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Spontaneous Repair of FullThickness Defects of Articular
Cartilage in a Goat Model
A PRELIMINARY STUDY
BY DOUGLAS W. JACKSON, MD, PEGGY A. LALOR, PHD,
HAROLD M. ABERMAN, DVM, AND TIMOTHY M. SIMON, PHD
Investigation performed at the Orthopaedic Research Institute,
Southern California Center for Sports Medicine, Long Beach, California
Background: Full-thickness defects measuring 3 mm in diameter have been commonly used in studies of rabbits
to evaluate new procedures designed to improve the quality of articular cartilage repair. These defects initially
heal spontaneously. However, little information is available on the characteristics of repair of larger defects. The
objective of the present study was to define the characteristics of repair of 6-mm full-thickness osteochondral
defects in the adult Spanish goat.
Methods: Full-thickness osteochondral defects measuring 6 × 6 mm were created in the medial femoral condyle
of the knee joint of adult female Spanish goats. The untreated defects were allowed to heal spontaneously. The
knee joints were removed, and the defects were examined at ten time-intervals, ranging from time zero (immediately after creation of the defect) to one year postoperatively. The defects were examined grossly, microradiographically, histologically, and with magnetic resonance imaging and computed tomography.
Results: The 6-mm osteochondral defects did not heal. Moreover, heretofore undescribed progressive, deleterious changes occurred in the osseous walls of the defect and the articular cartilage surrounding the defect. These
changes resulted in a progressive increase in the size of the defect, the formation of a large cavitary lesion, and
the collapse of both the surrounding subchondral bone and the articular cartilage into the periphery of the defect.
Resorption of the osseous walls of the defect was first noted by one week, and it was associated with extensive
osteoclastic activity in the trabecular bone of the walls of the defect. Flattening and deformation of the articular
cartilage at the edges of the defect was also observed at this time. By twelve weeks, bone resorption had transformed the surgically created defect into a larger cavitary lesion, and the articular cartilage and subchondral bone
surrounding the defect had collapsed into the periphery of the defect. By twenty-six weeks, bone resorption had
ceased and the osseous walls of the lesion had become sclerotic. The cavitary lesion did not become filled in
with fibrocartilage. Instead, a cystic lesion was found in the center of most of the cavitary lesions. Only a thin
layer of fibrocartilage was present on the sclerotic osseous walls of the defect. Specimens examined at one year
postoperatively showed similar characteristics.
Conclusions: Full-thickness osteochondral defects, measuring 6 mm in both diameter and depth, that are created
in the medial femoral condyle of the knee joint of adult Spanish goats do not heal spontaneously. Instead, they
undergo progressive changes resulting in resorption of the osseous walls of the defect, the formation of a large
cavitary lesion, and the collapse of the surrounding articular cartilage and subchondral bone.
Clinical Relevance: As surgeons apply new reparative procedures to larger areas of full-thickness articular cartilage loss, we believe that it is important to consider the potential deleterious effects of a “zone of influence” secondary to the creation of a large defect in the subchondral bone. When biologic and synthetic matrices with or
without cells or bioactive factors are placed into surgically created osseous defects, the osseous walls serve as
shoulders to protect and stabilize the preliminary repair process. It is important to protect the repair process until
biologic incorporation occurs and the chondrogenic switch turns the cells on to synthesize an articular-cartilagelike matrix. It takes a varying period of time to fill a large, surgically created bone defect underlying a chondral surface. The repair of such a defect requires bone synthesis and the reestablishment of a subchondral plate with a
tidemark transition to the new overlying articular surface. The prevention of secondary changes in the surrounding
bone and articular cartilage and the durability of the new reparative tissue making up the articulating surface are
issues that must be addressed in future studies.
COPYRIGHT © 2001
BY
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S
urgically created full-thickness articular cartilage defects have been studied in a variety of animal models to
evaluate the effect of new procedures designed to elicit
articular cartilage repair1-8. Although these surgically created
defects differ from the defects that occur in human patients
following trauma and/or cartilage degeneration9,10, they have
been used to study techniques and methodologies that might
eventually be used in humans. In large osteochondral defects
in animal models, both the cartilage and the bone surrounding the defect undergo immediate changes and have different
reparative responses depending on the size, shape, location,
and depth of the lesion11 as well as on the animal model being
used. In the rabbit, 3-mm defects initially heal spontaneously
with repair tissue composed of hyaline or fibrocartilage8. The
spontaneous repair of larger defects has not been systematically studied in a rabbit model, to our knowledge. In the goat,
a 3-mm defect in the femoral groove (which is relatively small
compared with the size of the joint) also undergoes repair
initially2. Moreover, lesions in the femoral groove tend to heal
better than those in the rigorous loading environment of the
femoral condyle. The repair of larger defects, especially those
in the medial femoral condyle, has not been studied in a goat
model, to our knowledge. New procedures designed to elicit
articular cartilage repair must be analyzed, and the results
must be compared with the spontaneous changes that occur
in untreated defects of the same size. The untreated defects
used for comparison must also be site-matched for the specific location under examination. It is essential to be certain
that a new methodology enhances repair or prevents the deleterious effects of a similar untreated lesion, and this approach
requires long-term controls.
The goat model has been used to evaluate different techniques designed to elicit articular cartilage repair2,5. The purpose of the present study was to characterize the sequential
changes that occurred within and around a large full-thickness
defect that was created in the weight-bearing region of the
medial femoral condyle of the goat.
Materials and Methods
full-thickness defect, 6 mm in both diameter and depth,
was created in the middle one-third of the medial femoral condyle of the right knee (stifle) joint of twenty-four adult
female Spanish goats with use of a specially designed instrument. The center of the defect was in the middle portion of
the medial femoral condyle. The articular cartilage in this region is approximately 2 mm thick, and the defect penetrated
into and resulted in the removal of approximately 4 mm of
the underlying subchondral bone.
The defect was created unilaterally in eighteen goats and
bilaterally in six goats. The untreated defects were allowed to
heal spontaneously. The goats were killed humanely, the joints
were removed, and the defects were examined at time zero (immediately postoperatively); at fifteen and thirty minutes; at
two days; and at one, two, six, twelve, twenty-six, and fifty-two
weeks. The six goats that were killed within two days postoperatively constituted the short-term group, and the eighteen goats
that were killed one to fifty-two weeks postoperatively constituted the long-term group (Table I). The study protocol was
reviewed and approved by the Institutional Animal Care and
Use Committee, and all of the animals received humane care
in compliance with the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health.
Changes in the adjacent surrounding cartilage, the characteristics of the repair tissue that formed in the defect, and
changes in the subchondral bone underlying and adjacent to
the defect were observed and recorded. The contralateral joint
in the eighteen animals in the long-term group served as controls. Immediately after the animals were killed, both stifle
joints (except those undergoing magnetic resonance imaging
and computerized axial tomography) were opened, grossly
evaluated, disarticulated, and fixed in neutral buffered formalin and then in ethanol. The specimens were cut into 2-mm
slabs in the coronal plane, through the center of the defect.
Each slab was placed onto autoradiographic film (X-OMAT
AR; Eastman Kodak, Rochester, New York) and into an x-ray
A
TABLE I Data on the Evaluation of Twenty-four Goats with Full-Thickness Cartilage Defects
Evaluation†
Time-Point*
Short-term group
0 and 2 days
15 and 30 mins
Long-term group
1 wk
2 wks
6 wks
12 wks
26 wks
52 wks
No. of
Goats
No. of
Defects
Histologic
Sections
Microradiography
MRI
CT
3
3
6
6
6
6
6
6
0
0
0
0
3
3
3
3
2
4
3
3
3
3
2
4
3
3
3
3
2
4
3
3
3
3
2
4
0
0
0
0
0
2
0
0
0
0
0
3
*The defect was created bilaterally in the six goats in the short-term group. In three goats, the defect was created in the left knee at time
zero and in the right knee at two days. In the remaining three goats, the defect was created in the right knee at fifteen minutes and in the
left knee at thirty minutes. The defect was created unilaterally in the eighteen goats in the long-term group. †The values are expressed as
the number of defects. MRI = magnetic resonance imaging, and CT = computerized axial tomography.
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Fig. 1
Gross appearance of the articular cartilage defect in the medial femoral condyle at selected time-intervals after creation of the defect. A: Time zero
(immediately after creation of the lesion). B: One week. C: Two weeks. D: Six weeks. E: Twenty-six weeks. F: Fifty-two weeks.
machine (Faxitron; Hewlett Packard, Wheeling, Illinois) set to
a 20-kV peak. Following a fifteen-second exposure, the film
was developed with an x-ray film processor (Mini Medical series; AFP Imaging, Elmsford, New York). The samples were
decalcified and then were embedded in paraffin. Serial sections were cut and were stained with hematoxylin and eosin
for routine histologic evaluation. Additional sections were
stained with safranin O for evaluation of changes in the glycosaminoglycan content of the cartilage matrix.
Magnetic Resonance Imaging
Two knees that had a defect and two control knees were evaluated with magnetic resonance imaging in addition to histologic analysis at one year. The knees were removed 8 cm
proximal and distal to the joint line immediately after the
animals were killed. The knees were wrapped in a moistureproof plastic bag, extended, immersed in a saline bath, and
placed in a standard knee-imaging coil. Magnetic resonance
imaging scans were made on a high-resolution, 1.5-tesla
scanner (Magnetom Vision; Siemens, Iselin, New Jersey). The
standard examination consisted of contiguous 3-mm images
in the coronal and sagittal planes. A turbo spin-echo sequence
with a pulse-repetition time of 4100 to 4700 ms and an effective echo-delay time of 19 to 93 ms was used. An 18-cm field
of view and a 256-by-256 matrix were used, resulting in a
pixel size of 0.7 × 0.7 mm.
Computerized Axial Tomography
Three specimens were evaluated with computerized axial tomography at one year. The specimens were prepared for analysis in a manner similar to that used for the knees that were
evaluated with magnetic resonance imaging. One-millimeterthick images of each medial femoral condyle were then made
in the coronal plane with use of a computerized axial tomography scanner (Somatom Plus 4; Siemens).
Overlay Studies
At time zero and at one year, the medial profile of the medial
femoral condyle of knees with a defect and control knees was
captured with use of image-analysis software (Cue-2; Olympus, La Palma, California). All images were made with the
camera at the same calibration settings and magnification.
The images were converted to binary black-and-white images
that were then analyzed for curvature in order to determine
whether the creation of the defect caused any change in the
contour of the medial femoral condyle. For specimens that
were evaluated at time zero, the profile of the normal condyle
was captured, the condyle was drilled to create the defect, the
profile of the same condyle was captured again, and the resulting image was overlaid onto the first image. For the specimens
that were evaluated at one year, the profile of the contralateral
condyle was captured, mirrored, and overlaid onto the profile
of the condyle with the lesion.
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Results
he gross appearance of the lesions
demonstrated consistent and reproducible changes over time (Fig. 1, A
through F). Immediately after the fullthickness defect was created (time zero),
the edges of the cartilage defect were
sharply defined. Within fifteen minutes
the adjacent cartilage matrix began to
flow over the rim of the defect, and it
remained in that position at all of the
subsequent time-periods. The adjacent
articular cartilage surface demonstrated
a gradual flattening surrounding the le-
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sion in an associated “zone of influence”
(Figs. 1 and 2). The zone of influence
expanded over time. The defects were
empty at time zero, but within fortyeight hours a blood clot had filled the
defects to within 2 mm of the surface.
The clot was attached to the rim of the
cartilage defect, with a concavity toward
the center. By twelve weeks, fibrillation
of the articular cartilage adjacent to the
defect and fraying of the inner rim of
the medial meniscus were observed. By
twenty-six weeks, repair tissue still had
not totally filled the defect and the sur-
Fig. 2
Microradiographic appearance of coronal sections of the lesion at selected time-intervals after
creation of the defect. A: Time zero (immediately after creation of the lesion). B: Thirty minutes.
C: Two days (note the blood clot filling the defect). D: Two weeks. E: Six weeks (note the widening
of the defect wall). F: Fifty-two weeks (note the marked change in the geometry of the lesion compared with the geometry in A).
face remained concave (Fig. 1, E). The
articular cartilage surrounding the lesion had collapsed into the upper part of
the defect (Fig. 1, E). By fifty-two weeks,
the original defect opening had narrowed in three of the four animals, leaving a central 2 to 3-mm gap separating
the edges of the cartilage surrounding
the previously created defect (Figs. 1, F
and 2, F). In one of the animals evaluated at fifty-two weeks, there was no
central gap and the defect was occupied
by tissue containing deep clefts that appeared to have originated from collapsed surrounding cartilage.
Histologic sections also demonstrated progressive changes in the cartilage and bone surrounding the defect
as well as within the repair tissue filling
the defect (Figs. 3 through 6). A summary of the histologic changes is given
in Table II. At time zero, histologic sections demonstrated a well-defined defect
involving articular cartilage and subchondral bone. By thirty minutes, there
was deformation of cartilage into the
peripheral rim of the defect. However,
no changes in the bone surrounding
the defect were observed. Approximately 20% of the defect was filled
with tissue composed of fibrin, red
blood cells, and occasional neutrophils.
Within forty-eight hours, chondrocyte clusters were present in the
cartilage along the margins of the defect, particularly in areas where the
cartilage matrix protruded into the
defect. More neutrophils were seen in
the tissue filling in the defect as well as
in the surrounding bone. This tissue
demonstrated a fibrinoid upper layer
that was attached to the edges of the
articular cartilage defect and had a
concave surface (Fig. 3, A).
By one week, extensive osteoclastic activity was observed in the trabecular bone and osteogenesis was noted at
the base and in the walls of the defect.
Chondrocyte cloning was more extensive in the articular cartilage edges of all
of the defects, and it continued to be a
prominent feature at later time-points.
The concave surface layer of the tissue
in the defect contained fibroblast-like
cells and collagen fibers oriented parallel to the surface. Safranin-O staining
showed a loss of proteoglycans in the
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TABLE II Summary of Observations in the Subchondral Bone, Repair Tissue, and Surrounding
Artcular Cartilage at Each Time-Point
Observations
Time-Point*
No. of
Defects
Subchondral
Bone
Repair
Tissue
Surrounding
Articular Cartilage
Short-term group
0 mins
3
Lesion creation, fresh cut
bone edges
No visible change in bone
No visible change in bone
Bleeding in defect
Lesion creation, welldefined sharp edges
Deformation into defect
Deformation into defect
15 mins
30 mins
3
3
2 days
3
Increase in cellularity and
red blood cells in marrow
1 wk
3
Bone resorption and
formation in walls and
base of defect
2 wks
3
6 wks
3
Resorption of walls of defect,
endochondral bone formation at base and walls of
lesion
Sparse osteoclastic activity
except in subchondral
area at lesion edges,
sparse endochondral bone
formation
12 wks
3
Structural collapse of lesion
walls; endochondral bone
formation under cartilage,
walls, and base
26 wks
2
Defect walls extending farther
outward due to structural
collapse, sclerotic thickening,
endochondral bone formation
at periphery of lesion and
subchondral area
52 wks
4
Sclerotic thickening, narrowing
(3 goats) and closure (1 goat)
of lesion aperture, vascular
subchondral bone plate,
osteophytes, sparse bone
resorption, endochondral bone
formation at periphery of
lesion and subchondral area
Bleeding in defect
Fibrin strands, red blood
cell clot, and sparse
polymorphonuclear
neutrophils
Fibrin strands at surface
attached to cartilage
edges, central area
containing fibrin-rich
blood clot and more
polymorphonuclear
neutrophils
Deformation into defect
Long-term group
Concave upper layer
containing fibroblast-like
cells and collagen fibers,
central area containing
fibrin-rich material
Concave upper layer similar
to that at 1 wk, central
area containing loose
fibrous repair tissue
Concave fibrous upper layer
integrated with cartilage
edge, collagen-fiber repair
tissue oriented perpendicular to surface layer
Concave fibrous upper layer,
periphery of lesion demonstrating transition of fibrocartilage to vascular tissue
with small central void
Concave fibrous upper layer
contiguous with adjacent
surrounding cartilage,
fibrocartilage at base,
transition to fibrous tissue
with central cyst, focal
safranin-O staining at
periphery and base of lesion
Thin fibrous upper layer
contiguous with cartilage
edge, periphery demonstrating transition of fibrocartilage to disorganized
fibrous tissue with central
cyst, focal safranin-O
staining at periphery and
base of lesion
Deformation into defect,
chondrocyte clusters at
cut edge
Deformation of upper edges
into defect, increased
chondrocyte clusters at
cut edge
Deformation, flattening,
chondrocyte clusters,
cartilage edges being
undermined by multinucleated giant cells in
repair tissue
Fibrillation, clefts, flattening,
chondrocytes (single and
clusters) present in edges
Fibrillation, condylar flattening, chondrocytes
(single and clusters),
narrowing of aperture,
safranin-O staining of
cartilage to edge of lesion
except superficial layer
Fibrillation, flattening of
newly formed repair
cartilage and integration
with old cartilage but with
irregular surface, tidemark
not reestablished, narrowing
of aperture, safranin-O
staining of cartilage to edge
of lesion
*The defect was created bilaterally in the six goats in the short-term group. In three goats, the defect was created in the left knee at time
zero and in the right knee at two days. In the remaining three goats, the defect was created in the right knee at fifteen minutes and in the
left knee at thirty minutes. The defect was created unilaterally in the eighteen goats in the long-term group.
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articular cartilage adjacent to the periphery of the defect.
By two weeks, osteoblastic bone formation was observed
at the edges and base of the defect and was occasionally seen in
the calcified cartilage zone at the edges of the defect. In addition, foci of endochondral bone formation could be seen at
the base of the defect. Further collapse of the edges of the articular cartilage into the defect was noted (Fig. 3, B).
By six weeks, the edges of the cartilage and subchondral
bone adjacent to the defect were being undermined by multinucleated giant cells that were present in the tissue filling the
defect (Fig. 3, C). Sparse osteoclasts were seen and little bone
Fig. 3
VO L U M E 83-A · N U M B E R 1 · J A N U A R Y 2001
formation was observed in the surrounding bone. The fibrous
tissue layer at the surface was still present. The cells and collagen fibers within the defect were oriented perpendicular to
the fibrous tissue along the surface.
By twelve weeks, structural collapse of the subchondral
bone adjacent to the defect was noted (Fig. 3, D). Endochondral
bone formation was noted beneath this cartilage-like material.
Beneath the concave surface of the repair tissue, fibrocartilage
was present at the periphery of the defect and vascular fibrous
tissue was present within the center of the defect.
By twenty-six weeks, the osseous walls of the defect had
Histologic sections at selected time-intervals after
creation of the defect. A: Low-magnification view at
two days, showing that a blood clot has nearly filled
the defect (hematoxylin and eosin, ×1). B: Lowmagnification view at two weeks, showing boneremodeling in the walls of the lesion and a dense
cellular connective tissue lining the walls and penetrating into the marrow space (hematoxylin and
eosin, ×1). C: Low-magnification view at six weeks,
showing a defect nearly filled with repair tissue and
a small, central cyst-like structure. The repair tissue
forms a concave surface that is integrated with the
articular cartilage edges (hematoxylin and eosin, ×1).
D: Low-magnification view at twelve weeks, showing
a defect containing repair tissue and a large, central
cyst. The bone comprising the walls of the defect
has been resorbed. In this specimen, fibrillation and
clefts developed in the articular cartilage adjacent
to the lesion (hematoxylin and eosin, ×1). E: Lowmagnification view at twenty-six weeks, showing an
increase in the size of the defect due to resorption
of the bone in the sides and base of the defect. The
walls of the defect have become sclerotic. A cyst
containing loose fibrous tissue is present in the central portion of the lesion. This tissue appears to be
integrated with the surrounding cartilage. The aperture of the lesion is narrowing as the surrounding
articular cartilage and bone collapse into the lesion
(hematoxylin and eosin, ×1). F: View of the same
area depicted in E, showing the extent of safranin-O
staining. Note the focal areas of uptake around the
periphery of the lesion (safranin O-fast green, ×1).
G: Low-magnification view of another defect at
twenty-six weeks, showing extensive resorption of
bone surrounding the defect. A central cyst contains
loose fibrous repair tissue that appears to be integrated with the surrounding cartilage. The aperture
of the lesion is narrowing as the surrounding articular cartilage extends into the lesion (hematoxylin
and eosin, ×1). H: View of the same area depicted in
G, showing the extent of safranin-O staining. Note
the lack of focal areas of uptake around the periphery of the lesion (safranin O-fast green, ×1).
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further extended outward because of bone resorption and continued structural collapse (Fig. 3, E through H). The walls were
buttressed by a thickened shell of bone that was undergoing
active bone formation (Fig. 3, E and G). Endochondral bone
formation was seen in the base of the defect. The defect was
filled with fibrocartilage, fibrous tissue, and a central cyst. The
tissue filling the defect was still covered by a concave fibrous
tissue layer that was contiguous with the surrounding cartilage.
By fifty-two weeks, the initial cylindrical geometry of
Fig. 4
VO L U M E 83-A · N U M B E R 1 · J A N U A R Y 2001
the defect had changed and was characterized by outwardly
extending walls, collapse, and osteophyte formation (Fig. 4,
A through L). The repair tissue in the lesion was fibrocartilaginous at the periphery. However, most of the defect
contained disorganized fibrous tissue surrounding a central
cyst. Safranin-O staining demonstrated small amounts of
proteoglycan at the bone-fibrocartilage interface (Fig. 4, D,
E, F, J, K, and L). The persistent layer of fibrous repair tissue
at the surface was much thinner but was still contiguous
Histologic sections at fifty-two weeks after creation of the
defect. A through F are from one goat, and G through L
are from another goat.
A: Low-magnification view showing the large increase in
the size of the defect resulting from resorption and collapse of the bone in the walls and base of the defect.
Sclerotic bone surrounds the lesion. Repair tissue in the
cyst is mostly disorganized, with some fibrocartilage
forming at the base and lower walls of the lesion. The
aperture of the defect has narrowed greatly (hematoxylin
and eosin, ×1). B: Higher-magnification view showing the
upper edge of the lesion with sclerotic subchondral bone
and a thin band of repair tissue integrated with the cartilage edge (hematoxylin and eosin, ×10). C: Highermagnification view showing the base of the lesion and
the wall with fibrocartilaginous matrix repair tissue. The
sclerotic bone has vascular elements adjacent to the
repair tissue (hematoxylin and eosin, ×10). D: View of the
same area depicted in A, showing uptake of safranin O in
the original articular cartilage, surrounding articular cartilage, and fibrocartilaginous matrix repair tissue at the
periphery of the lesion (safranin O-fast green, ×1). E: View
of the same area depicted in B, showing uptake of safranin O (safranin O-fast green, ×10). F: View of the same
area depicted in C, showing uptake of safranin O
(safranin O-fast green, ×10).
G: Low-magnification view of another defect at fifty-two
weeks, showing extensive remodeling. The aperture of
the lesion is quite narrow compared with the 6-mm
aperture of the original lesion (hematoxylin and eosin,
×1). H: Higher-magnification view showing the upper edge
of the lesion, with sclerotic bone surrounding the defect
and very little repair tissue attached to the cartilage surface (hematoxylin and eosin, ×10). I: Higher-magnification
view showing the interface of the base of the lesion with
the fibrocartilaginous matrix repair tissue (hematoxylin
and eosin, ×10). J: View of the same area depicted in G,
showing uptake of safranin O in the original articular
cartilage and the fibrocartilaginous matrix repair tissue
at the periphery of the lesion (safranin O-fast green, ×1).
K: View of the same area depicted in H, showing uptake
of safranin O (safranin O-fast green, ×10). L: View of the
same area depicted in I, showing uptake of safranin O
(safranin O-fast green, ×10).
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Fig. 5
Histologic sections demonstrating common features observed at fifty-two weeks after creation of the defect. A: This section shows increased vascularity in the subchondral bone under the normal articular cartilage close to the lesion (hematoxylin and eosin, ×50). B: In this section, the repair
tissue filling the cyst consists of loose, disorganized fibrous tissue with sparse cellularity (hematoxylin and eosin, ×50). C: In this section, a
tartrate-resistant acid phosphatase staining shows osteoclastic activity (dark-staining cells [arrows]) in the bone at the base of the lesion (×50).
D: This section shows active osteoblastic bone formation on the wall and base of the lesion (hematoxylin and eosin, ×50). E: This section shows
the interface (arrows) between the native articular cartilage and the newly formed repair articular cartilage. The original tidemark is still evident but
is absent from the area where the lesion was created. In this specimen, the newly formed articular cartilage is thinner than the original cartilage
(hematoxylin and eosin, ×50). F: This section of a different specimen also demonstrates the interface (arrow) between the original articular cartilage and the newly formed repair articular cartilage. The original tidemark is still evident but is absent from the area where the lesion was created
(hematoxylin and eosin, ×50).
with the cartilage edges, and it followed the contour of the
lesion walls more closely. The surrounding articular cartilage showed degenerative changes consisting of fibrillation,
cleft formation, and condylar flattening. The original 6mm-diameter aperture of the lesion had narrowed to 2-3
mm in three goats and was entirely closed over in one goat.
Safranin-O staining was evident up to the edge of the articular cartilage but was absent in the most superficial layer
(Fig. 4, E and K). Sclerotic bone surrounded the lesion and
adjacent subchondral areas. Sparse bone resorption was observed at the base of the lesion. Features common to all of
the specimens examined at one year are shown in Figure 5.
These features included a vascular subchondral bone-cartilage
interface near the edge of the lesion; disorganized fibrous
repair tissue filling the lesion; sparse osteoclastic activity at
the base of the lesion; marked endochondral bone formation; repair articular cartilage closely apposed to, but not
always well integrated with, the native cartilage edge; and a
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Fig. 6
Gross appearance, serial microradiographs, and histologic sections of three specimens at fifty-two weeks after creation of the defect. A, D, G, and J
are from one goat; B, E, H, and K are from a second goat; and C, F, I, and L are from a third goat. D, E, and F are 1-mm sections taken 2 mm from
the center of the lesion. G, H, and I are 1-mm sections taken from the center of the lesion. J, K, and L are safranin-O-stained histologic sections
from a 1-mm wafer taken from the center of the lesion. A, B, and C show the gross appearance of the lesions at the time of evaluation. Note the
variation among the animals in the size of the apertures of the lesions, which ranged from fully closed to 2 to 3 mm in diameter. D through I demonstrate the bone-remodeling changes and the development of the central cyst; these were consistent findings, although some variation among animals was observed. J, K, and L show consistent uptake of safranin O by the articular cartilage but with varying intensity in the repair tissue lining
the lesion. The central cyst was consistently filled with repair tissue.
poorly formed tidemark (Fig. 5, E and F). The surrounding
articular cartilage had irregular surfaces, varied in thickness, and showed signs of degeneration, with fibrillation
and clefts. The one-year evaluations showed variations and
similarities in the reparative response among different ani-
mals (Fig. 6, A through L). On gross examination, the
aperture of the lesion still appeared open, with a 1 to 3-mm diameter, or was completely closed by repair tissue. Serial microradiographs demonstrated large central cavitary lesions,
but the size and morphology (geometry) of the cavitary
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Fig. 7
Magnetic resonance images (A, B, and C) and a computerized axial tomographic image (D) of an articular cartilage lesion fifty-two weeks after creation of the defect. A: Coronal image demonstrating a clearly demarcated area of high signal intensity (arrow) at the site of the cavitary lesion in the
medial femoral condyle. B: Sagittal image of the medial femoral condyle demonstrating an enlarged area of higher signal intensity at the site of the
lesion. C: Sagittal image of the defect shown in B, made with fat suppression. D: Coronal computerized axial tomographic image through the center
of the lesion, showing changes in the geometry of the lesion and the central cyst. The specimen is the same as that depicted in Fig. 2, F. Note the
marked difference in comparison with Fig. 2, A.
lesions varied (Figs. 6, D through I). Histologic sections
stained with safranin O demonstrated proteoglycan in the
native articular cartilage and repair cartilage adjacent to the
lesion as well as focal proteoglycan synthesis in the fibrocartilaginous repair tissue at the periphery of the lesion
(Fig. 6, J, K, and L).
At one year, computerized axial tomography (three
specimens) and magnetic resonance imaging (two specimens) consistently showed a large cavitary lesion in the region of the defect (Fig. 7, A through D). Resorption of the
subchondral bone resulted in margins that were wider and
deeper (an increase of up to 15%) than those of the original
defect, with collapse of the articular surface relative to that of
the contralateral control. The subchondral bone and its overlying cartilage surrounding the lesion had continued to collapse into the lesion. The collapse of the lesion walls appears
to have contributed to the flattening of the condyle in the area
of the defect.
Discussion
n the present study, the osteochondral defects that were created in the medial femoral condyle of the goat disrupted the
subchondral bone plate and established communication with
the underlying marrow space. Over time, these large defects
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demonstrated progressive changes in both the bone and the
articular cartilage. In the first week, the initial cylindrical geometry of the osseous walls of the lesion showed evidence of
resorption, which continued to progress, resulting in cavitation and a persistent central cyst. Simultaneous endochondral
bone formation occurred at one year, apparently in response
to the weakening bone structure. However, structural collapse
still occurred by twelve weeks and was present at the completion of the study. Sclerotic bone developed around the cavitary
lesion, and the opening of the lesion narrowed. The articular
cartilage adjacent to the edge of the freshly cut defect quickly
deformed, or “flowed,” into the lesion. This deformation became more pronounced at six months, with collapse of underlying bone and condylar flattening. At one year, repair tissue
was seen adjacent to the surrounding cartilage, which varied
in thickness, smoothness, integration, and quality. The 6-mm
opening of the original defect gradually decreased in diameter.
At one year, the large cavitary lesion was filled by fibrous tissue
and a large central cyst.
The articular cartilage adjacent to the defect was also affected, and it underwent changes in a region referred to as the
“zone of influence.” There was deformation of the articular
cartilage in this zone, characterized grossly by flattening and
thinning. These changes in the zone of influence progressed
throughout the duration of the study.
The shape of the affected condyle at one year was characterized by a loss of contour caused by the creation of the defect followed by condylar flattening surrounding the defect.
This encompassing zone of influence has been predicted in
finite-element models of cartilage damage12. As the size of a
defect reaches a critical diameter beyond which healing is not
possible, increased compressive stresses are predicted along its
periphery, indicating that there is a mechanical overloading
component to the creation of the zone.
The bone compartment demonstrated a thickening at
the periphery of the walls of these surgically created lesions,
narrowing of the diameter of the upper bone margins, and a
cystic vacuolization at the subchondral portion of the defect.
Although bone has the capability of spontaneously regenerating itself 3, the bone compartment in these defects did not
regenerate or repair itself completely. It appears that, following destruction of the subchondral plate in the weight-bearing
surface of the medial femoral condyle in association with the
size of these defects, there are structural and mechanical
changes that substantially alter the bone-repair process. Major defects in the bone compartment remained present at one
year, and no functional tissue developed within these surgically created defects.
The size and location of the 6-mm-diameter and 6-mmdeep defects used in the present study presented a most challenging repair problem. The defects exceeded a critical size
and did not spontaneously achieve complete repair. In contrast, Butnariu-Ephrat et al. reported that smaller, 3-mmdiameter defects underwent complete repair in a goat model2.
Convery et al., in a study of defects in the distal aspect of the
femur of horses, reported that a large, 9-mm-diameter lesion
did not heal but that a smaller, 3-mm-diameter lesion was
VO L U M E 83-A · N U M B E R 1 · J A N U A R Y 2001
fully repaired at approximately three months11. In the present
study, the creation of the lesions in the weight-bearing area of
the medial femoral condyles exposed the defects to a changing
mechanical environment with high loading conditions13. The
animals were allowed immediate weight-bearing as tolerated.
A period of non-weight-bearing and passive motion might
have altered the extent of the reparative process and the deleterious effects that were documented. By twelve months, the
defects in our study were clearly visible and showed secondary
changes that were suggestive of continued degeneration, making complete repair unlikely9. From previous work with goats,
it has become apparent that defects of this size that are created
in the medial femoral condyle behave differently from those
that are created in the femoral groove5. Lesions of similar size
in the trochlear groove in the same goat and dog models generally heal, with bone filling the base and fibrocartilage filling
the area above5,14.
Strategies for articular cartilage repair must consider the
size, shape, depth, and location of the lesion. Investigators designing prospective studies involving large animals with large
osteochondral lesions that disrupt the subchondral plate may
want to consider providing initial protection from the potential detrimental effects of loading in weight-bearing areas during the initial repair process. Comparisons of defect location,
shape, size, and rehabilitation are warranted to assess the
spontaneous repair and potential deleterious responses following the surgical creation of a lesion. The progressive
changes documented in these surgically created defects in the
weight-bearing portion of the medial femoral condyle present
problems with regard to both the articular cartilage and the
bone compartment. If an enhancement of the cartilage reparative process or any regeneration methodology is developed3,7,15,
it should address the zone of influence with its thinning and
flattening of the articular cartilage and surrounding condyle,
deformation of the articular cartilage into the margins of the
defect, regeneration or replacement of the subchondral bone
plate, and regeneration of bone within the defect. It is unlikely
that a successful regeneration of the overlying articular cartilage will be possible until these secondary changes are addressed in a new treatment technique. Douglas W. Jackson, MD
Harold M. Aberman, DVM
Timothy M. Simon, PhD
Orthopaedic Research Institute, Southern California Center for Sports
Medicine, 2760 Atlantic Avenue, Long Beach, CA 90806
Peggy A. Lalor, PhD
SkeleTech, 22002 26th Avenue S.E., Room 104, Bothell, WA 98021
Although none of the authors has received or will receive benefits for personal or professional use from a commercial party related directly or
indirectly to the subject of this article, benefits have been or will be
directed to a research fund, foundation, educational institution, or other
nonprofit organization with which one or more of the authors is associated. Funds were received in total or partial support of the research or
clinical study presented in this article. The funding sources were the
Douglas W. Jackson Orthopaedic Research Trust and an unrestricted
research grant from Howmedica.
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