Current strategies for knee cartilage repair

Current Strategies for Knee Cartilage Repair Nick Kalson, Panagiotis Gikas, Timothy Briggs To cite this version: Nick Kalson, Panagiotis Gikas, Timothy Briggs. Current Strategies for Knee Cartilage Repair. International Journal of Clinical Practice, Wiley, 2010, 64 (10), pp.1444. ฀10.1111/j.17421241.2010.02420.x฀. ฀hal-00566327฀ HAL Id: hal-00566327 https://hal.archives-ouvertes.fr/hal-00566327 Submitted on 16 Feb 2011 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. International Journal of Clinical Practice rP Fo #" $ % $ )% $ & * 0, ' + ,1 . $ rR ( ee " ! + 2 11 + - # . $ $ - . $ / # # / / +2 +2 w ie ev ly On International Journal of Clinical Practice International Journal of Clinical Practice Page 1 of 26 Current Strategies for Knee Cartilage Repair Nicholas S. Kalson, Panagiotis D. Gikas*, Timothy W. R. Briggs Bone Tumour Service, Royal National Orthopaedic Hospital, Brockley Hill, Fo Stanmore, Middlesex, UK. HA7 4LP. rP * Author for correspondence. Email, [email protected], Telephone +44 7958342989 ee Key words: Knee, cartilage, injury, microfracture, autologous chondrocyte implantation, mosaicplasty iew ev rR ly On 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 International Journal of Clinical Practice Page 2 of 26 International Journal of Clinical Practice Abstract Defects in knee articular cartilage can cause pain and disability and present the clinician with an extremely challenging clinical situation. This article describes the most up-to-date surgical techniques that aim to repair and/or regenerate symptomatic focal defects in articular cartilage, which include arthroscopic debridement, microfracture bone marrow stimulation and autologous osteochondral allografting, with an emphasis on autologous chondrocyte implantation (ACI). In the Fo future, refinement of tissue engineering approaches promises to further improve outcome for these patients. iew ev rR ee rP ly On 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 International Journal of Clinical Practice International Journal of Clinical Practice Page 3 of 26 Introduction Knee articular cartilage (AC) defects have long presented a challenge to physicians. In 1743 the famous English anatomist William Hunter wrote ‘an ulcerated cartilage is a trouble-some problem… that, once destroyed, it is not recovered’ [1]. Today, more than 250 years later, cartilage damage is still an issue for physicians and patients and there is still no universally accepted and successful treatment approach for damaged AC. However, the result of research into novel surgical therapies developed over the Fo last two decades, described in this article, have the potential to consign this statement to history. ee rP Importance of knee cartilage defects rR Articular cartilage lesions are common. In patients undergoing arthroscopic investigation for knee symptoms the incidence of cartilage defects has been found to be 61% [2] and 63% [3] and the prevalence of work- or sport-related articular lesions ev has been reported at 22% and 50% [4, 5]. Furthermore, in patients with anterior cruciate laxity the incidence of articular pathology is as high as 54% [6]. Although iew more common with age, these injuries are also frequent in patients less than 55 years old [3, 7], in whom a prosthetic joint replacement, with a limited lifespan, is not recommended. Therefore alternative treatments are required. Focal AC defects On are most often traumatic in origin, resulting from a high-load impact or repetitive shear and torsional loads on the superficial zone of articular cartilage [8]. A small proportion of lesions are caused by osteochondritis dessicans (less than 5%)[9]. Focal ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 AC defects are separate from osteoarthritis, a chronic degenerative disease, which has distinct clinical, radiological and arthroscopic findings. Natural history of knee cartilage defects International Journal of Clinical Practice International Journal of Clinical Practice Hyaline AC is predominantly composed of a unique extra-cellular matrix (ECM), formed from embryonic mesenchyme in a complex and incompletely understood developmental process [10]. The two principal components of AC are proteoglycans, negatively charged glyocsaminoglyan chains that swell and hydrate AC, and collagen type II, a fibrillar collagen that traps the proteoglycans and provides tensile strength. This ECM is specialised to cope with its singular biomechanical environment; to regain a functional joint, cartilage defects would ideally be replaced by tissue of this Fo precise composition. Injury to some musculoskeletal tissues, such as bone, result in recapitulation of rP embryonic development processes and regeneration of fully functional tissue identical to the pre-injured tissue. However, there are several barriers to intrinsic ee articular cartilage repair: 1) It is avascular, meaning that the nutrients required for energetic repair processes and the removal of metabolic waste products are limited rR by diffusion to/from surrounding tissues. 2) It is relatively acellular, therefore few cells are available to effect repair. These obstacles conspire to limit repair of defects ev to a fibro-cartilaginous substitute tissue with different molecular composition (more type I collagen, less proteoglycan) and biomechanical behaviour (less proteoglycan iew and collagen type II, more collagen type I), compared to the original hyaline tissue [11, 12]. Despite this clear pathological response to injury the natural history of untreated AC On lesions is not fully understood [13]. Shelbourne et al. (2003) reported a series of patients identified with AC defects discovered at the time of arthroscopic cruciate ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 4 of 26 ligament reconstruction. Patients left with untreated AC lesions had similar subjective patient scores at an average follow up of nine years than control subjects with no AC defects. Interestingly, the authors also noted that a number of patients with significant AC defects have no/mild clinical symptoms [5]. In another treatment intervention trial patients treated only with debridement and no surgical repair procedure showed spontaneous improvement [14]. Therefore, although some lesions will be asymptomatic, AC defects have the potential to manifest as continued joint pain, impaired movement and functional disability, that will need treating in a International Journal of Clinical Practice International Journal of Clinical Practice Page 5 of 26 carefully selected group of patients. Additionally, it is known that AC defects increase the risk of osteoarthritis, which may require knee replacement [15]. Therefore, it is desirable to intervene not only to reduce current morbidity but also in order to reduce the likelihood of future joint disorder. Patient selection and indication for surgery Fo A wide-range of non-specific symptoms may lead clinicians to consider that an AC defect is the source of a patient’s pain, including locking, pain at rest, swelling, pain rP with activity, instability and retropatellar crepitus [16, 17]. Approximately two thirds of patients with chondral defects have associated ligamentous or meniscal pathology ee and AC damage has been reported in association with 23% of ACL injuries and 54% of knees with chronic anterior cruciate ligament laxity or instability [6]. Focal AC rR defects are distinct from osteoarthritis, which often involves more widespread cartilage damage and prominent subchondral bony changes, is predominantly a ev disease of old age, and has a chronic, gradually worsening course. iew Cartilage lesions are graded I-IV according the International Cartilage Repair Society scale [18]. Grade I lesions are nearly normal with only superficial fissures, grade II lesions extend less than 50% of cartilage depth, grade III are severely abnormal lesions extending more than 50% of cartilage depth, but not into the subchondral On bone, and grade IV lesions include the subchondral bone. ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Clinical examination is supported by arthroscopic assessment, the gold standard investigation for chondral defects, which allows direct visualisation of the chondral surface. In addition, magnetic resonance imaging (MRI) has a high sensitivity and specificity to detect chondral defects (greater than 95% for grade III lesions [19]). High resolution MRI can provide sufficient information for operative planning, and might in future obviate the need for diagnostic arthroscopy. Most importantly, the commonly occurring asymptomatic AC defect makes it essential that care is taken during clinical examination and investigations to determine that findings correlate International Journal of Clinical Practice Page 6 of 26 International Journal of Clinical Practice with clinical symptoms, therefore ensuring that treatment is not misdirected [5]. Patient selection and indications for surgery vary according to the treatment type, and are considered further below. Current treatment options Fo Orthopaedic surgeons have developed a wide arsenal of treatment options for treating focal knee AC defects [20]. Those most commonly employed today include, but are not limited to: 1) arthroscopic debridement, in which loose cartilage is rP trimmed, 2) microfracture, in which bone marrow based repair is stimulated, 3) autologous osteochondral grafting, in which bone-cartilage plugs are harvested from ee non-weight bearing joint sites and implanted directly into the defect, and 4) autologous chondrocyte implantation, a two-stage procedure involving harvest of rR chondrocytes, growth in vitro, then re-implantation. ev Which treatment is chosen depends on several factors, including size of lesion, availability of particular treatments and the age and requirements of the patient. iew Small lesions may be conservatively managed with arthroscopic debridement and careful monitoring [14, 21], whereas more extensive lesions require greater intervention. The first choice treatment for lesions less than 2.5 cm2 is bone marrow stimulation by microfracture [8, 22-24]. Larger lesions may be treated by On mosaicplasty[17], this technique is limited by the availability of donor tissue, or by autologous chondrocyte transplantation, which is becoming more widely available ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 [8]. Other treatments, such as abrasion chondroplasty and the use of carbon fibre pads, are either less widely practised, or have been superseded, and are therefore not discussed. Arthroscopic debridement International Journal of Clinical Practice Page 7 of 26 Small defects in which there are loose, overhanging flaps of cartilage may initially be treated by arthroscopic debridement [14, 21]. These lesions often present with locking. However, larger, more complex defects, perhaps with no obvious loose body, require more complex procedures, which either stimulate repair tissue (microfracture) or replace damaged cartilage (osteochondral transplantation or autologous chondrocyte implantation). Fo Bone marrow stimulation by microfracture Bone marrow stimulation by microfracture is widely considered the first choice rP treatment for small lesions (less than 2.5 cm2) [8, 22-24] (Figure 3). Bone marrow stimulation techniques aim to induce bleeding for the subchondral bone followed by ee the formation of a fibrin clot, migration and recruitment of bone marrow derived stem cells and the formation of a fibrocartilaginous repair tissue that covers full- rR thickness chondral lesions. Bony drilling into the defect, first described by Pridie in 1959 [25], was prevalent until the advent of microfracture in the 1990s [26]. Pridie ev drilling uses a hand-driven or motorised drill to penetrate the subchondral plate. This is thought to cause heat-related tissue damage, whereas microfracture uses a iew gentler arthroscopic awl, which does not generate significant heat [27, 28]. Microfracture is now more popular than other bone marrow stimulation techniques (drilling and arthroscopic abrasion arthroplasty [29]). On Microfracture has demonstrated good or excellent results in 60-80% of patients [27, 30, 31]. There is some evidence that MF works best in patients under 40 years old ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 International Journal of Clinical Practice that might have intrinsically superior healing responses to those in older patients [32]. It benefits from the low-morbidity of an arthroscopic procedure with a relatively quick recovery period and low complication rate [30, 33]. Treatable lesions are 1-2.5 cm2 large, and well shouldered with protected edges [8]. Microfracture involves debridement of unstable cartilage to bone level to form a stable rim of healthy cartilage around the defect. Specially designed awls are then used to make multiple holes 2-4 mm deep and 3-4 mm apart in the subchondral International Journal of Clinical Practice International Journal of Clinical Practice bone [34]. Rehabilitation includes continuous passive motion and partial weight bearing for 6-8 weeks. Interestingly, non-human primate models of microfracture show repair tissue to be immature after six weeks, suggesting a longer rehabilitation period might be necessary [35]. The procedure may be less-well suited to the patello-femoral joint or the tibia, which in one study showed deterioration after 18 months following microfracture [24], or Fo to lesions larger than 4 cm2, which have been reported to fair better after treatment with autologous chondrocyte transplantation [22, 23]. Complications include degenerative changes in the subchondral area, such as cysts, osseous overgrowth rP and intra-lesional osteophytes in approximately 33% of cases [24, 27]. The significance of these findings has not been proven, but changes to the subchondral ee plate likely underlie failed MF treatment [33]. rR Microfracture is not a curative treatment, but it can provide relief for a number of years. However, doubts remain over the durability of the repair tissue produced, ev which is fibrocartilagenous and has inferior biomechanical properties compared to hyaline tissue. Mithoefer et al. (2009) conducted a systematic review examining the iew clinical efficacy of MF for knee AD defects. They identified six randomised control trails, which all showed improved knee function during the first 24 months postoperation, but the longevity of the initial improvement was not consistent between studies [36]. Furthermore, a recent report of microfracture used to treat On professional athletes concluded that ‘from a strict scientific stand point an untreated control group would be valuable to demonstrate that microfracture does not just ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 8 of 26 mirror the natural course of healing’ [37]. There are currently no published studies comparing MF (or any other intervention) to an untreated control group. This should be an important future research goal. Autologous osteochondral grafting / mosaicplasty Autologous osteochondral allografting, also known as mosaicplasty, most commonly involves transplantation of small (less than 1cm2) cylindrical cartilage plugs International Journal of Clinical Practice Page 9 of 26 harvested from non-weight bearing areas such as the lateral femoral condyle or the trochlea, directly into the defect in a one-stage procedure [17] (Figure 2). The use of different size plugs allows defect filling of more than 90%, and the graft needs to be perpendicular and flush to the surface to prevent catching with knee motion [17]. This technique has the advantage of directly implanting hyaline cartilage onto the defect. The procedure may be done open or arthroscopically, and is not recommended in individuals over 50 years old [17]. Good to excellent results have Fo been reported in 85-95% of treated defects of the femoral condyles, tibial surfaces and patellar/trochlear lesions [38-43]. rP It is important to note that repair using autologous tissue technique is most suited to small (less than 4 cm2) lesions, being limited by the availability of donor tissue and by ee potential donor-site morbidity [17, 44]. Larger defects may be filled with allogenous cartilage tissue from a cadaveric donor, although this risks immunologic rejection rR and disease transmission from donor to recipient. Therefore osteochondral allografts are generally reserved for uncontained (not well-defined) lesions greater ev than 4 cm2 where there is significant osseous damage [8]. iew Autologous chondrocyte implantation By 2003 more than 15,000 patients have undergone ACI worldwide [45] and it is now widely considered the frontline treatment for defects larger than 2 cm2 [8] (Figure On 4). The procedure is recommended for ICRS grade III/IV lesions of the femoral condyle or trochlear region, but more recently has been used with success for ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 International Journal of Clinical Practice patellar lesions. The optimum candidate is a highly motivated patient, less than 5055 years old, with a high functional demand and high potential for compliance with the long-term rehabilitation required (reviewed in [8]). Indications The size of a lesion best suited to ACI is still debated. Conventional thinking is that lesions less than 2-2.5 cm2 may be treated initially with microfracture, and that ACI may be used in patients that continue to have pain after microfracture. However, International Journal of Clinical Practice Page 10 of 26 International Journal of Clinical Practice although microfracture was considered a ‘non bridge-burning procedure’ [33], a recent study suggests that previous microfracture reduces the chances of successful ACI by 30% [33]. Bone involvement is not a contraindication, but when bone involvement is deeper than 6 – 8 mm autologous bone grafting should be undertaken (Petersen 2003). Reciprocal (kissing) lesions are generally a contraindication. Fo Pre-operative assessment In pre-operative planning weight loss is central, and a BMI less than 30 kg/m2 is recommended. Weight loss has been associated with improved activities of daily rP living scores and SF-36 Physical Component Summary Scores following cartilage repair procedures [27]. Clinical assessment should include knee alignment and ee associated injuries. Malalignment should be corrected by osteotomy, and knee ligaments reconstructed. Meniscal lesions require repair or resection at initial rR arthroscopy. Radiographic assessment includes postero-anterior weight bearing views to assess for medial/lateral compartment narrowing, bilateral Merchant views ev to assess patellar facet wear, subluxation and tilt, and bilateral long-limb standing radiographs to examine the leg axis and potential sites of increased load to the iew repair site. Magnetic resonance imaging has a high sensitivity and specificity (over 90%) for detecting AC defects, but only lesions that correlate with clinical symptoms should be treated. Surgical technique On Two separate procedures are required for ACI. First, arthroscopic assessment is ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 performed after physical examination and radiographic studies. If areas of ICRS grade III/IV are found, the lesions are measured. If the reciprocal surface is not severely damaged and the patient is an appropriate candidate for chondrocyte implantation a biopsy is taken. Harvest is from a non-weight bearing area of articular cartilage, such as the medial edge of the trochlear groove. Approximately 200-300 mg of tissue are taken, which corresponds to approximately 300,000 cells. It is important to remove tissue from a healthy area in order that ‘normal’ chondrocytes are collected. Chondrocytes are cultured for 4-6 weeks in a laboratory compliant International Journal of Clinical Practice International Journal of Clinical Practice Page 11 of 26 with Good Manufacturing Practice guidelines. It is important that chondrocytes are not cultured longer than this, or phenotypic changes emerge. Either a chondrocyte suspension, or chondrocytes seeded on a collagen-based scaffold (matrix assisted autologous chondrocyte implantation – MACI) is then implanted in a second procedure. The defect is prepared by debriding the edges to normal articular cartilage. Damage to the underlying chondral bone is avoided to prevent bleeding into the defect. In ACI, a periosteal graft, which may be harvested from the proximal Fo tibia, is used to cover the implanted cells [46], or chondrocytes can be implanted beneath a collagen membrane (ACI-C). In the MACI technique, cells are seeded on a collagen type I/III scaffold at a precise concentration (1 million cells per cm2). The rP membrane is placed directly into the defect and secured with fibrin glue, eliminating the need for suturing to surrounding cartilage and use of a cover, which can damage ee surrounding healthy cartilage. Rehabilitation rR Rehabilitation protocols vary widely, but always involve a long and cautious process, ev requiring high motivation and patient compliance. When planning rehabilitation it is important to remember that a biological healing process is occurring, which involves iew cell proliferation (0-6 weeks), matrix production (first 6 months), and matrix remodeling (6 months onward). Most protocols require reduced weight bearing for 10 weeks, aiming to avoid impact loading and twisting or shearing forces which might damage the repair tissue. One protocol uses a plaster of Paris for week one, On then toe-touch weight bearing with flexion-extension exercises at weeks two-six [47]. From six weeks partial weight bearing is used, and from ten weeks full weight ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 bearing is allowed. Other regimes use passive movement from day one onwards, which aims to stimulate implanted cells via mechanical signals as early as possible [48]. It ought to be noted that the ideal mobilization protocol aims to optimize the repair process, and it is tailored to the individual case. Well-contained lesions are protected by surrounding cartilage and may begin weight bearing at 4 weeks, whereas large poorly contained lesions should not bear weight fully until 8-12 weeks post-surgery [8]. International Journal of Clinical Practice International Journal of Clinical Practice Post-operative assessment Arthroscopy remains the gold standard for post-operative evaluation, often carried out at one year post-operation, and allows visualisation of the repair and biopsy for histological assessment. Probe indentation stiffness can also be measured, and has demonstrated up to 80% stiffness compared with native articular cartilage [49]. Gikas et al. (2009) demonstrated progressive development from fibrocartilage to hyaline cartilage with increasing time from operation in patients having undergone Fo ACI/MACI. The appearances of the repair tissue can also be investigated with MRI [50]. In one series ACI provided better defect filling than microfracture [51]. More sophisticated MRI techniques use intravenously administered gadolinium, which can rP penetrate cartilage, and T1 imaging can estimate glycosaminoglyan content, and T2 mapping allows evaluation of collagen content (for review see [52]). rR Clinical results of ACI ee Clinical results for ACI have been encouraging. Numerous case-series report positive effectiveness of ACI for treatment of knee AC defects, with follow-up now available ev more than 10 years post-procedure [53-56]. Furthermore, there are randomised trials (RCT) comparing ACI to microfracture [20, 23, 57] and to mosaicplasty [58], and iew these RCTs have been reviewed in an attempt to determine an optimum treatment for focal AC defects. A Cochrane Collaboration meta-analysis identified four randomised control trials On comparing ACI with microfracture or mosaicplasty that met their eligibility criteria [23, 58-61]. One of these trials reported superior outcome for ACI versus ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 12 of 26 mosaicplasty [58], whilst the other trials did not find a superior treatment. In one study one year after treatment ACI was associated with a tissue regenerate that was superior to that of microfracture [23]. Overall, they could not find evidence to support ACI over microfracture or mosaicplasty, and concluded that further randomised trials are required. Since publication of the Cochrane review (2006) [61], further RCTs have been published. Knutsen et al. (2007) reported no difference in clinical or radiographic International Journal of Clinical Practice International Journal of Clinical Practice Page 13 of 26 outcome measures at 5-year follow up of patients treated with either microfracture or ACI [20]. Saris et al. (2008) report similar short-term clinical outcome was for ACI and microfracture groups [62]. Similarly, Van Assche et al. (2008) reported on 67 patients randomised to microfracture or ACI. Follow-up at two years did not show differences in functional outcome [63]. Recently, Magnussen et al. (2008) reviewed five randomised control trials comparing Fo ACI/MACI, osteochondral autograft transfer and microfracture. All treatments improved clinical outcome measures compared to pre-operative assessment, but no technique consistently had superior results, and no study used non-operative control rP groups [64]. The authors’ recommendation is that a large prospective trial be conducted and that non-operated controls be included. ee These trials are consistent in reporting clinical improvement following ACI. rR Furthermore, economic analysis has demonstrated cost effectiveness of ACI [65]. There is emerging evidence that that the repair tissue produced in ACI is more ev hyaline-like and more durable than that following microfracture. [20, 62]. However, there is currently no firm evidence that ACI provides improved patient outcomes iew compared to either microfracture or mosaicplasty. Furthermore, the quality of trial methodology investigating knee AC defects could be improved by adequately describing randomisation procedures, including untreated control groups, use of validated outcome measures and the use of an independent investigator or outcome assessment [61, 66]. ly On 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Matrix-assisted/induced autologous chondrocyte implantation Autologous chondrocyte implantation is considered to be the first widely available and commercially successful cell-based therapeutic intervention. Undoubtedly, in the future more cellular therapies will become available to treat a wide variety of disorders. The pioneering position of ACI at the forefront of medical technology has understandably led to close scrutiny from medical regulatory authorities. Wood et al. (2006) reported that the rate of adverse reactions in patients treated with Carticel, an autologous chondrocyte implant system, was 3.8% (497/7500). Adverse reactions International Journal of Clinical Practice International Journal of Clinical Practice included graft failure (25%), delamination (22%) and tissue hypertrophy (18%) [67] and most often occurs within 6 months after surgery in approximately 25% cases and can require surgery [54]. It is thought that tissue hypertrophy is related to the use of a periosteal graft to cover the implanted chondrocytes, which in addition is technically difficult to harvest and can cause joint stiffness and arthrofibrosis. The technical advantages of scaffold- Fo based techniques (e.g. MACI), which remove the need for an arthrotomy and the risk of perosteal hypertrophy, have led to some surgeons preferring scaffold techniques [54]. Therefore, there has been evolution towards implants in which cells are seeded rP in a 3D matrix that does not require periosteal cover. Since the late 1990s, when the European Drug Agency licensed the use of collagen and hyaluronan based scaffolds ee for implantation with cultured autologous chondrocytes, several different matrix based implants have been devised, including Matrix induced autologous rR chondrocyte implantation (MACI, Verigen Transplantation Service, Copenhagen, Denmark), Hyalograft C (Fidia Advanced Biopolymers Laboratories, Padova, Italy), ev and CaReS (Ars Arthro, Esslingen, Germany). Mid-long term follow-up is now becoming available [68], and suggests that MACI gives similar or slightly improved iew clinical outcome compared to ACI [47] or microfracture [56]. Biopsy results have also been encouraging, showing the production of hyaline cartilage [47, 50]. Nevertheless, randomised trials are required to investigate these new procedures [69]. On Histological analysis of repair tissue following ACI/MACI reveals that approximately ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 14 of 26 50% of patients have hyaline-like or mixed hyaline and fibrocartilage tissue [20, 50]. Although this is certainly improved compared to microfracture [62], why some chondrocyte implants produce hyaline tissue and others fibro cartilaginous tissue is not known. This may be due to specific patient, cell-culture or knee injury factors, and investigation into predicting which patients respond best will be important in the future. Saris et al. (2008) have begun to investigate manipulation of histological outcome by characterising and selecting chondrocytes for implantation by gene expression profile analysis for a number of cartilage marker genes, such as collagen International Journal of Clinical Practice Page 15 of 26 type II. They found that superior structural tissue was formed in the ACI group, which used characterised chondrocytes, compared with microfracture. This is a promising approach, but further study comparing un-characterised cultured chondrocytes is required to determine whether cell-selection results in improved histological outcome [62]. Fo Future perspectives Treatment for articular cartilage lesions has pioneered tissue-engineering rP techniques, illuminating a path that other therapeutic interventions will undoubtedly tread. Improvement in clinical outcome has been demonstrated following ACI ee treatment, and there are clear routes forward which involve the development of matrix-based implants. Currently minimally invasive rR procedures such as microfracture are probably best for small defects (less than 2.5 cm2), and ACI for larger lesions. However, it has been said that no treatment has demonstrated long- ev term efficacy [16, 67]. The evidence for ACI providing superior outcomes compared with treatment by microfracture bone-marrow stimulation is not yet well established iew [61, 66] and improvement in the quality of randomised control trials that are undertaken is required [61, 66]. Chondrocyte implantation holds great promise for future development. The On refinement of tissue engineering techniques will include evaluation of different cellscaffold combinations, genetic manipulation of implanted cells, and use of ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 International Journal of Clinical Practice alternative cell sources such as mesenchymal stem cells. In the future, therapies might incorporate mechanical stimulation of the tissue ex vivo prior to implantation (NeoCart), the use of allogenic chondrocyte transplantation (DeNovo ET), use hydrogel or hyaluronic acid-based scaffolds [70]. There is also a push to develop single-stage arthroscopic cell-based treatments that use allogenous cells, or autologous cells of non-cartilage origin (e.g. mesenchymal stem cells) cultured and differentiated in vitro prior to implantation. Although none of these procedures yet International Journal of Clinical Practice Page 16 of 26 International Journal of Clinical Practice have regulatory approval, the scope for future development of chondrocyte implantation techniques will, hopefully, result in superior treatments. Key points Articular cartilage defects are a common injury, particularly in the young and active They still present a challenging problem with no universally accepted treatment Fo Whether to treat must be directed primarily by clinical information, not solely by the presence of a lesion rP Microfracture is a successful temporary repair procedure, recommended for small lesions, which produces fibrous tissue and can provide relief for several years ee Autologous chondrocyte implantation offers the possibility of regeneration with a rR hyaline tissue, and is the recommended front-line treatment for larger defects Future research will refine tissue engineering techniques to improve outcome with ev cell-scaffold treatments iew Review criteria Articles published in English were identified by searching PubMed in December 2009 On using the following search terms: ‘cartilage and repair’, ‘cartilage and regeneration’, ‘cartilage and articular chondrocyte implantation’, ‘cartilage and osteochondral autograft’, ‘cartilage and microfracture’, and ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ‘cartilage transplantation’. International Journal of Clinical Practice and periosteal Page 17 of 26 Figure Legend Figure 1. Schematic of a focal knee cartilage defect. (A) A fibrillated cartilage lesion. (B) Debridement of the defect to healthy cartilage with smooth vertical borders. Reproduced with permission from [71]. Figure 2. Arthrotomy mosaicplasty. (A) Miniarthrotomy mosaicplasty on the medial Fo femoral condyle for the treatment of a chondral defect. Three osteochondral plugs can be seen implanted in the defect. (B) Mosaicplasty on the medial talar dome to rP treat an osteochondritis dessicans defect. Images kindly provided by Laszlo Hangody. ee Figure 3. Bone marrow stimulation by microfracture. (A) Small holes 3-4 mm apart are created in the bone of the defect. Bleeding is induced, which results in healing by rR production of fibrocartilagenous tissue. (B) Femoral condyle defect that has been filled with newly formed fibrocartilagenous tissue. Reproduced with permission from Lutzner et al. (2009) [72]. iew ev Figure 4. Autologous chondrocyte implantation. (B) A focal cartilage defect that has been debrided to healthy cartilage. (B) Autologous cultured chondrocytes have been On implanted into the defect, over which a periosteal flap will be sutured. Reproduced with permission from Gikas et al. (2009) [47]. ly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 International Journal of Clinical Practice International Journal of Clinical Practice Page 18 of 26 International Journal of Clinical Practice References 1. 2. 3. 9. 12. 13. ly 11. On 10. iew 8. ev 7. rR 6. ee 5. rP 4. Hunter W. On the structure and diseases of articulating cartilage. Phil Trans Royal Soc. 1743;42B:514-21. Hjelle K, Solheim E, Strand T et al. Articular cartilage defects in 1,000 knee arthroscopies. 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Fo 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 International Journal of Clinical Practice Page 23 of 26 w ie ev rR ee rP Fo ly On 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 International Journal of Clinical Practice International Journal of Clinical Practice International Journal of Clinical Practice w ie ev rR ee rP Fo ly On 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 24 of 26 International Journal of Clinical Practice Page 25 of 26 w ie ev rR ee rP Fo ly On 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 International Journal of Clinical Practice International Journal of Clinical Practice International Journal of Clinical Practice w ie ev rR ee rP Fo ly On 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 26 of 26 International Journal of Clinical Practice