Knee salvage procedures: the indications, techniques and outcomes of large osteochondral allografts. World J Orthop 2015; 6:340-350.
44. Levy YD, Gortz S, Pulido PA, McCauley JC, Bugbee WD. Do fresh osteochondral allografts successfully treat femoral condyle lesions? Clin Orthop Relat Res 2013; 471:231-237.
45. Gracitelli GC, Meric G, Pulido PA, McCauley JC, Bugbee WD. Osteochondral allograft transplantation for knee lesions after failure of cartilage repair surgery. Cartilage 2015; 6:98-105.
46. Raz G, Safir OA, Backstein DJ, Lee PT, Gross AE. Distal femoral fresh osteochondral allografts: follow-up at a mean of twenty-two years. J Bone Joint Surg Am 2014; 96:1101-1107.
47. De Caro F, Bisicchia S, Amendola A, Ding L. Large fresh osteochondral allografts of the knee: a systematic clinical and basic science review of the literature. Arthroscopy 2015; 31:757-765.
48. Kon E, Filardo G, Perdisa F, Venieri G, Marcacci M. Clinical results of multilayered biomaterials for osteochondral regeneration. J Exp Orthop 2014; 1:10.
49. Filardo G, Kon E, Perdisa F, Di Matteo B, Lacono F, Zaffagnini S et al. Osteochondral scaffold reconstruction for complex knee lesions: a comparative evaluation. Knee 2013; 20:570-576.
50. Kon E, Filardo G, Di Martino A, Busacca M, Moio A, Perdisa F et al. Clinical results and MRI evolution of a nano-composite multilayered biomaterial for osteochondral regeneration at 5 years. Am J Sports Med 2014; 42:158-165.
51. Delcogliano M, de Caro F, Scaravella E, Ziveri G, De Biase CF, Marotta D et al. Use of innovative biomimetic scaffold in the treatment for large osteochondral lesions of the knee. Knee Surg Sports Traumatol Arthrosc 2014; 22:1260-1269.
52. Berruto M, Delcogliano M, de Caro F, Carimati G, Uboldi F, Ferrua P et al. Treatment of large knee osteochondral lesions with a biomimetic scaffold: results of a multicenter study of 49 patients at 2-year follow-up. Am J Sports Med 2014; 42:1607-1617.
53. Marcacci M, Zaffagnini S, Kon E, Marcheggiani Muccioli GM, Di Martino A, Di Matteo B et al. Unicompartmental osteoarthritis: an integrated biomechanical and biological approach as alternative to metal resurfacing. Knee Surg Sports Traumatol Arthrosc 2013; 21:2509-2517.
54. Christensen BB, Foldager CB, Jensen J, Jensen NC, Lind M. Poor osteochondral repair by a biomimetic collagen scaffold: 1- to 3-year clinical and radiological follow-up. Knee Surg Sports Traumatol Arthrosc 2015. [Epub ahead of print].
55. Gobbi A, Karnatzikos G, Sankineani SR. One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee. Am J Sports Med 2014; 42:648-657.
56. Feeley BT, Gallo RA, Sherman S, Williams RJ. Management of osteoarthritis of the knee in the active patient. J Am Acad Orthop Surg 2010; 18:406-416.
57. Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden NK et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage 2010; 18:476-499.
58. Hollander JL. The local effects of compound F (hydrocortisone) injected into joints. Bull Rheum Dis 1951; 2:3-4.
59. Pekarek B, Osher L, Buck S, Bowen M. Intra-articular corticosteroid injections: a critical literature review with up-to-date findings. Foot (Edinb) 2011; 21:66-70.
60. Strauss EJ, Hart JA, Miller MD, Altman RD, Rosen JE. Hyaluronic acid viscosupplementation and osteoarthritis: current uses and future directions. Am J Sports Med 2009; 37:1636-1644.
61. Goldberg VM, Buckwalter JA. Hyaluronans in the treatment of osteoarthritis of the knee: evidence for disease-modifying activity. Osteoarthritis Cartilage 2005; 13:216-224.
62. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006; (2):CD005321.
63. Goldberg VM, Goldberg L. Intra-articular hyaluronans: the treatment of knee pain in osteoarthritis. J Pain Res 2010; 3:51-56.
64. Filardo G, Kon E, Roffi A, Di Matteo B, Merli ML, Marcacci M. Platelet-rich plasma: why intra-articular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration. Knee Surg Sports Traumatol Arthrosc 2015; 23:2459-2474.
65. Filardo G, Di Matteo B, Di Martino A, Merli ML, Cenacchi A, Fornasari A et al. Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med 2015; 43:1575-1582.

Stefano Zaffagnini M.D. 

Francesco Perdisa M.D.

Giuseppe Filardo M.D., Ph.D

Biomechanics Laboratory – II Clinic

Rizzoli Orthopaedic Institute

Bologna, Italy

email: stefano.zaffagnini@unibo.it

Image via Singapore Sports Council