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Osteoarthritis and Cartilage xxx (2015) 1e17

Review

An educational review of cartilage repair: precepts & practice e myths & misconceptions e progress & prospects Q3

E.B. Hunziker*, K. Lippuner a, M.J.B. Keel b, N. Shintani c Departments of Osteoporosis, Orthopaedic Surgery and Clinical Research, Inselspital, University of Bern, Bern, Switzerland

a r t i c l e i n f o

s u m m a r y

Article history: Received 10 July 2014 Accepted 12 December 2014

Objective: The repair of cartilaginous lesions within synovial joints is still an unresolved and weighty clinical problem. Although research activity in this area has been indefatigably sustained, no significant progress has been made during the past decade. The aim of this educational review is to heighten the awareness amongst students and scientists of the basic issues that must be tackled and resolved before we can hope to escape from the whirlpool of stagnation into which we have fallen: cartilage repair redivivus! Design: Articular-cartilage lesions may be induced traumatically (e.g., by sports injuries and occupational accidents) or pathologically during the course of a degenerative disease (e.g., osteoarthritis). This review addresses the biological basis of cartilage repair and surveys current trends in treatment strategies, focussing on those that are most widely adopted by orthopaedic surgeons (viz., abrasive chondroplasty, microfracturing/microdrilling, osteochondral grafting and autologous-chondrocyte implantation (ACI)). Also described are current research activities in the field of cartilage-tissue engineering, which, as a therapeutic principle, holds more promise for success than any other experimental approach. Results and Conclusions: Tissue engineering aims to reconstitute a tissue both structurally and functionally. This process can be conducted entirely in vitro, initially in vitro and then in vivo (in situ), or entirely in vivo. Three key constituents usually form the building blocks of such an approach: a matrix scaffold, cells, and signalling molecules. Of the proposed approaches, none have yet advanced beyond the phase of experimental development to the level of clinical induction. The hurdles that need to be surmounted for ultimate success are discussed. © 2014 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

Keywords: Articular Cartilage Repair Tissue engineering Osteoarthritis Review

Introduction The bony ends of mammalian synovial joints are lined with a layer of articular cartilage (Fig. 1), which permits congruency between the two opposing skeletal elements, facilitates the transfer of forces between these and their practically frictionless movement, and acts as an absorber of weight during sustained static loading1.

* Address correspondence and reprint requests to: E.B. Hunziker, Center of Regenerative Medicine for Skeletal Tissues, Departments of Osteoporosis, Orthopaedic Surgery and Clinical Research, Inselspital, University of Bern, Murtenstrasse 35, P.O. Box 54, 3010 Bern, Switzerland. Tel: 41-31-632-86-85; Fax: 41-31-63249-55. E-mail addresses: [email protected] (E.B. Hunziker), kurt.lippuner@ insel.ch (K. Lippuner), [email protected] (M.J.B. Keel), nahoko.shintani@dkf. unibe.ch (N. Shintani). a Tel: 41-31-632-31-28; Fax: 41-31-632-95-96. b Tel: 41-31-632-22-13; Fax: 41-31-632-18-80. c Tel: 41-31-632-09-37; Fax: 41-31-632-49-99.

Articular cartilage is a highly specialized tissue. Lesions therein seldom heal, or heal only partially under certain biological conditions. They are frequently associated with symptoms such as joint pain, joint-locking phenomena and reduced or disturbed joint function. Moreover, the progression of such lesions is generally believed to forebode the onset of osteoarthritis (OA)2e4. In Western countries, OA is one of the most common diseases suffered by elderly persons. It is a disabling joint disorder of multifactorial aetiology, and, consequently, of usually unknown origin in individual cases (primary OA). However, it can be precipitated also by physical injury [e.g., by sports or occupational accidents (secondary OA)]. The incidence of OA is positively correlated not only with age but also with obesity, and due to the upward trends in both life-expectancy and youth overweight, a steady increase in the prevalence of the disease is expected5e7. Although joint pain is a common concomitant of OA, this symptom is not correlated with the size of the articular-cartilage lesion, and the mechanism underlying its generation is largely unknown8e10.

http://dx.doi.org/10.1016/j.joca.2014.12.011 1063-4584/© 2014 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

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Lesioning of the articular-cartilage layer As aforementioned, structural lesioning of an articular-cartilage layer can be induced either traumatically or during the course of a disease-based process. Once the process of lesioning has begun, it cannot be arrested, but progresses inexorably with time, the reason for which is unknown14e17. Superficial cartilaginous lesions, viz., structural defects that are confined to the articular-cartilage layer itself and do not penetrate the subchondral-bone plate, represent one of the first overt signs of OA (namely, fibrillation of the cartilaginous layer and loss of proteoglycans therefrom)18e20. Such lesions do not heal spontaneously21,22. With the lapse of time, they broaden and lengthen, such that what is initially a discrete condition progresses insidiously towards a crippling disease. The reason why lesions confined to the layer of adult articular cartilage do not heal lie mainly in the nature of this tissue's structure and physiology: it is avascular, aneural and harbours but a sparse population of cells (chondrocytes)23,24, which endure and remain in their allotted positions throughout the life of the host (as is the case for neurons of the central nervous system and for cardiomyocytes). Under metabolically pathological conditions, and in the vicinity of traumatically-induced lesions, the chondrocytes respond but sluggishly to internal and external stimuli; they manifest only a limited proliferative capacity and a reduced potential for the de-novo synthesis of an extracellular matrix25e27. Spontaneous repair

Fig. 1. Light micrograph of vertically-sectioned articular cartilage, derived from the femoral condyle of a 17-month-old bovine cow, illustrating its subdivision into superficial (S), transitional (T), upper-radial (UR), lower-radial (LR) and calcified-cartilage (C) zones; the latter abuts on the subchondral-bone plate (B). 1 mm-thick section, stained with Toluidine Blue. Bar: 200 mm.

The larger joints of the human body, for example, the knee, the hip and the shoulder, are most frequently affected by OA. During the early stages of the disease, a localized pattern of lesioning of the articular-cartilage layer is a characteristic occurrence11. However, even in unlesioned areas of the affected joint, the metabolism of the chondrocytes is disturbed12,13. Once initiated, the lesioning process is progressive, and no prophylactic (medicational) or interventional measures are at hand to arrest it14e17. Likewise, no biologically-based treatment strategies are available to induce an efficacious healing of the structural defects. This review briefly surveys the biological basis of cartilage repair, as well as current trends in the treatment of articular-cartilage defects, and points out the misconceptional elements in these approaches. Particular emphasis is placed on research activities in the field of cartilagetissue engineering. The major scientific and practical hurdles that need to be overcome for successful articular-cartilage repair are discussed; so, too, are the shortcomings of repair-evaluation protocols. Suggestions for improvements in the analytical approach are made.

From the point of view of its working status, a synovial joint (Fig. 2) can be considered as an organ. The articular-cartilage layer represents but one component of a functional unit, having structural and physiological relationships with the synovial fluid, the synovial membrane, the subchondral-bone plate and the subchondral-bone marrow, as well as with the trabecular bone and its vascular system. It is from these associated, highly-vascularized tissue-compartments that we might expect supportive activities for articular-cartilage repair21 e as well as destructive influences28. It was appreciated already at the beginning of the 20th century that if articular-cartilage lesions penetrate the layer of subchondral bone and the bone-marrow spaces e and as a consequence become

Fig. 2. Schematic drawing of a normal synovial joint.

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imbued with blood bearing diverse chondroprogenitor cells and fibrin (which acts as the supportive scaffold of a blood clot) e a limited healing response may ensue26,29. But the repair tissue laid down by the blood-borne and bone-marrow-derived cells of diverse nature does not endure for more than a few months17,30,31, and even if it persists for a longer period of time, it is deficient in functional competence32e35. Despite this poor outlook, many of the surgical treatment strategies that are in clinical use today endeavour to foster this spontaneous repair reaction. Interventions of this kind are often categorized as “bone-marrow-stimulation” approaches (for review, see27,36e38). Current surgical strategies Treatment strategies that exploit the spontaneous repair response by a “stimulation of the bone marrow” These surgical approaches include abrasion chondroplasty22,29, Pridie drilling39 and microfracturing40 (recently refined to microdrilling41,42). The aim of these techniques is to expose the lesioned cartilaginous tissue to the bone-marrow spaces, which, together with other vicinal compartments (such as the vascular and perivascular spaces, the bony tissue itself, adipose tissue and the synovium), are thereby stimulated. In essence, these interventions lead to a spontaneous repair response, which is based upon surgically-induced bleeding from the subchondral-bone spaces and subsequent blood-clot formation. The induction of such a spontaneous repair response is well known from animal experiments. However, the ensuing healing response is highly variable and nonreproducible, and the tissue formed is of a fibrous43, unenduring nature26,30. These techniques were introduced several decades ago44, at which time no alternative or more efficacious strategies were available, and in the intervening years a considerable body of clinical experience has been gained with them. Various retrospective clinical investigations appertaining to abrasion chondroplasty have been conducted45e48. The success rates are quite variable49 and depend upon many factors, such as the patient's age and physical-activity level, the severity of the arthritic condition and the follow-up period. One relevant clinical trial has been conducted: patients suffering from OA and painful knee conditions were subjected either to concomitant abrasion chondroplasty and osteotomy (for realignment and pain relief) or to osteotomy alone. Individuals who underwent the combined approach manifested significantly higher levels of a “hyaline-like”

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type of cartilaginous repair tissue and lower incidences of tissue degeneration 12 months after surgery than did those who underwent osteotomy alone. However, no difference in the clinical outcome was observed after 2 (and up to 9) years45e49. The idea of drilling holes through damaged areas of the articular-cartilage layer into the subchondral bone-marrow spaces was conceived by Pridie in 195939,50,51. As aforementioned, the rationale behind this concept is to stimulate a spontaneous repair reaction. But, perforce, the tissue formed is variable in composition, structure and durability. The intervention is now performed chiefly in young patients with osteoarthritic conditions, such as osteochondritis dissecans50. The aim is to bring symptomatic relief and to improve joint functionality52,53 by promoting a resurfacing of the articular layer with a fibrocartilaginous type of repair tissue. Clinical reports suggest that patients suffering from generalized arthroses derive the greatest benefits from Pridie drilling54. However, this procedure appears to confer short-term benefits only, and only in patients of younger age; in the long-run (several years after surgery), these beneficial effects are lost55. The microfracturing technique e a modification of the Pridie approach e was elaborated by Steadman et al.40. After the removal of the calcified-cartilage layer, multiple holes, 1- to 2-mm in diameter and 3 to 5 mm apart, are created [with either a pointed metallic (ice-pick-like) instrument40 or a narrow-calibre drill41,42] in the bone plate and the bony trabeculae. This process is associated with bleeding and blood-clot formation (Fig. 3). The technique has been recently modified. The improved “microdrilling” version is better controllable, more reproducible and less traumatic41,42,56. The microfracturing technique has thus developed into a “microPridie” drilling approach and relies on the same biological principles. The advantage of the latter technique was originally believed to lie in the avoidance of the thermal necrosis that was thought possible with abrasion and drilling. However, this concern has not been confirmed either experimentally or clinically. Microdrilling is now performed more widely than any other bone-marrowstimulation technique. Albeit so, no prospective clinical trials have been undertaken that would either confirm or refute the claimed advantages of this over other bone-marrow-stimulation techniques. Microdrilling and microfracturing have been advocated chiefly for young patients, in whom good results (improved joint functionality and relief from pain in 60 to 80% of cases) have been reported56e59, probably owing to the larger numbers and the higher activity-levels of the participating precursor-cell pools in these individuals, thereby leading to a more exuberant repair

Fig. 3. Schematic representation of the microfracturing technique. The floor of a chondral defect is perforated in several places using either a pointed instrument or a narrowcalibre drill. By this action, the marrow space of the subchondral bone is opened. Blood percolates into the defect e bearing with it local bone-marrow-derived MSCs e and therein forms a haematoma.

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response than in older ones. Since there is some evidence that microdrilling and microfracturing are most effective in patients below 40 years of age60, it is questionable whether these techniques would be appropriate for OA-patients, who are usually older, whose spontaneous tissue-repair potential is impoverished, and in whom the number and the availability of bone-marrow-derived stem cells is reduced61e63. With a view to improving the clinical outcome of microdrilling and its reproducibility, this intervention has been combined with the introduction of a thin-layered, blood-absorbing matrix (see Section 5.2: Matrix scaffolds) of either collagen types I and III64,65 or chitosan glycerol phosphate41,66. However, available data afford no evidence of any beneficial effect of this combined approach. The disappointing results may reflect the relatively high bioincompatibility of the implanted matrical material, which triggers an inflammatory response. Indeed, when this combined approach is adopted, the defect site is confronted not only with the extrinsic matrix but also with the intrinsic one, namely, fibrin, which fills the area after the induction of bleeding, and which likewise triggers an inflammatory response. Hence, inflammatory reactivity is augmented by the introduction of an extrinsic matrix. One possible way to improve the repair result that is achieved in the presence of an extrinsic matrix is to enhance its biocompatibility and to minimize its pro-inflammatory properties. Recent clinical studies that have been conducted using a collagenous membrane with such attributes have yielded fairly favourable results67e71. This type of collagenous matrix is introduced into the defect void after a stimulation of the bone marrow by microdrilling. For this combined approach, clinicians have coined the term autologous matrixinduced chondrogenesis (AMIC), which is a misleading misnomer, since the carrier material is not in itself chondrogenic. The advantages of the AMIC-approach are that it involves no celltransplantation, that it can be performed during a single surgical intervention, and that it is cost-effective. Prospective randomized clinical trials of a comparative nature are currently underway to assess the practical usefulness of the AMIC-approach relative to that of ACI and/or MACI. A surer means of achieving an additional improvement in the clinical outcome of microdrilling-based therapies would be to introduce an on-the-site-prepared local population of autologous stem cells (either isolated or in the form of tissue-fragments), derived, for example, from the synovial membrane or the bone marrow. An approach that draws on the on-site preparation of autologous material would involve fewer regulatory hurdles and circumvent prior laboratory processing, and would, therefore, be cost-effective. The reproducibility of the repair results could probably be improved by the introduction of a vehicle-borne growth-factor cocktail to induce the desired chondrogenic differentiation of the stem cells, which could be conceived as a commercially-available, off-the-shelf product72e74, and which would have to be applied together with a functional or structural barrier75,76 to prevent the up-growth of underlying bone into the cartilaginous compartment. A concept that is based on the use of fragments of synovial membrane would be the one most likely to meet with success, since stem cells of synovial origin have a higher chondrogenic potential than those derived from either the bone marrow, the periosteum, adipose tissue or muscle, at least in vitro77. Moreover, it would even be advantageous to introduce the cells in the form of tissue-fragments rather than as isolates, since, when supported by their physiological scaffold, their responsiveness to the applied chondrogenic differentiation factor(s) would be better assured78. New treatment strategies should be preferably conceived from the onset as single surgical interventions or arthroscopic approaches e with a view to clinical practicability and to reduce the risk of infection or other complications, as well as to

lessen the burden on health-care systems, which would, in turn, render them more affordable to the average citizen in Western societies79. Transplantation strategies Osteochondral autografting (mosaicplasty) The idea of implanting chondral or osteochondral tissue itself within articular-cartilage defects dates back to the beginning of the last century80e82. And this concept still forms the basis of clinical strategies involving both autografts83e86 and allografts87e89. Of the autologous osteochondral treatment strategies currently in use, mosaicplasty (Fig. 4) is the one with the longest history. This technique is used for large, full-thickness lesions, and involves the introduction of several or multiple pieces (plugs) of autologous graft-material into the defect void. The advantage of this treatment strategy is that it can be performed during a single intervention. Upon exposure and surveillance of the diseased joint, the orthopaedic surgeon is able to promptly decide from which regions autologous donor material should be removed and can then proceed immediately with the autotransplantation (Fig. 4). Mosaicplasty has for some years been the favoured technique of orthopaedic surgeons in Japan and Europe, but is of only limited popularity in North America. Indeed, for various reasons (see below), the approach is now losing credibility among surgeons in all geographic regions. One of the most serious drawbacks of the technique relates to the destiny of the areas from which the autologous osteochondral plugs are removed. In taking such tissue, the surgeon is artificially creating additional lesions within an already diseased joint (Fig. 4), and in so doing establishes additional sites of joint degeneration, thereby exacerbating rather than assuaging the local pathological process. Given the not inconsiderable size of the osteochondral plugs that are excised by the surgeon, the donor sites probably fail to heal. For this reason, some surgeons apply a matrical material to the surgically-created lesions, with a view to promoting a spontaneous repair response90. Similarly, we have but a poor conception of what occurs at the acceptor sites after the transplantation of autologous tissue-plugs. The drilling procedures that are used to remove the osteochondral tissue expose chondrocytes within the transplanted plug e as well as those bordering the cavity created at the donor site e to extremely high temperatures and drying conditions, which are liable to impair their vitality. The osteochondral plugs, once removed, are then press-fitted by hammering into the subchondral-bone bed. This hammering process probably induces an injurious compression of the transplanted cartilage91, which could precipitate the immediate death of the chondrocytic population91. Moreover, if the tissue is transferred from a low-to a highweight-bearing region of the joint, it will be subjected to unphysiological conditions of mechanical loading for which it was not conceived, thereby accelerating its degeneration. The insertion of several serried plugs within the defect void, without taking measures to promote knitting between them, might also give rise to complications: the absence of structural bonding around the entire circumference of each plug will certainly pose nutritional as well as functional problems from the outset, and these will tend to prompt tissue degeneration (see Ref. 27). Only a few attempts have so far been made to clarify these issues. Hence, although mosaicplasty is still used, there exists no sound scientific basis for the contention that patients subjected to this treatment strategy benefit in the long run92e98. Osteochondral allografting For many decades now, allogeneic osteochondral grafts have been used for the filling of articular-cartilage defects. The approach

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Fig. 4. Schematic representation of the principle of mosaicplasty. Cylindrical plugs of osteochondral tissue are drilled from a non-weight-bearing area of the knee joint (using a special surgical instrument) and then press-fitted, side-by-side, within the damaged zone. The number of plugs removed will depend upon the surface diameter of the acceptor site. The denuded donor sites are either filled with osteochondral tissue that is removed from the damaged acceptor site during its surgical preparation for the plugs, or left empty. When viewed from above, the fitted plugs form a mosaic of circular profiles interspersed with empty spaces; hence the name “mosaicplasty”.

does not attempt to induce a cartilage-repair response, but represents a means of substituting failed or lost tissue with healthy articular cartilage, which is usually derived from cadavers80. The biological rationale for this approach is based on the knowledge that large osteochondral defects do not heal spontaneously and that it is extremely difficult to elaborate a suitable stimulatory system to promote effective repair in a compartmentspecific manner within the cartilaginous and the osseous carrels. It has thus been deemed simpler to replace the lost tissue with cadaverous osteochondral allografts99e101. Immunological problems are inevitably to be counted amongst the drawbacks of this technique102,103. Nevertheless, patients with large osteochondral defects, such as those generated by tumour resection, osteonecrosis, extensive trauma, widespread OA or osteochondritis dissecans, benefit greatly from this treatment strategy104,105. Clinical experience with this therapeutic option has been surprisingly good, immunological reactions being apparently less extensive in humans than in experimental animals103,106,107. Human osteochondral allografts also survive for longer periods (some years), even after freezing or lyophilization87,88,102,108. Clinical success rates have been reported to range from 65% to 85%, even after monitoring periods of up to 10 years100,109e111. The major drawbacks that are associated with the implementation of this methodology in clinical practice include the scarcity of fresh donor material and the storage of frozen tissue112. The small but everpresent risk of disease transmission must also be borne in mind111. Autologous-chondrocyte implantation (ACI) When the ACI technique (Fig. 5) was introduced on the clinical scene by Brittberg et al. in 1994113, it took the orthopaedic world by storm, generating much hope and enthusiasm. The concept was in

fact the brainchild of Grande et al., who tested it in a preclinical study with rabbits in 1989114. According to the ACI-technique, a biopsy of healthy articular cartilage is first arthroscopically harvested from a low- or non-load-bearing location of the diseased joint. The cartilaginous tissue is then enzymatically digested to release the chondrocytes, which are subsequently expanded in culture, thereby generating more than 10 million cells from the few hundred thousand that are contained within the biopsy. A suspension of the expanded autologous chondrocytes is introduced directly into the defect, beneath a surgically-sutured periosteal flap, which is usually removed from the medial tibia. Systems involving the application of freely-suspended cells are technically more complex than those in which matrix-embedded cells are grafted, since the careful placement and suturing of periosteal flaps (or other types of material with a comparable function) are required to ensure their retention and optimal integration with the surrounding articular cartilage. Furthermore, the postoperative delamination of such flaps e which can and does occur, even after suturing115 e must be prevented by a temporary immobilization (partial or complete) of the joint. More recently, a matrixassociated variant of the ACI-approach (the so-called MACI-technique) was introduced116. According to this MACI-technique, the autologous chondrocytes are embedded within a matrix (e.g., collagen or hyaluronan) rather than suspended in a fluid, thereby obviating the need for a periosteal flap. However, the use of a matrix introduces a new set of problems, such as the issues of bioincompatibility, inflammation and degradation (see Section 4.2: Transplantation strategies, and Refs. 27,117). The ideal carrier118 has not yet been developed. Albeit so, this is still a goal towards which researchers aspire, and efforts in this direction have not been thwarted by either the slowness of the progress or the set-backs of failure.

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Fig. 5. Schematic representation of the ACI-technique. A fragment of articular cartilage is removed from the periphery of the joint that bears the lesion. This fragment of tissue is digested to release the chondrocytes, which are expanded in vitro for 11e21 days. A periosteal flap is then removed from the medial tibia and sutured over the lesion. A suspension of the expanded chondrocytes is injected beneath the flap into the lesion.

A considerable disadvantage of ACI-based strategies is that surgical intervention is required on two separate occasions, which is a costly process necessitating long-term patient planning. The creation of additional lesions within the joint during the harvesting of healthy cartilage is also a drawback. Although only a small biopsy is taken from a non-weight-bearing area of the joint, some investigators claim that this may heighten the risk for the development of OA119,120. It has also been suggested that the chondrocytes could be removed from osteoarthritic rather than from normal articular cartilage, or even from other tissue sources121,122. Although the ACI-technique is still highly popular, its superiority to simpler interventions, such as microfracturing or microdrilling, has not been established. Knutsen et al.123 have published the results of a prospective randomized clinical trial in which patients with circumscribed cartilaginous lesions in the femoral condyle were treated either conventionally, namely, by microfracturing, or according to the ACI-technique. The findings of this 5-year trial revealed the latter strategy to confer no advantage over the conventional one. Although the repair tissue that was evident 1 year after treatment according to the ACI-technique was reported to be structurally superior to that laid down after microfracturing, the clinical outcome was the same124. An ongoing long-term follow-up analysis of the same cohort of patients has confirmed the earlier (5-year) findings: 15 years after treatment by microfracturing or according to the ACI-technique, the clinical results were the same in each group, which argues in favour of the less traumatic, less risky and less costly microfracturing approach (Gunnar Knutsen: personal communication). A possible explanation for these short- and long-term findings is, that from a biological and biomechanistic point of view, the treatments are basically the same. When the ACItechnique is performed, the floor and the walls of the defect are usually “neatened” by shaving, which induces local bleeding and a spontaneous repair response from the bone-marrow spaces.

Almost unbelievably, this possibility has not been excluded in the published studies by the establishment of the appropriate controls [viz., an “empty” defect (negative control): no injection of chondrocytes beneath a periosteal flap114,116; and a defect filled with another cell type (positive control), e.g., fibroblasts]. Neither microfracturing/microdrilling nor ACI is clinically effective in patients over 50 years of age, probably because the bone-marrow-derived (mesenchymal) stem cells (microfracturing technique) and the transplanted autologous chondrocytes (ACItechnique) suffer age-related losses in their potential to proliferate and differentiate125. Hence, especially for elderly persons, who are particularly prone to osteoarthritic lesioning of the articularcartilage layer, there exists an undisputed need for an effective cell-based repair strategy. We have to face the bleak fact that very little progress in this area has been made since the bone-marrowstimulation technique e of which microfracturing/microdrilling is a variant e was introduced by Pridie in the 1950s44. However, one source of comfort is that cell-based cartilage-repair strategies, such as the ACI-technique, do not elicit worse healing results than those that are based on a stimulation of the bone marrow. A refinement of the ACI-technique has been recently introduced, which involves a selection from the harvested cells of specific sub-populations of (characterized) chondrocytes with particularly high chondrogenic potentials. However, 2 years after treatment according to the refined ACI-technique, the clinical benefits were reported to be only incremental126. And 5 years after treatment by microfracturing or according to the refined ACI-treatment, the clinical outcome was ultimately the same in each patient-group127, despite some differences during the follow-up course128. Given the high degree of technological finesse that is now achievable, and against the backdrop of knowledge and experience that have been gained over the past 60 years with Pridie drilling and over the last 20e30 years with the ACI-approach [as well as

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with its variations/modifications (e.g., MACI)], both strategies are accessible to improvement. As aforementioned (Section 4.1), in an attempt to improve the clinical outcome of microdrilling and its reproducibility, the approach has been combined with the introduction of a thin-layered, blood-absorbing matrix (enhanced microfracturing) of either collagen types I and III64,65, “manipulated” collagen (as in AMIC67) or chitosan glycerol phosphate41,66. The available data afford evidence that the clinical results are reproducible68,71, and, possibly, that the long-term outcome (compared to the conventional technique) is improved70. As heretofore mentioned, the introduction of a local population of autologous stem cells (e.g., in the form of small tissue-fragments, which could be derived from a local source, such as the synovium) would probably be a fruitful route to pursue in the future. However, the currently practiced approaches, which involve the transplantation of either fragments of juvenile allogeneic cartilage129e131 or pieces of adult autologous articular cartilage129,132e134, are based on the false premiss that the cells can migrate out of the tissue. Tissueembedded chondrocytes are incapable of migration; they can undergo only indirect translocation via a directional resorption of the surrounding matrical coat and its neoformation135. Migration is possible only if the cells undergo dedifferentiation (which occurs during the late stages of osteoarthritis) and if the pericellular and territorial matrical compartments are destroyed by excessive catabolic activity136e138. Clinical studies that have dealt with these approaches129,133 suffer from fundamental shortcomings, which include insufficient numbers of patients, the absence of a basis for comparison (e.g., sham surgery), and the failure to instigate random-selection procedures. The data that have been gleaned from such trials serve only to demonstrate that the interventions can be safely implemented; they do not permit the drawing of comparative conclusions. The same arguments hold true for clinical studies that have evaluated the efficacy of approaches involving the application of a bone-marrow-aspiration concentrate (BMAC)139e141 or of platelet-rich-plasma (PRP), either alone or in combination with BMAC140,141. PRP- and BMAC-based strategies are classical examples of empirical, “alchemistic” approaches to the engineering of cartilaginous tissue. Using the former approach (PRP), an ill-defined soup of multifarious growth factors at unknown concentrations and with diverse e antagonistic as well as synergistic e workings is administered; and using the latter (BMAC), a similarly ill-defined soup of diverse cells in variable numbers is applied. Owing to inter-individual variations in the compositions of these pot-pourris, the exerted effects will be likewise variable and thus irreproducible; and even if these are positively rated, an identification of the key-player(s) is impossible. Current research activities relating to tissue-engineeringbased strategies Many more research teams around the world are now moving away from an overly empirical approach to cartilage repair, which was hitherto the norm, towards a more biologically rational one. Current activities tend to focus on the elaboration of novel tissueengineering-based strategies142. Tissue engineering can be defined as the art of reconstituting mammalian tissues, both structurally and functionally. Such reconstructive processes can be conducted (1) entirely in vitro, (2) initially in vitro and then in vivo (in situ), or (3) entirely in vivo. Three key constituents usually form the building blocks of a tissue-engineering-based approach: a matrix scaffold, cells, and signalling molecules (such as growth factors or genes). Most of the experience so far gained with these techniques has been derived from in-vitro studies, although experiments with laboratory animals and humans have also been conducted. In the following

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sections, the key constituents of a tissue-engineering-based approach to cartilage repair are described. Cell sources Success in tissue-engineering-based strategies would obviate the need for the transplantation of cartilaginous tissue. And if appropriate precursor-cell pools could be identified, then the numerous problems that are associated with the use of donor (allogeneic) material would be circumvented. Precursor-cell pools of diverse tissue origin are known to exist within adult mammalian organisms, each of which has the potential to differentiate into cartilageproducing chondrocytes and which can be used for transplantation purposes. And in some instances, the tissue of origin has the potential for self-repair after the removal of not insubstantial quantities of material. The tissue sources include the cambial layers of the perichondrium and the periosteum, the bone-marrow stroma, the synovial membrane, muscle, fat143e145 and adult cartilage itself (autologous or allogeneic chondrocytes146e148). Perinatal cells149, as well as foetal or embryonic stem cells and chondroblasts, can also be employed150. The search for suitable and hitherto untested types continues unabated151e153. Due to the limited availability of autologous chondrocytes, the focus is now more on allogeneic sources. However, the use of allogeneic cells raises other problematic issues, such as bioincompatibility and immunogenicity142,152. Mesenchymal stem cells (MSCs) are now frequently used experimentally for cartilage-tissue engineering, owing to their capacity for self-renewal and their accessibility143e145. Amongst the various tissue sources, bone-marrow-derived MSCs have been the most intensively investigated, both in vitro and in vivo, since the time of their original isolation by Friedenstein in 1966154. Bonemarrow-derived MSCs evince a high capacity for chondrogenesis only in the presence of appropriate stimulation factors78,155,156. In a clinical setting, Kuroda et al.157 treated a large full-thickness articular-cartilage defect within the femoral condyle of an athlete with autologous bone-marrow-derived stromal cells. The bone marrow was aspirated from the patient's iliac crest 4 weeks before surgery and the cells were expanded in culture after their separation from the erythrocytes. The undifferentiated cells were then embedded within a collagenous gel, which was transferred to the articularcartilage defect and covered with an autologous periosteal flap. Although the knee-outcome scores improved with time, biopsies revealed the presence of fibro-, not of hyaline, cartilage. In this study, no exogenous agents were applied to guide the course of differentiation. This fact suggests that the formation of a hyaline type of repair cartilage by MSCs requires the presence of appropriate stimulation factors (see Section 5.3: Signalling molecules), which may be locally absent, or present at insufficiently high levels to guide the process of differentiation in the desired direction. Although MSCs have been claimed by some investigators to furnish their own supply of growth factors158,159 and to be conferred with the capacity for immunomodulation160, experimental experience gained over the past 20 years in the field of cartilage repair has revealed these activities e if indeed they exist e to be too low to support an efficacious healing response. One of the limitations of bone-marrow-derived MSCs is that their chondrogenic potential declines with increasing patient age125. MSCs that are derived from the synovium do not suffer from this drawback161. Furthermore, the chondrogenic potential of MSCs originating from the synovium appears to be superior to that of MSCs originating from either the bone marrow, the periosteum, adipose tissue or muscle, at least in vitro77. However, as yet, we are still in the dark as to which tissue source of MSCs is ideal for the clinical repair of articular cartilage, since convincing in-vivo data have not been forthcoming to date.

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Table I Chemical classes of matrix 1. Protein-based polymers Fibrin Collagen Gelatine 2. Carbohydrate-based polymers Polylactic acid Polyglycolic acid Hyaluronan Agarose Alginate Chitosan 3. Artificial polymers Dacron (polyethylene terephthalate) Teflon (polytetrafluoroethylene) Carbon fibres Polyesterurethane Polybutyric acid Polyethylmethacrylate Hydroxyapatite 4. Within/between classes Cross-linkage Chemical modulations Geometrical modifications (to produce fibrillar forms or foams) Matrix combinations Reproduced e in a slightly modified form e with permission from30.

Irrespective of the type of stem cell that is employed, tremendous hurdles must still be surmounted before the goal of cartilage regeneration can be achieved. Our knowledge of the regulatory and signalling pathways that are implicated in the biology of stem cells generally, and more especially that govern their commitment to differentiate along a specific course and to form a specific type of cartilaginous tissue, namely, fibro-, hyaline or elastic, is still very incomplete. Information appertaining to the temporal course of chondrogenic differentiation and its regulation is also lacking. With respect to induced pluripotent stem (iPS) cells162, for example, it still remains to be ascertained whether the point in time at which they are induced to undergo committed differentiation along a specific course is or is not programmed into their genetic apparatus; and, if so, whether the “age”, viz., maturation state, of the newly-formed cells and tissues matches that of the donor. The same questions arise also when dealing with foetal, embryonic or adult stem cells. Moreover, we are still in the dark as to whether the tissue-differentiation and growth processes that ontogenetically span decades in time can indeed be speeded up therapeutically so as to be completed within the matter of a few weeks only. Furthermore, although our knowledge of the human genetic code is now fairly complete, information relating, for example, to the

programming of joint-surface shape or of locational differences in structure, composition and thickness23,24, is lacking. Knowledge of this kind is indispensable for the fruitful development of more sophisticated epigenetic and higher-level approaches to cartilage repair. Only against a background of improved knowledge and understanding can we hope to engineer a mechanically-competent and durable type of articular cartilage. At present, research in this area has attained a hyatal status and is moving in circles rather than forward. Matrix scaffolds The use of matrices as cell-carriers in cartilage-repair strategies dates back to the 1960s163. Many different types of matrix have been tested e not only in vitro but also in experimental animals and human patients e for their capacity to facilitate or promote articular-cartilage repair. These matrices can be broadly categorized according to their chemical nature into protein-based polymers, carbohydrate-based ones, artificial materials, and combinations of these (Table I). Even when a naked matrix (viz., one that carries no cells or signalling substances) is deposited within an articularcartilage defect, it must be considered as an information-carrying device: its three-dimensional structure will, according to its peculiar geometrical configuration, specifically guide, or at least influence, the process of tissue growth, whilst the chemical and physical properties of its surface will impact cell attachment and the binding of growth factors in the niche environment. Hence, as an “active biologic”, such a naked matrix will elicit a biological response within a bodily tissue-compartment, which may or may not be desirable, but which cannot be prevented unless specific modulations of an appropriate nature are made to guide the process in the desired direction [e.g., by means of AMIC (see discussion above)]. The basic requirements of a matrix to be used in a biological environment are summarized in Table II [see also Refs. 27,117,118]. Although some of the listed materials are already in clinical use164, most of them, and especially the synthetic ones, are still being tested in preclinical trials165. Moreover, using scaffolding materials that have been applied for awhile in the field of cartilage repair, such as collagen166, fibrin167, hyaluronan168,169 and polylactate170, as well as those that have appeared on the scene more recently, attempts are now being made either to produce them in nanofibrillar forms171, to enhance their porosity172, or to manufacture them in a state that is conducive to injection173. The common aim of these endeavours is usually to create an absorbable, biomimetic material174, even when using synthetic polymers, such as polydioxanone175.

Table II Matrix requirements Matrix property

Biological basis

1. 2. 3. 4. 5. 6. 7.

Cell migration Lodgement and release of signalling substances Cell attachment Physiological remodelling Smooth surface contour of repair tissue flush with that of native articular cartilage Good contact with the native-tissue compartment Enhances interfacial integration between collagen fibrils in repair- and native-tissue compartments Prevention of matrix outflow Resiliency during and following dynamic or static deformation Promotion of native anisotropic tissue organization

Porosity Carrier Adhesion Biodegradability Volume stability Biocompatibility Bonding

8. Internal cohesiveness 9. Elasticity 10. Structural anisotropy Matrix properties specific to the mode of surgical application A. Fluid state during application with subsequent solidification in situ B. Stiff and amenable to press-fitting

Arthroscopic implantation Arthrotomy (open surgery of a joint)

Reproduced e in a slightly modified form e with permission from30.

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More recently, it has become the vogue to use biphasic scaffolds176,177. These bilayers consist of two different materials: an upper one that is deemed to be conducive to chondrogenesis and which is destined for the cartilaginous compartment of osteochondral defects, and a lower one of a ceramic-like substance, which can be press-fitted as a plug into the subchondral bone176. Apart from the obvious issues that must be addressed when testing a scaffold, such as biocompatibility, biodegradability and toxicity, its integration with native cartilage is also a troublesome problem, and one that has not yet been overcome178. During the past decade, no matrices with basically new chemical features have been inaugurated. However, physical or chemical modifications to existing materials have been effected, with a view to enhancing the efficacy of clinicallyestablished methodologies, such as microfracturing/microdrilling41,64e66, by AMIC68,70 or ACI (by MACI)116, or, in the context of more experimental tissue-engineering-based approaches, with the aim of guiding cartilage-formation in a spatially-defined manner [three-dimensional bioprinting (see discussion below)]. The dearth of genuine innovation in this field partially reflects the unfavourable investment climate that prevails in the commercial world, which encourages low-cost, incremental improvements in existing strategies rather than revolutionary novelty. This is a regrettable circumstance, since it is precisely this flux of ingenuity that is now needed to push research in a really fruitful direction. However, one positive aspect of this dilemmatic situation is that any newlyconceived therapeutic principle must now be not only of a truly impressive nature but also backed up by rigorous experimentation before any willingness to invest in clinical trials can be expected. Signalling molecules One of the trends now foremost in the field of tissue engineering relates to the elaboration of constructs that consist not only of a matrix and cells but also of signalling molecules to specifically guide the course of differentiation in the desired direction. In most cartilage-engineering strategies, the chosen cell type is applied together with free or appropriately-encapsulated growth factors. The efficacy of various growth factors to induce chondrogenesis has been evaluated mainly in vitro and to only a limited degree in vivo [for reviews, see Refs. 179e183]. In-vitro experiments have involved various combinations of matrix, cell type and growth factors. These include collagenous matrices containing bone-marrow-derived stromal cells and transforming growth factor (TGF)-ß1184,185, agarose matrices containing chondrocytes and fibroblast growth factor (FGF)-2186, fibrinous matrices containing chondrocytes and insulin-like growth factor (IGF)-1187, and polylactatous matrices containing perichondrial cells and TGF-ß1188. In some instances, MSCs have been cultured in the absence of a matrix (viz., under scaffold-free conditions), namely, as high-density pellets (or aggregates)183,189,190. Under such conditions, not only growth factors, but also dexamethasone, a synthetic glucocorticoid, is frequently applied. However, this agent can elicit undesired effects in a manner that depends upon the source of the cultured cells and the absence or presence of the natural (physiological) extracellular matrix78,155,156. Successful testing in vivo has been achieved using equine191 and mature miniature-pig models72. The study that was conducted using the latter model has served to show how different the in-vivo situation may be from the in-vitro one. Under in-vitro conditions, various types of growth factor have been shown to support chondrogenic activities192, whereas in vivo, principally only those of the TGF-b superfamily are effective193. A recentlydiscovered compound, namely, kartogenin194, is now attracting some attention. However, this molecule appears to exert a generalized anabolic effect on chondrocytes rather than being specifically chondrogenic.

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There are three possible approaches to the engineering of articular cartilage. According to the first, the repair tissue is engineered completely in vitro, the fully-differentiated construct being then implanted within the defect void. The advantage of this approach lies in the fact that cell metabolism and differentiation are subject to better control in vitro than in vivo, provided that the appropriate bioreactor systems195,196, growth factors and delivery systems are available. Its drawbacks are, that the problems associated with the integration and the mechanical fixation of the repair tissue cannot be readily anticipated and solved. Moreover, the simulated mechanical-loading conditions of the extracellular matrix may not be ideally suited to the specific needs of the prospective repair site. Furthermore, biocompatibility and immunological problems are frequently associated even with this in-vitro approach and in the absence of a scaffold197. Furthermore, the natural curvature of the joint surface poses a challenge to the process of press-fitment whereby the engineered construct is introduced into the defect void. The second approach, which is more frequently adopted, aims to engineer only the basic building block, namely, a matrix scaffold containing a homogeneous population of cells and signalling molecules entrapped within an appropriate delivery system. The vehicle-bound signalling molecules ensure that the desired differentiation process takes place in a controlled and timely manner in vivo and that chondrocytic activity within the repair tissue is sustained. According to this approach, the differentiation and the remodelling of the repair tissue occur in vivo under physiological conditions of mechanical loading. Repair tissue that is formed in situ is more likely to adhere to and integrate with native articular cartilage than is that produced in vitro, and it will also adapt naturally to the contour of the synovial joint, provided that appropriate measures are taken to promote the bonding of the implant that has been generated in culture198e200. One of the disadvantages of this “second” approach is that cell activity is more difficult to control on a long-term basis. Moreover, appropriate measures must be taken to avoid “contamination” from cells and signalling substances that are involved in the spontaneous healing response, since the tissue thereby formed would compromise the quality and the mechanical competence of the final repaircomposite. The third approach involves the direct application of exogenous growth factors (entrapped within a matrix) to the defect site; these then stimulate the intrinsic formation of cartilaginous tissue in situ72. An appropriate matrix is first introduced into the defect to define the space that is to be repaired. The laying of this physical “track” is necessary to guide the movements of the intrinsic precursor cells, which have a limited spatial awareness21. The growth factors are usually introduced into the matrix in two different states: as a freely-soluble agent e to stimulate the immediate recruitment of the intrinsic population of precursor cells from their site of origin, their migration into the defect area, and their proliferation therein21 e and as a vehicle-bound one for gradual delivery at a steady rate that is sustained for several weeks e to stimulate the chondrogenic differentiation of the defect-filling population of cells72. Hence, an intelligent, internally-programmed matrix is applied to the defect. The freely-soluble signalling agent that is applied is usually IGF-1, bFGF or a TGF-b (at low concentration). As aforementioned, the growth factor in this form stimulates the recruitment of precursor cells from the synovium21, their migration into the defect space, and their subsequent proliferation therein. The vehicle-bound signalling agent that is applied to induce the chondrogenic differentiation of the defect-filling population of cells is usually a member of the TGF-b superfamily, for example, BMP-2, BMP-9, BMP-13 or TGFb1 (at high concentration). Various drugdelivery systems have been employed, including microspheres,

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liposomes, microparticles and fibrillar networks. The principle underlying this approach was first published by our group in 1991201. A full description of the strategy appeared in the literature in 199621 and then, in an optimized form, in 200172. The approach has since been summarized in several publications27,202. The principle has been recently confirmed by an independent group of investigators203 (2010) using TGF-b3 as the chemotactic and chondrogenic differentiation agent, a hydrogel as the drug-release system, and three-dimensional-printed poly-ε-caprolactone-hydroxyapatite as the matrix. Unfortunately, the authors chose not to cite the original pioneering work on this topic and coveted the idea as a new one. Actually, the novelty of the study lay in the use of polyε-caprolactone-hydroxyapatite as a three-dimensionally-printed matrix. A matrix of this kind is implemented with a view to guiding tissue formation in a spatially-defined manner. As appertaining to articular cartilage, the aim is to reproduce the anisotropic organization of the chondrocytes and their extracellular matrix that is so characteristic of the mature tissue and that is indispensable for its mechanical competence. Although three-dimensional bioprinting is an old technique (for a review of the topic, see Refs. 204), it has recently undergone a revival: owing to technological advancements, sophisticated materials can nowadays be manufactured with greater facility and more cheaply than heretofore. The material of which the matrix is formed needs to be sufficiently porous to allow the infiltration of cells27,201 and also biodegradable. Ideally, it should also have a well-defined anisotropic organization, which forces the cells to align themselves into vertical columns during the process of remodelling205 and which is important for the mechanical competence of the tissue as a whole, as aforementioned. In this context, the three-dimensional-printed matrix that represented the sole novelty of the study by Lee et al.203 may be advantagenous. One problem appertaining to the chondrogenic differentiation of the defect-filling population of cells that we have recently addressed relates to the timely arrestation of the process prior to the stage of terminal hypertrophy and matrix mineralization73. This undesired event can be avoided by the addition of TGF-b1 at a low concentration73. Other investigators have achieved similar results using alternative agents206e212. Consequently, to achieve optimal cartilage-repair results, minimally three sets of growth-factor-stimulated “activities” need to be embraced in the applied cocktail of signalling agents72e74. This necessity, which is not always recognized (cf203), renders the approach unattractive to cost-conscious commercial parties and/or investors. Principally two novel growth-factor-based therapeutic strategies are now at the conceptual stage of development: the aforementioned one, which is designed to recruit cells with chondrogenic potential from a local intrinsic source, such as the synovial membrane21,72,203; and a second approach, which involves the injection into the defect site of MSCs that have been transfected with genes encoding the factors necessary for chondroprogenitor commitment213,214. Both approaches are still at a preliminary stage of development; exhaustive short- and long-term preclinical studies79 are requisite prior to the launching of clinical trials. Scientific evaluation After perusing this review article, the reader will no doubt be left with the impression that in the area of cartilage repair, research activity over the past 10 years or so has turned around in circles, not moved forward in excitingly new and fruitful directions e which is a regrettable situation for hopeful patients. The circumstance is the less excusable in so far as the technological advancements that have been made during this time span have greatly aided the probing of many facets of cartilage biology, thereby permitting an enrichment of knowledge and understanding in the targeted disciplines.

In this review, suggestions for fruitful directions of pursuit in the future have been made. But what is now needed is a revolutionary turnaround in our conception of cartilage repair and a more thorough and systematic approach to its evaluation. We should not stagnate, but break free of the bounds of our comfort zone as represented by the old well-worn ruts e the trusted, tried and tested tracks of yore e the pursuit of which can contribute no more than incremental or cosmetic information to the body of existing data that has accumulated over the past decade. A fundamental change in the general attitude of scientists, PhDstudents and supervisors towards the evaluation of cartilage repair is also called for. In many laboratories, the analytical process is conducted on an elementary e almost routine e and insufficiently discriminative level. Nowadays, repair cartilage is all too commonly presented as a tissue that contains lacuna-mantled cells (chondrocytes), that stains histochemically with a cationic dye (such as Toluidine Blue or Safranin O), and that manifests immunohistochemical reactivity for type-II collagen. Attempts to quantify the characteristics of the tissue are confined to parameters that insufficiently describe the true nature of articular cartilage. These parameters are gauged using subjective and biased scoring systems, such as those propounded by Mankin215, O'Driscoll216 and the ICRS217. The parameters that are evaluated using these tools afford no information relating to the maturation status of the repair cartilage, viz., whether it is of a foetal, ontogenetically-transient, early postnatal or adult type; nor is any information gleaned as to whether the repair cartilage is of a joint-specific type or not. Similarly, these rudimentary evaluations yield no information respecting the metabolic status of the tissue, viz., whether the anabolic and the catabolic activities are in a state of equilibrium or not. Very often, the repair cartilage is sweepingly designated as being “hyaline-like” without adequate supportive evidence. The repair cartilage needs to be subjected to a rigorous analysis: its maturation status should be defined; so, too, should its architectonic and ultrastructural features, including the degree of anisotropy. These and other structural characteristics should be quantified morphometrically, not using subjective scoring systems. Another drawback of scoring-system-based approaches is that they attempt to evaluate too many parameters, whereas ideally, three to maximally four pertinent ones should be evaluated. The impact of a repair strategy on the individual parameters can vary greatly (ranging from positive to negative), and yet, in the end, an average score for all is calculated. Hence, there is the danger that positive findings for some parameters will be “diluted” by negative effects on others, and, in extreme cases, that falsely-negative results will be generated; the reverse situation also holds true. Unfortunately, one cannot escape from the reality that scoring-systembased approaches are subjective and biased, since they attempt to describe the situation that appertains within the volume of a defect void from two-dimensional images of histological sections without respecting the laws of random sampling and stereology. And it is precisely these laws that a morphometric analysis does respect. The authors feel the necessity of dissuading investigators from implementing a scoring-system-based approach, which may not “go down well” with those who have used such regimes for many years. However, “a man should never be ashamed to own he has been wrong, which is but saying, in other words, that he is wiser today than he was yesterday” (Alexander Pope: [Miscellanies]). Investigators should not be daunted by the prospect of undertaking a morphometric analysis. Once the basic principles of the approach have been grasped (for a simple introduction to these, see Ref. 218), all that is needed for an objective and unbiased evaluation of a few pertinent parameters are correctly-sampled tissue-sections and an appropriate grid-system. The investigator's task is then a simple “counting” one; moreover, he or she is not burdened with the

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responsibility of “judgment”, which is the case when a scoring system is implemented. In addition to structural data, information appertaining to the post-translational metabolic status of the chondrocytes should be derived by monitoring the gene-expression levels of representative anabolic and catabolic markers. The conception of truly novel therapeutic approaches to cartilage repair is greatly encouraged. But all the ingenuity in the world will be as wind-blown chaff unless we make a stand against the quick-and-easy attitude that is now sadly enough the brand of modern times. Prospects for the future Current trends in the induction of cartilage repair seem to point towards a more tissue-engineering-based approach. The aim of tissue engineering is to develop methodologies whereby bodily defects can be repaired in such a manner as to restore the structure and the functional competence of the affected tissues. Tissues and organs that do not heal spontaneously are induced to repair by attempting to overcome the biological limitations that undermine this process in Nature. At the stage of its conception, a tissueengineering-based principle must be screened to ascertain the size of the patient population that will be targeted, its socioeconomic impact, the feasibility and likely cost of its manufacture, and its surgical practicability. Hence, tissue engineering is an interdisciplinary enterprise79. There exists no magical formula for the engineering of a product that would be universally applicable to all bodily tissues. An engineered construct must be tailor-made on a tissue-specific basis. To yield a product that will be beneficial to the targeted patient population, a tissue-engineering-based principle should be experimentally developed along systematic and, whenever possible, rational lines, and in the light of a thorough understanding of the biological system in hand. Conclusion We are still a long way from achieving our goal of cartilage regeneration. However, Nature affords the clues to this end if they are sought, and if we have the fortitude to pursue them rationally and systematically. Only by following such a course can we hope for ultimate success in the generation of an endurable, structurally and functionally competent type of cartilaginous repair tissue. Contributions Conception and design: EBH, KL, MK, NS. Analysis and interpretation of the data: EBH. Drafting of the article: EBH, KL, MK, NS. Critical revision of the article for important intellectual content: EBH. Final approval of the article: EBH, KL, MK, NS. Obtaining of funding: EBH. Administrative, technical, or logistic support: EBH. Collection and assembly of data: EBH. Competing interests The authors have no conflicts to declare. Acknowledgements The authors would like to thank Dr Yoshihiro Suzuki for his help €rg Ha €uselmann, Roland with the artwork, and are indebted to Hans Jo

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Jakob and Gunnar Knutsen for their valuable input respecting the critical analysis of clinical studies.

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An educational review of cartilage repair: precepts & practice--myths & misconceptions--progress & prospects.

The repair of cartilaginous lesions within synovial joints is still an unresolved and weighty clinical problem. Although research activity in this are...
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