The Journal of Bone and Joint Surgery (American) 85:45-57 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.
Histological Assessment of Cartilage Repair
A Report by the Histology Endpoint Committee of the International Cartilage Repair Society (ICRS)
Pierre Mainil-Varlet, MD, PhD,
Thomas Aigner, MD,
Mats Brittberg, MD, PhD,
Peter Bullough, MD,
Anthony Hollander, PhD,
Ernst Hunziker, MD,
Rita Kandel, PhD,
Stefan Nehrer, MD,
Kenneth Pritzker, MD,
Sally Roberts, PhD and
Edouard Stauffer, MD
Corresponding author: Pierre Mainil-Varlet, MD, PhD
Institute of Pathology, University of Bern, Murtenstrasse 31, CH- 3010 Bern, Switzerland. E-mail address: pierre.mainil{at}pathology.unibe.ch
In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from ICRS/SNF (4046-58623). None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
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Introduction
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Physical injury frequently causes tissue damage, including laceration. Repair of the damage usually results in the formation of a scar; complete anatomic healing and true regeneration are rare.
Connective tissues tend to heal naturally and successfully only if the injury is minor. If the damage is more severe, then a good functional result can be achieved only if Nature is assisted by surgical intervention. The efficacy of such measures has been established in the cases of bone and tendon injuries but not in the case of cartilage damage
1 . In the latter situation, we are still prejudiced by Hippocrates' opinion that "ulcerated cartilage is universally allowed to be a troublesome disease."
2 In addition, our view is necessarily colored by the scarcity of successful therapeutic modalities
3 .
Articular cartilage is a narrow layer of specialized connective tissue that permits smooth, frictionless movement of diarthrodial joints. It is comprised of a relatively small number of cells (chondrocytes) embedded in an abundant extracellular matrix
4 . The latter consists predominantly of type-II collagen, proteoglycans, and water, along with smaller amounts of other collagen types and noncollagenous proteins. Histologically, articular cartilage is divided into three zones, which are distinguished by the shape of the chondrocytes and the arrangement of type-II collagen fibers. The superficial zone is characterized by flattened disc-like chondrocytes, a low proteoglycan content, and densely-packed, horizontally-arranged collagen fibrils of uniform diameter. This layer has been described as a tension-resisting diaphragm
5 by virtue of its tendency to curl when the articular cartilage is released from the subchondral bone
6 . In the middle zone, chondrocytes attain a more rounded profile, proteoglycan content increases, and the collagen fibers decussate to provide an oblique transitional network between the superficial tangential zone and the deep radial zone. The deep radial zone is characterized by spheroid chondrocytes arranged in columns, a high proteoglycan content, and a radially-oriented collagen network
4 . A microscopically distinct line—the tidemark—separates the lower radial zone from the underlying zone of calcified cartilage; deep to the calcified cartilage lies the subchondral bone plate
7,8 .
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Operative Procedures
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Surgically-based attempts to induce cartilage repair are now being undertaken in many clinical centers around the world. Various techniques have been employed. Transplantation regimes include the grafting of autologous perichondrial
9 , synovial
10 , or mesenchymal
11 tissue; the implantation of autologous chondrocytes
12-14 ; and the grafting of autologous
15-17 or allegeneic
18-20 osteochondral tissue. Other strategies include lavage
21,22 , continuous passive motion
23 , chondral shaving
24 , spongialization
25 , subchondral drilling
26 , and microfracture
27 , which are implemented either alone or in combination with transplantation. The limited availability of donor chondrocytes has led to the use of alternative cell sources and of tissue-engineering techniques, in conjunction with which a variety of biomaterials have been employed to create chondrocyte-seeded or cell-free implants
28 .
Most of the methods have been tested in animal models at some stage of their development
29 , with the ultimate aim being to stimulate the production of an extracellular matrix that is capable of bearing load and fulfilling the various other functions of normal articular cartilage.
In histological studies, the morphological appearance of the repair tissue is likely to be predictive of its functionality and durability. Tissue morphology also can be assessed with several other imaging techniques, including magnetic resonance imaging (MRI)
30 , computerized tomography (CT)
31 , and optical computerized tomography (OCT)
32 . However, this information needs to be verified histologically.
In order to render histological observations more objective and, to some extent, quantitative, many scoring systems have been developed. However, most of these systems have been developed for animal studies, in which the whole joint is available for excision and examination. For the assessment of cartilage repair in human patients, the amount of material available for study is clearly limited. Most surgeons remove a tissue core that does not exceed 2 mm in diameter.
The recommendations for the histological scoring of biopsy specimens in this article reflect the consensus reached by participants of the ICRS workshop in 2002, which included pathologists, orthopaedic surgeons, rheumatologists, and basic scientists from around the world. Individual physicians will have to decide to what extent they wish to adhere to these recommendations and how they intend to adapt them to the social, economic, ethical, and medical realities of the population they serve.
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Terminology
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There are different types of cartilage, including hyaline cartilage, fibrocartilage, and elastic cartilage.
Hyaline cartilage (from
Hyalos [Greek], meaning glass, and
Cartilago [Latin], meaning gristle) is generally nonvascularized in adult organisms. In young persons, it is bluish-white and translucent. In older individuals, it is yellowish and opaque. Hyaline cartilage is firm, yet pliable. It deforms under pressure, but, on removal of the deforming pressure, it recovers its original shape; that is, it is resilient. In growing individuals, it provides the anlage for the osseous skeleton and is the means whereby bone elongates. In adults, it covers the articular ends of the long bones and is the supportive skeletal structure of the nose, trachea, and bronchial tree. The microscopist recognizes mature hyaline cartilage by the absence of blood vessels and nerves; by the abundant, usually inhomogeneous, extracellular matrix; and by the sparsity of rounded chondrocytes occupying well-defined lacunae.
Fibrocartilage contains a high proportion of type-I collagen. This forms itself into coarse fibers, which are usually patent in the light microscope (transmitted light). It is found in the semilunar cartilages, the annulus fibrosus, and at the sites of insertion of ligaments into bone.
Elastic cartilage contains a high proportion of elastin fibers and is found in the external part of the ear and the epiglottis.
In both fibrocartilage and elastic cartilage, the cells are rounded and appear to lie within lacunae, which gives them a superficial resemblance to the chondrocytes of hyaline cartilage. However, the mechanical functions of the fibrocartilage and elastic cartilage differ somewhat from those of the hyaline cartilage in that the former two are concerned mainly with resistance to tension whereas the latter is burdened with compression.
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Scoring Systems
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Early histopathological studies of articular cartilage focused on degenerative arthritic conditions. Formerly, osteoarthritis was believed to be a disease of "wear and tear"—that is, a disorder in which mechanical forces physically degraded the joint material independent of a biological response. However, similar to other tissues, the reaction of articular cartilage to injury follows a defined sequence of events involving an increase in water content, matrix degradation by endogenous enzymes, cell apoptosis, and necrosis, followed by disruption of the extracellular matrix and a loss of its constituents into the joint space, which triggers an inflammatory response in the synovium. Subsequently, repair takes place. This involves limited cell replication activities, increased synthesis of extracellular matrix, and a reorganization of the matrix by endogenous cells
33 .
The degree of osteoarthritis and the quality of cartilage repair procedures have been graded with use of various histological/histochemical systems, such as those proposed by Mankin et al.
34 and O'Driscoll et al.
35 as well as others who have proposed modifications of the latter system
36-41 . Unfortunately, they have not yielded reproducible data
42-44 . Moreover, in general, too many parameters were considered, rendering the systems impractical.
In 2001, the ICRS established a "Histological Endpoint Committee" with the aim of providing a standardized scoring system and a web-based morphological catalogue for assessing cartilage repair (www.cartila ge.org), which could be used also for the validation of other techniques, such as magnetic resonance imaging, mechanical testing, and biomarkers.
Following meetings held during 2002 in Bern and Toronto, the Committee recommended the establishment of a scoring system that (1) was applicable only to small biopsy specimens of repair tissue derived from humans (that is, 2-mm-diameter, full-depth cores); (2) was visual, with each parameter being scored against a series of example images ranked from low to high; (3) was modular and could be combined with additional scoring systems developed at a later date for animal models in which whole joints would be available for assessment; (4) was "fluid," at least initially, being subject to periodic reappraisal in light of input not only from committee members but also from other members of the ICRS or nonmembers investigating cartilage repair.
The ICRS will take the responsibility for setting up a web-based catalogue of cartilage repair images (www.cartilage.org/histology). Initially, these images will be the samples upon which the scoring system is based (vide infra). It is hoped that the collection of images will be added to by researchers visiting the site and employing the visual scale. The database is therefore expandable, and the more it is expanded, the more useful it should become. It will provide an objective foundation for evaluating the results of various repair procedures.
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The ICRS Visual Histological Score
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In the opinion of the ICRS Committee, histological comparisons are easier to make and more reliable if they are based on a system of visual patterns rather than on verbal descriptions. Previous visual scales that have been used for the evaluation of other organ systems have proved to be very reliable, with only small intraobserver variance. Furthermore, such a system is useful for individuals with different levels of experience and, as such, the analysis of repair tissue need not be performed exclusively by so-called experts. With use of the visual scale, the observer attempts to evaluate one feature at a time, with the most prevalent feature on each specimen being matched to a graded panel of images that it resembles most closely. The highest score (3) is applied to the ideal repair result (i.e., truly regenerated tissue), whereas the lowest score (0) is applied to the poorest repair result (
Figs. 1-A ,
1-B ,
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2-D ,
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4-C ,
5-A ,
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6-A , and
6-B ).
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Fig. 2-A: Hyaline cartilage. The matrix shows a typical hyaline aspect with cells organized in columns. Under polarized light, collagen fibers in the matrix exhibit a typical configuration (not shown here) (objective, x5).
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Fig. 2-B: Mixture of hyaline and fibrocartilage. In this case, the transition between the two is abrupt and one can recognize a tear at the nterface of both tissues (objective, x10).
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Fig. 3-D: Disorganized distribution of individual chondrocytes within their matrix. The cells are small and slightly elongated (objective, x10).
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Fig. 4-B: Mixed population of viable, necrotic, and apoptotic cells. Some cells exhibit a normal morphology, some cells present pyknotic nuclei, and in some cases no nuclei can be recog-nized. (The absence of a nucleus should be confirmed on serial cuts) (objective, x20).
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The order in which the criteria appear in
Table I does not reflect their relative importance. Indeed, at the present time, their relative importance is not known. Hence, the scores should not be summed. The six criteria are listed below.
(I) Surface. A smooth, slippery surface is an essential feature of the normal joint.
(II) Matrix. The unique combination of collagen and proteoglycans in hyaline cartilage provides the correct viscoelastic properties for the articular surface.
(III) Cell distribution. A columnar distribution of cells in the middle and lower zone of the cartilage layer indicates normal maturation, whereas a disruption of this alignment indicates abnormal maturation.
(IV) Cell population viability. A viable cell population is essential for matrix turnover.
(V) Subchondral bone. The subchondral bone determines the geometry of the joint and therefore the pattern of its loading.
(VI) Mineralization. Mineralization within the cartilage layer is a pathological phenomenon and is indicative of functional impairment.
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Biopsy Technique
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In the clinical evaluation of cartilage defect repair therapies, biopsy specimens become available for various reasons. In most cases, they are sent for histopathological examination because of graft failure. In other instances, tissue is excised primarily so that its morphological characteristics can be determined and then correlated with mechanical indentation measurements, MRI findings, or clinical outcome.
At the first meeting of the ICRS Histological Endpoint Committee, approximately 100 biopsy specimens were examined. In a large number (approximately 55%) of the samples submitted to the Committee, it was not possible to assess the quality of the tissue because the biopsy techniques had not been satisfactory and the biopsy material did not include the entire defect depth. Frequently encountered problems included acquisition of an incomplete sample and fragmentation of the sample.
Given the high incidence of inadequate biopsies, the committee recommends that biopsy specimens not be considered for assessment unless (1) their orientation is clear (i.e., the surface is identifiable) and (2) they are complete (i.e., they include the calcified cartilage layer and the underlying subchondral bone plate).
It is recommended that biopsy specimens be obtained with use of disposable instruments, which would enhance the ability to obtain reproducible dimensions by preserving sharp edges for subchondral bone cutting.
The biopsy specimen should be taken from the center of the original defect, and the instrument should be held perpendicular to the joint surface.
Communication Between the Orthopaedic Surgeon and the Pathologist
A full and accurate clinicopathological correlation is feasible only if the pathologist is furnished with accurate information regarding the biopsy location, treatment modalities, follow-up time, and relevant arthroscopic and clinical findings. The arthroscopic information should include a brief narrative and a diagram indicating the position of the focal lesions and of any abnormal-appearing areas. Arthroscopic images are particularly helpful and important for verifying the biopsy site. Other pertinent aspects gleaned from the patient's medical history should also be included.
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Fixation and Staining
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Investigators should be aware of the problem of preserving proteoglycans when using aldehyde-based fixation protocols
45 . Principally, all aqueous chemical fixation methodologies employing aldehydes (formaldehyde, glutaraldehyde, paraformaldehyde, etc.) are associated with a high loss of proteoglycans, in the range of 15%
46-48 . The same holds true for alcohol and acetone-based fixation protocols. In these latter two cases, cell morphology is also very poorly preserved
49 . It should also be borne in mind that proteoglycan extraction is grossly exacerbated during demineralization, with a total loss of approximately 70% being incurred
50 . With a view toward reducing proteoglycan loss, some authors have proposed adding safranin O to the fixative solution or employing a mixture of formalin and cetylpyridinium chloride or cetrimide
51 . In order to facilitate comparisons of biopsy material collected at various centers, the ICRS Histological Endpoint Committee believes that it is important to standardize the fixation and staining techniques and to keep them as simple as possible. It is recommended that buffered formalin be used for fixation and that samples be routinely stained with hematoxylin and eosin (as is usually the case).
Special stains should include one specific for proteoglycans and another for collagens (probably in conjunction with visualization under polarized-light conditions). Rosenberg found that the cationic dye safranin O binds stoichiometrically to polyanions, with one dye molecule per negatively-charged group on either chondroitin 6-sulphate or keratan sulphate
52 . In permanently mounted histological sections, safranin O binds to polyanions as an orthochromatic dye but without the development of metachromasia. Because of these properties, the staining intensity should correlate positively with the fixed-charge density in the cartilage matrix. This has rendered possible a semiquantitative estimation of glycosaminoglycans in histological sections with microspectrometry and computerized image analysis
53,54 . The quantification of proteoglycans with use of safranin O requires a reproducible system, as suggested by Hyllested et al. in their detailed review of histochemical analyses of the extracellular matrix of human cartilage
55 .
Toluidine blue is also used as a proteoglycan stain in many laboratories, although its stoichiometric relationship is probably inferior to that of safranin O. Alcian blue is also frequently employed, but its staining pattern varies with pH and the concentration of the salt in the dye. Hence, the result is somewhat unpredictable. The ICRS Histological Endpoint Committee does not wish to recommend a particular proteoglycan stain as there is no clear evidence in the literature as to which is the optimal choice. Collagens can be stained with either Masson trichrome, Mallory trichrome, or Sirius red. It is important to observe the stained sections under polarized light, which renders visible the orientation of the collagen fibers. This is also one of the easiest ways of distinguishing between hyaline cartilage and fibrocartilage and of revealing whether repair tissue is continuous with the subchondral bone.
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Discussion
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Despite some advances in our understanding of the etiology, pathogenesis, and repair of cartilage injuries, the terminology and reporting practices have largely failed to keep pace and may have become a source of confusion. The recent advent of the term "hyaline-like" is one such source of confusion. The real value of a histopathological grading system for cartilage repair lies in its capacity to differentiate between normal articular cartilage and different types of repair tissue across a broad spectrum, from minimally to completely unstructured tissue. It should also permit histological criteria and other morphological modalities, such as MRI, to be correlated with biomechanical data or with the clinical outcome, for we still do not know whether the native ultrastructure of cartilage tissue really needs to be restored for a good, durable clinical result.
A number of monoclonal antibodies against specific epitopes of cartilage collagens, noncollagenous proteins, and proteoglycans are now available. Hence, immunohistochemical staining should further advance our understanding and interpretative skills. At the present time, the Committee does not recommend the use of any specific antibodies. This topic will be addressed in future meetings, after more basic difficulties have been ironed out. Other methods currently being investigated, such as RNA microarrays, also may ultimately be incorporated into the assessment
56 .
Observations pertaining to type-X collagen should also be considered. Type-X collagen was first isolated from hypertrophic chondrocytes of the epiphyseal plate and was believed to play a pivotal role in the subsequent mineralization of the matrix. More recently, however, it has been found also in normal articular cartilage and in the intervertebral disc. It is considered to be a marker for the chondrocytic change to a hypertrophic state. The presence of type-X collagen in biopsy samples of repair tissue could indicate that endochondral ossification is underway, which might improve the integration of newly-formed articular cartilage with the subchondral bone; alternatively, it may be indicative of cartilage remodelling
57,58 .
Ultimately, we hope to see pathological reports that include information regarding the absence or presence of as many typical cartilage components as possible. But we must also learn from past experience with osteoarthritis scoring systems, which failed in terms of utility because of the inclusion of too many parameters.
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What Lies Ahead?
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What is the use of classification systems? Thus far, they have proved to be of little quantitative value. Notwithstanding this discouraging circumstance, we believe that if the basic sampling and processing criteria necessary for valid comparisons are simplified, unified, and religiously satisfied, then such a classification system for cartilage repair could yield invaluable biological and clinical information. We now need to put the proposed ICRS Visual Scale to the test.
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Introduction
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