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Temporomandibular joint in miniature pigsAnatomy cell replication and relation to loading.

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THE ANATOMICAL RECORD 266:152–166 (2002)
DOI 10.1002/ar.10049
Temporomandibular Joint in
Miniature Pigs: Anatomy, Cell
Replication, and Relation to Loading
Department of Orthodontics, University of Washington, Seattle, Washington
The mechanical environment is a regulator of growth and adaptation of
the musculoskeletal system, including joints. Although pigs (Sus scrofa) are
used frequently as models for temporomandibular joint (TMJ) dysfunction,
no systematic description of microanatomy exists for this species. We injected the thymidine analog 5-bromo-2⬘-deoxyuridine (BrdU) into 10- to
11-month-old miniature pigs that were undergoing measurements of TMJ
bone strain. Ten hr later, the animals were sacrificed and their heads were
perfused. Histological sections were used to map the distribution of replicating cells. Additional observations were made on gross dissections of jaw
joints obtained from an abattoir. The pig TMJ is better supported than that
of humans laterally and medially, but more vulnerable posteriorly. The
posterior attachment area of the intra-articular disc is fibro-fatty rather
than vascular, as in humans. Cartilage lines the articular eminence as well
as the condylar surface. At the posterosuperior region of the condyle, the
cartilage ends abruptly and is replaced by an invaginating, actively replicating periosteum. Almost all of the BrdU-labeled cells resided in the
prechondroblastic zones. The condyle had more replicating cells than did
the eminence (P ⬍ 0.02), but lateral and medial locations did not differ in
either element. In sagittal sections, the condyle had more replicating cells
posteriorly (P ⬍ 0.001), but no A-P differences were seen in the eminence.
Comparisons of these data with data on bone strain indicate that increased
loading is negatively associated with cell replication. Anat Rec 266:
152–166, 2002. © 2002 Wiley-Liss, Inc.
Key words: bone strain; BrdU; cell replication; pig; TMJ
Dissonance in the clinical literature relative to treatment modalities for temporomandibular joint (TMJ) dysfunction (Greene et al., 1999) makes it obvious that animal models are needed to define and control experimental
variables. Although no animal model can exactly duplicate
the human condition, a number of authors have argued
that despite its prognathism the pig, Sus scrofa, is the best
nonprimate analog for human TMJ form and function
(Meister et al., 1973; Ström et al., 1986; Bermejo et al.,
1993; Herring, 1995). Like higher primates, pigs have
bilateral occlusion at full closure, a symphysis that fuses
after infancy, and sliding joint mechanics. The pig TMJ
has already been used to study discal mechanical properties (Nickel and McLachlan, 1994; Kuboki et al., 1997;
Nickel et al., 2000), synovial fluid pressure (Roth et al.,
1984), reactions to occlusal disturbances (Ulrici et al.,
1988; Dannhauer, 1992; Sindelar et al., 2000), and as a
mechanical (Liu and Herring, 2000b) or surgical (Timmel
and Grundschober, 1982) model. Proteoglycan content has
been examined in the disc (Sindelar et al., 2000) and the
condylar soft tissues (Müller et al., 1996; Roth et al.,
1997), and Moroco et al. (1997) have looked at age changes
of collagen II and TGF-␤ in the condylar cartilage.
Despite this burgeoning popularity, only very sketchy
information about pig TMJ morphology has been pub-
Grant sponsor: U.S. Public Health Service, National Institute
for Dental and Craniofacial Research; Grant numbers: DE08513
and DE11962.
*Correspondence to: Susan W. Herring, University of Washington, Dept. of Orthodontics, Box 357446, Seattle, WA 98195-7446.
Fax: (206) 685-8163. E-mail:
Received 11 July 2001; Accepted 26 November 2001
Published online 14 February 2002
lished, and the coverage in veterinary texts is even more
cursory. The best description of the pig TMJ (Meister et
al., 1973) is unfortunately not readily accessible to English-speaking workers. The osseous elements of the joint
have been described grossly (Herring and Scapino, 1973;
Meister et al., 1973; Ström et al., 1986) and in terms of
trabecular architecture (Teng and Herring, 1995; Teng et
al., 1997). The disc has also been the subject of both
macroscopic (Meister et al., 1973; Bermejo et al., 1993)
and histologic (Berg and Meister, 1974; Christensen,
1975; Albu et al., 1979) investigation. There are no available reports on the sectional anatomy of the pig TMJ,
either in terms of computed tomography (CT) or magnetic
resonance imaging (MRI) or of overall histology. Most
striking in its absence is any description of pig TMJ ligaments, including the attachments of the disc and ligaments to the osseous elements. Ligaments and discal attachments are likely to be critical elements in TMJ
function and dysfunction. These structures are responsible for the dynamic and static stabilization of the disc
(Schmolke, 1994; Sato et al., 1996; Amor et al., 1998). Disc
displacements may be a consequence of weak disc attachments and clearly involve their disruption (Osborn, 1995;
McNeill, 1997).
Equally lacking is a comprehensive description of cell
kinetics in the pig TMJ that would enable comparison
with other frequently used animal models, such as macaque monkeys and the laboratory rat (Luder, 1996). Cell
replication subserves growth, tissue turnover, and adaptation to new circumstances. In skeletal tissues generally
and in the TMJ particularly, mechanical loading is commonly considered a potent regulator of replication. Although controversial, the general consensus is that tensile
stress leads to increased replication in ligaments and their
attachments to bones (Yen et al., 1990; Yousefian et al.,
1992). Although hydrostatic compression is necessary to
maintain articular cartilage (Frost, 1990; Carter and
Beaupré, 2001), elevated compressive stress may inhibit
local replication and directional growth (Ngan et al.,
1992). Because the pig TMJ has been the subject of biomechanical investigation and the broad outlines of its
loading are known (Liu and Herring, 2000a, 2000b), the
opportunity arises to explore the connection between loading and cell replication in the joint.
The purpose of this investigation was therefore threefold: 1) to provide an overall description of the pig TMJ
with emphasis on histology and ligamentary attachments,
2) to define sites of cell replication, and 3) to relate these
findings to probable loading patterns in the normally functioning joint. To assess replication we employed the thymidine analog 5-bromo-2⬘-deoxyuridine (BrdU) to detect
S-phase cells in situ (Gratzner, 1982). In addition to the
general identification of areas involved in replication,
counts of BrdU-labeled cells were made from selected areas, including capsular ligament/disc attachment areas.
These counts were used to test hypotheses about loading.
Specifically, local replicative activity was expected to be
lowest in the direction of the compressive load and, because soft tissue attachments are presumed to be tensile,
higher in attachment areas than in nonattachment areas.
Macroscopic observations of ligamentous anatomy were
made on approximately 12 farm pig heads obtained from a
local abattoir. Sex and age were unknown, but it is likely
that the animals were about 6 months old. Blocks containing the TMJs were removed using a band saw and individually frozen in saline until dissection. The histological
and mechanical part of the study used eight male and
eight female miniature pigs, Hanford strain (Charles
River, Wilmington, MA), obtained at the age of 8 months.
All domestic pigs, including farm animals and miniature
breeds, are members of a single species, Sus scrofa. Sexual
maturity occurs at 6 –7 months, but growth is not complete until animals are at least 1 year old. Thus, all animals in this study were at a stage roughly equivalent to
the early teen years of humans. The diet of the miniature
pigs was a commercial pelleted pig chow; that of the farm
pigs was unknown. All procedures were reviewed and
approved by the University of Washington Animal Care
A subsample (n ⫽ 6) of the miniature pigs was imaged
by MR and CT, performed on different days. For MRI, the
pig was anesthetized by acepromazine/ketamine (8:1) i.m.,
followed by ketamine/xylazine i.v. for maintenance. The
pig was placed in a prone position on a 1.5-T Signa MRI
system (GE, Milwaukee, WI). Using a head coil, two initial
scout sections were performed to locate the condyle sagittally and coronally. Then, circular 3-inch surface coils
were placed over right and left TMJs. Sagittal and coronal
T1-weighted scans produced a series of seven sagittal and
eight coronal slices, 2.2 mm thick with 0.3-mm spacing,
through each joint (TR ⫽ 2400, TE ⫽ 24, field of view
(FOV) ⫽ 16 cm, matrix ⫽ 512 ⫻ 256). For CT, the pig was
anesthetized by mask inhalation of halothane in O2/N2O
and was placed prone in the bed of a GE High Advantage
Tomography scanner. After an initial scout, a 3-mm helical scan of the pig’s head was performed (FOV ⫽ 24 cm,
matrix ⫽ 512 ⫻ 512, kV ⫽ 120, mA ⫽ 180), allowing 1-mm
coronal slices to be reconstructed.
The entire sample of 16 animals was used for cell replication studies. At approximately 10 months of age and
45–70 kg of body weight, animals were anesthetized via
mask inhalation of halothane in O2/N2O and injected i.p.
or i.v. with BrdU (40 mg/kg as a 10 mg/ml solution in
phosphate-buffered saline (PBS)). Stacked rosette strain
gauges were bonded to the lateral surface of the left squamous temporal bone at the level of the articular eminence
and to the lateral surface of the left condylar neck. Temporal and condylar bone strains were recorded during
natural mastication. This methodology and the results
from a larger group of pigs have been reported elsewhere
(Liu and Herring, 2000a, 2000b). For the present paper,
we reanalyzed the strain data from the subset of animals
receiving BrdU and examined the correlations between
cell replication and bone strain. After these strain measurements and 10 hr subsequent to BrdU injection, the
anesthetized animals were injected i.p. with 3,000 units of
heparin and sacrificed by an intracardiac injection of pentobarbital. The head was removed and both common carotid arteries were cannulated. Using a peristaltic pump,
heparinized (1,000 units/l) PBS was perfused until the
solution exiting the veins was clear; this was followed by
perfusion with 10% neutral buffered formalin. After the
tissues became stiff, the head was sagittally sectioned and
blocks of tissue containing the TMJs were isolated and
Fixation continued for 2 days in fresh solution, followed
by demineralization in Christiansen’s solution (8N formic
acid, 1N sodium formate, 1:1), which required several
Fig. 1. Diagram of the condyle in frontal view illustrating the division
of each TMJ block into lateral, central, and medial thirds. The central
third was sectioned in the parasagittal plane, whereas the lateral and
medial thirds were cut in the coronal plane.
months for completion. The demineralized blocks were
divided into medial, lateral, and central thirds and embedded in paraffin for sectioning (Fig. 1). The medial and
lateral thirds were sectioned coronally, the central third
parasagittally. Sections were cut at 7– 8 ␮m with a steel
blade on a rotary microtome, floated onto a warm water
bath (42°– 44° C), and mounted on polylysine-coated
slides. Slides were dried on a slide warmer (32°–35° C) for
2 hr and stored at room temperature for at least 24 hr
before further processing.
For histology the sections were deparaffinized in a citrus-based clearing agent and hydrated in an ethanol series. For hematoxylin-eosin (H&E) sections were stained
in Mayer’s hematoxylin followed by a dH2O rinse; stained
in eosin; dehydrated in an ethanol series; cleared; and
mounted with no. 121 coverslips. In addition to sections
from the experimental animals, H&E sections of intact
TMJs were available from a similarly sized animal. These
had been embedded in celloidin and sectioned at about 25
␮m, the left side in the coronal plane and the right side
parasagittally. For trichrome staining, Anton’s (1999)
modification, which omits Mayer’s hematoxylin, was used.
Slides were stained with acid fuchsin/orange G, rinsed,
stained with phosphotungstic acid, rinsed again, stained
with light green, dehydrated, cleared, and mounted.
BrdU immunohistochemistry followed the procedures of
Decker et al. (1996): deparaffinization; H202-methanol to
inactivate endogenous peroxidases; 10% normal horse serum to minimize nonspecific binding of immunoglobulins;
the primary mouse monoclonal antibody to BrdU (Becton
Dickinson, Franklin Lakes, NJ) diluted 1:25 or 1:50; the
secondary antibody, biotinylated horse antimouse IgG
(Vector Labs, Burlingame, CA); the tertiary antibody, avidin-biotin-peroxidase (ABC Reagent, Vector Labs, Burlingame, CA); and reaction with 3,3⬘ diaminobenzidine-4HCl
containing 0.02% H2O2 with nickel enhancement. Specificity controls included 10% normal horse serum substituted for primary antibody, PBS substitution alone, or
omission of primary incubation entirely. The reacted sections were counterstained with 2% methyl green, washed
repeatedly in N-butanol, and mounted with no. 121 coverslips.
Light microscopic examination and counting of cells positive for BrdU were performed under Köhler illumination
(Barer, 1953) using a Nikon E400 compound microscope
with panfluor objectives. Positive cells were examined
closely to confirm that the reaction was confined to the
nucleus and had the pointillistic character of the tertiary
antibody, peroxidase. Only sections that clearly showed
both upper and lower joint cavities were examined. Typically, one to eight sections from each block met this criterion; all were counted and the results were averaged. For
most subjects, only the right TMJ was available for analysis. For the few cases in which both sides were available,
counts from right and left sides were averaged.
Sites for quantification of replicating cells were chosen
to compare areas of capsule/disc attachment with nonattachment areas, based on the idea that tensile stresses
associated with attachment might increase local cell replication. All counts were performed by the same investigator (J.D.D.), who was not involved in the functional
observations and was not aware of their results. Counts
were made directly under the microscope. For the central
third of the TMJ (parasagittal sections), counts were made
using the 10⫻ objective at the anterior and posterior discal attachments (“anterior” and “posterior”) and midway
between them (“middle”) for both the condyle and articular eminence, a total of six sites (Fig. 2A). The sites were
defined by a circle 1 mm in diameter formed by the field
diaphragm (0.8 mm2). For lateral and medial thirds (coronal sections), counts were made at the ligament/disc attachment sites (“lateral and medial poles”) and at the
bearing surfaces (“lateral and medial”) of the condyle and
eminence, for a total of four sites/section. Because labeled
cells were less dense in the coronal sections, the 4⫻ objective was used and a larger area was examined. Each
6.6-mm2 site was defined by the ocular reticle, and each
bearing surface site was 1.5 mm distant from its respective polar site (Fig. 2B). A Zeiss 5⫹100/100-mm calibration slide was used to confirm the area counted. Because of
high individual variation, the results were analyzed using
nonparametric rank order statistics (Friedman analysis of
variance (ANOVA) followed by post hoc Wilcoxon signedrank tests, SPSS for Windows). To investigate regional
variation in BrdU labeling, each articular surface was
considered separately in each plane of section. Ranks were
CCD camera (Diagnostic Instruments, Sterling Heights,
Bony Elements and Articular Surfaces
Fig. 2. Overall histology of the TMJ, showing areas where BrdUpositive cells were counted. A: Central third of the TMJ, cut parasagittally, trichrome stain, showing the six 0.8-mm2 sites (circles): anterior
and posterior disc attachments and middle area for both condyle and
articular eminence. A higher magnification of the boxed region is shown
in Figure 5A. B: Coronal section through the TMJ, H&E stain, showing
the 6.6-mm2 areas (rectangles) at each polar discal attachment and 1.5
mm away on the lateral and medial articular surfaces. AE, articular
eminence; Ant., anterior; C, condyle; Z, zygomatic bone.
assigned for each individual based on the raw data (Table
1). Taking the last subject (pig 259) as an example, the
anterior, middle, and posterior sites of the articular eminence were ranked 3 (most labeled cells), 1 (least labeled
cells), and 2 (intermediate), respectively. Analogous sites
on the condyle were ranked 1, 2, and 3, respectively. The
articular eminence in the coronal sections could not be
ranked because of missing data, but the condyle in the
coronal sections was ranked 3 for the lateral pole, 4 for
the lateral surface, 1 for the medial surface, and 2 for the
medial pole. Photomicroscopy was accomplished with an
attached Nikon F4 camera body equipped with a DW-21
viewfinder and Ektachrome 160T film or with a Spot RT
In lateral view the TMJ is obscured by a flange of the
zygomatic bone that juts beneath the zygomatic process of
the squamosal part of the temporal bone (Fig. 3A). Removal of the arch reveals the presence of a distinct articular eminence oriented at 30°–50° to the occlusal plane
(Fig. 3B). In contrast to the large, well-developed eminence anteriorly, the mandibular fossa consists only of a
roof. Except for a small medial overlap of the mastoid area
(Marks et al., 1997), there is no posterior wall and thus no
postglenoid process (Fig. 3B). MR images demonstrate
clearly that at rest in vivo only the anterior-superior aspect of the condyle apposes the articular eminence and
that the intermediate zone of the TMJ disc is interposed
between these articular surfaces (Fig. 4).
As shown clearly in coronal CT scans (Fig. 3C), the
eminence sits entirely lateral to the braincase and appears to be cantilevered from it. The CT scans also show
that at their point of maximal congruence the articular
surfaces of both the eminence and the condyle slope from
dorsolateral to ventromedial (73° ⫾ 2° from the sagittal
plane, n ⫽ 6). The articular surfaces are also slightly
inclined in the horizontal plane, particularly the eminence, with the medial border lying posterior to the lateral
border (Fig. 3D).
The internal architecture of the eminence and condyle
differ markedly (Fig. 2), as reported elsewhere (Herring
and Liu, 2001). The eminence has a robust cortex, whereas
the condylar head has little or no cortical bone. The trabeculae of the eminence are large, relatively sparse, and
randomly arranged. In contrast, the condylar trabeculae
are fine, densely packed, and roughly perpendicular to the
condylar surface both in parasagittal and coronal sections.
In parasagittal sections the condylar trabeculae become
gradually finer and denser from anterior to posterior. Trabeculae are particularly long and thin beneath the posterior disc/capsular attachment (Figs. 2 and 5A).
The articular surfaces of the eminence and condyle are
similar in that both are lined by fibrous tissue underlain
by cartilage. Between the fibrous and cartilaginous layers
is a zone of fibroblast-like cells. This fibroblastic layer
contained the vast majority of proliferating (BrdU-positive) cells for both the eminence and the condyle (see
below). The cartilage layer is not continuous on the eminence, and even where present the cartilage is much thinner than on the condyle. Specifically, the eminence lacks
the hypertrophic, mineralizing, and erosive zones that
characterize growth cartilages, including the pig condyle
(Roth et al., 1997). The surface coverings of the articular
eminence show no obvious regional variation, but those of
the condyle show striking changes from anterior to posterior. The condylar cartilage is thin anteriorly and gradually thickens posteriorly. The thickening is most marked
from the central part of the condyle (underlying the intermediate zone of the disc in occlusion) to the posterior
retrodiscal attachment area (Fig. 2A). In the posterior and
polar areas of the condyle, perichondrial connective tissue
invaginates deeply into cartilage. At the retrodiscal attachment, where the elongated bony trabeculae nearly
reach the fibrous surface layer, the cartilage layer almost
disappears (Fig. 5A).
TABLE 1. BrdU-labeled cell counts by site
Parasagittal sections (0.8 mm2 areas)b
Articular eminence
Coronal sections (6.6 mm2 areas)b
Articular eminence
f, m, female, male.
Ant, Middle and Post are the regions indicated on Figure 2A; Lpole, Lat, Med, and Mpole are indicated on Figure 2B.
Dashes indicate data missing because of incomplete histological material.
Intra-articular Disc and TMJ Capsule
The pig TMJ disc and its similarities to the human disc
have been described often (Meister et al., 1973; Ström et
al., 1986). In brief, the disc is ovate in dorsal view and
biconcave in parasagittal section (Figs. 2A and 4A). The
anterior and posterior bands feature dense interwoven
collagen fibers oriented predominantly mediolaterally,
whereas the crimped collagen fibers of the intermediate
zone run anteroposteriorly (Sindelar et al., 2002). Elastic
fibers are abundant and multidirectional in the anterior
and especially the posterior bands, infrequent and aligned
anteroposteriorly in the intermediate zone (Christensen,
1975). The reflections of the anterior band form the anterior capsule (Fig. 2A), and the medial portion of this area
receives the partial insertion of the lateral pterygoid muscle (Herring and Scapino, 1973; Ström et al., 1986). The
posterior band expands into a massive retrodiscal pad of
fibrous tissue with internal clusters of adipose cells (Figs.
2A and 4A). The retrodiscal tissue divides into temporal
and condylar attachments and constitutes the posterior
part of the TMJ capsule. Medially and laterally the disc
attaches to the poles of the condyle (Figs. 2B and 4B). The
medial, lateral, and particularly the posterior disc attachments are robust compared to the anterior.
The TMJ capsule attaches to the borders of the articular
surfaces. This attachment is greatly enlarged posteriorly,
where the temporal and condylar divisions of the retrodiscal tissue insert broadly onto the expanded posterior aspects of the condyle and temporal bone (Figs. 3D and 6).
The capsule is closely associated with the disc not only
anteriorly and posteriorly, but also at the condylar poles,
where medial and lateral capsular thickenings, referred to
here as capsular ligaments, join the discal insertions
(Figs. 2B and 6). The lateral capsular ligament is a collateral thickening that begins at the medial side of the zygo-
matic/squamous temporal suture line at the level of the
posterior half of the articular eminence. The lateral ligament courses directly medially and attaches to the lip of
the condyle at its lateral pole; it is thin, ribbon-like, nearly
transparent, strong, and when distended, is approximately 4 –5 mm long, 2 mm wide, and 1 mm thick. The
medial capsular ligament is also a collateral thickening
and courses from a small pit posteromedial to the eminence to the medial condylar pole. The medial ligament is
prominent and dense, measuring approximately 4 –5 mm
in length, 4 –5 mm in width, and 2 mm in thickness. In
addition to these collateral ligaments, the anterior capsule
has an extension that stretches inferiorly and anteriorly
from the anterior edge of the eminence and condyle, eventually attaching to the border of the mandibular notch up
to the tip of the coronoid process. This anterior capsular
ligament is highly elastic and nearly transparent.
Small to medium vessels are frequent in the loose connective tissue anterior and lateral to the TMJ capsule. The
delicate anterior capsular ligament has an abundant vascular supply and occasional small deposits of adipose tissue. The retrodiscal tissue is comparatively avascular.
Cell Replication
Sections incubated without the primary antibody for
BrdU exhibited normal histologic characteristics and cellular architecture, but no nuclear reactivity. The positive
histochemical reaction for BrdU in cell nuclei is prima
facie evidence of DNA synthesis and thus of cells in the
S-phase of replication.
The distribution of replicating cells was very specific.
Most labeling was found in the fibroblast-like cells (presumably undifferentiated mesenchymal cells) between the
fibrous and cartilage layers of the articular surfaces (Figs.
5B, C and 7). Replicating cells were found throughout this
Fig. 3. Bony morphology of the TMJ. A: Lateral view, perpendicular
to sagittal plane. With the zygomatic arch intact, the articular surfaces of
the TMJ are obscured from view. B: Lateral view, perpendicular to
mandibular surface. With the arch removed and the teeth in occlusion,
the posterior aspect of the articular eminence can be seen to be in
relation to the articular surface on the anterior aspect of the condyle.
There is no posterior wall for the mandibular fossa. C: Coronal CT scan
through both TMJs, showing their dorsolateral to ventromedial inclination. D: Palatal view of the skull, showing the anterolateral to posteromedial slope of the articular eminence (outlined area); the hatched area
depicts the posterior attachment area for the disc/capsule. AE, articular
eminence; B, auditory bulla; C, condyle; H, hyoid bone; PT, posterior
temporal attachment area; ST, squamous part of temporal bone; Z,
zygomatic bone.
cambial layer, although there were some quantitative differences. Strikingly, the invaginations of the perichondrium into the cartilage at the medial and lateral poles
and the posterior aspect of the condyle included this layer
of replicating cells (Fig. 5B and C), creating an appearance
of labeled canals. There were no similar invaginations
subjacent to the disc attachment sites on the eminence.
BrdU labeling was also seen in presumed osteoprogenitor cells in the periostea and marrow cavities of both the
eminence and the condyle. Chondroblasts near the cambial layer were occasionally labeled. However, labeled
cells were never seen anywhere in the disc (Fig. 7B) or the
capsule, including the capsular ligaments.
Because of the locations of the quantified areas (Fig. 2),
the labeled cells counted were almost all from the cambial
layer between the fibrous articular covering and the underlying cartilage. Raw counts are presented in Table 1,
and Table 2 summarizes and compares the total counts for
the center of the TMJ, the articular eminence showed no
significant variation among the anterior, middle, and posterior sites, although there was a tendency (P ⫽ 0.12) for
higher cell replication anteriorly. However, regional variation in the condyle was highly significant (P ⬍ 0.001).
Here the anterior and middle areas had relatively low
BrdU labeling (but comparable to labeling in the eminence, Table 1), whereas the posterior condylar site had by
far the highest number of replicating cells.
In coronal sections through the lateral and medial
thirds of the TMJ, both the eminence and the condyle
showed higher BrdU labeling in the bearing surfaces of
the joint than at the poles, although this trend was significant only for the articular eminence (P ⫽ 0.015). Although the medial pole and surface tended to have more
replicating cells than the lateral pole and surface, respectively, these trends were not statistically significant for
either the eminence or the condyle (Fig. 8).
Correlations Between Replication
and Bone Strain
Fig. 4. MR images of the TMJ. A: Parasagittal slice through the
central area. The disc itself is dark because of its dense collagenous
structure, but the retrodiscal tissue can be seen to consist of fibrous
temporal and condylar attachments (arrows on dark bands) sandwiching
a more fatty internal area (labeled RT). B: Coronal slice through the
intermediate zone of the disc. The disc appears dark, but its attachments
to the lateral and medial poles of the condyle can be visualized (arrows).
The interior of condyle and articular eminence are lighter because of the
contained marrow. AE, articular eminence; C, condyle; D, disc; RT,
retrodiscal tissue; T, temporalis muscle; Z, zygomatic bone.
the eminence and condyle. Replicating cells were far more
numerous in the condyle, outnumbering those in the eminence 2:1 in parasagittal sections and 3:1 in coronal sections. There was a low but significant correlation between
total eminence labeling and total condylar labeling (r ⫽
0.73, P ⫽ 0.04). Individual variability was high, with
eminence totals ranging from 34 –242 and condylar totals
from 78 – 623.
In addition to the greater labeling in the condyle than in
the eminence, every region in the central part of the TMJ
showed more cell replication than every region in the
lateral and medial areas. This fact is not obvious from
Table 1 until it is remembered that the lateral and medial
sites counted in coronal sections were approximately eight
times larger than the central sites counted in parasagittal
sections (6.6 mm2 vs. 0.8 mm2).
The analysis of regional variation of cell replication is
presented in Figure 8. In parasagittal sections through
Masticatory strains for the present sample of pigs are
summarized in Table 3 and illustrated in Figure 9. Working and balancing side cycles differ little (Liu and Herring,
2000a) and were combined to represent the average loading of the TMJ during chewing. The gauges recorded
strain on the lateral surfaces of the bones, roughly equivalent to a parasagittal plane. The squamosal part of the
temporal bone was strongly tensed in the vertical direction, a pattern we have previously attributed to cantilever
bending of the articular eminence (Herring and Liu, 2001)
and out-of-plane bending of the entire zygomatic process
of the temporal bone (Rafferty et al., 2000). In contrast,
the condyle was mainly compressed, with the compressive
axis running from anterosuperior to posteroinferior.
Correlations between cell replication and the magnitude
of masticatory bone strain are presented in Table 4, and
Figure 10 shows scatter plots for the best correlations.
Strikingly, all correlations were negative. As bone strain
increased, cell counts decreased. In the articular eminence, BrdU labeling was negatively associated with all
measures of strain in the temporal bone, particularly
shear strain (P ⬍ 0.01; Table 4, Fig. 10), which is the sum
of the magnitudes of tensile and compressive strain. By
contrast, articular eminence labeling was not statistically
correlated with condylar strain. In the condyle, BrdU labeling was most closely related to compressive strain in
the condyle and compressive strain in the temporal bone,
although these correlations fell slightly short of statistical
significance (Table 4).
TMJ Anatomy: Pigs vs. Humans
Pigs (family Suidae) are hoofed mammals of the order
Artiodactyla. Other familiar members of the order are
hippopotamus, camels, deer, and bovids such as sheep and
cattle. TMJ anatomy is quite variable within the artiodactyls. Hippos and peccaries (family Tayassuidae, the sister
group of the suids) feature prominent pre- and postglenoid
processes that constrain the excursions of the condyle
(Herring, 1972, 1975). Deer and bovids differ from pigs in
the reverse direction, permitting unrestricted free movements of the concave condyle in almost all directions. It is
this laxity that makes the sheep TMJ so convenient as a
Fig. 5. A: Enlargement of the area outlined in Figure 2A,
showing the posterior aspect of condyle at the area of disc
attachment. Note that the site of attachment coincides with a
qualitative change in the condylar surface. The cartilage layer
(between black arrows) is largely replaced by bony trabeculae
perpendicular to the surface (white arrow). B: Coronal section
of the condyle, lateral segment, BrdU histochemistry with
methyl green counterstain. The lateral pole is to the left.
Low-power view, showing extensive invaginations of the perichondrium into the cartilage layer. The box is enlarged in C.
C: Higher-power view of the outlined area. The chondrocytes
are negative for BrdU, but labeled fibroblast-like cells are
numerous in the invaginating perichondrium.
surgical model (van Loon et al., 2000). Because of the
diversity among artiodactyls and because artiodactyls are
only very distantly related to primates, the resemblance of
the pig and human TMJ is clearly one of evolutionary
convergence, presumably due to similar function. The resemblance is far from exact. Nonhuman primates, such as
rhesus macaques, which share a recent common ancestry
with humans, are closer to humans in TMJ structure
(Tong and Tideman, 2001). Nevertheless, pigs will clearly
remain popular alternative research models, and it is important to understand the limits of interspecies comparisons.
As in the TMJ of humans, the pig condyle articulates
against the strongly curved articular eminence rather
than the mandibular fossa. As pointed out by other workers, the pig TMJ disc closely resembles that of humans
(Meister et al., 1973; Ström et al., 1986) in most details,
including its attachments. Also similar are the articular
surfaces that slope from lateral, dorsal, and anterior toward medial, ventral, and posterior. Internal architecture
is probably also similar. Like pigs, human mandibular
condyles are strongly trabecular with the trabeculae perpendicular to the condylar axis (Giesen and van Eijden,
2000). Less attention has been paid to the human articular eminence, but most photographs show it as having a
much thicker cortex than the condyle (e.g., Scapino, 1983).
This suggests that the robust construction of the eminence
in pigs is not due to its cantilevered position, because the
Fig. 6. Left TMJ, oblique inferior view. Capsular ligaments have been
drawn (pink) on a photograph of the skull. The medial (MCL) and lateral
(LCL) capsular ligaments are thickenings in the capsule. The anterior
capsular ligament (ACL) is a delicate, elastic extension from the anterior
capsule that inserts on the superior edge of the mandible from the
mandibular notch to the tip of the coronoid process. The hatched areas
on the condyle and squamosal part of the temporal bone indicate the
attachment areas of the posterior disc/capsule.
human eminence is buttressed by the braincase. Instead,
the thick cortex of both human and pig articular eminences suggests a commonality, either of loading or of
growth pattern.
Pig-human differences include overall dimensions. The
pig joint is larger relative to body size. Whereas adult
humans have condyles 15–20 mm in width (Hylander,
1992), 8-month-old miniature pigs weighing 46 ⫾ 4 kg
(comparable to a small human) have condyles 21–25 mm
wide (Sindelar, personal communication). An additional
difference is that the pig TMJ is more protected than the
human laterally and medially. Laterally, the TMJ capsule
is hidden by the overhanging zygomatic flange (Figs. 2– 4).
Medially, the bony configuration is similar, but whereas
the medial capsule of humans is composed of weak areolar
tissue (Loughner et al., 1997), that of pigs is strengthened
by a stout ligament (Fig. 6). The most striking morphological difference between pig and human TMJs is, however,
the retrodiscal area. Pigs have no postglenoid wall, leaving the posterior aspect of the TMJ unprotected by bone
and nearly subcutaneous. For this reason the posterior
approach can be used to access the lateral pterygoid muscle (e.g., Liu and Herring, 2000a). The missing bony wall
has consequences for posterior discal attachments. In humans the temporal and condylar attachments are separated by a delicate venous plexus, and the whole area is
sheltered by the postglenoid process. Luder has described
this area as serving to provide space for the distensible
discal attachments (Luder, 1996, p 49). The equivalent
space in the exposed pig TMJ is filled by a rubbery retrodiscal pad. If this tissue is capable of accommodating
condylar movements, it must use elasticity rather than
vascular volume compensation.
The general construction of the pig TMJ permits a range
of movements rather similar to those of humans. The soft
posterior wall of the joint may allow more retrusion than
in humans. In anesthetized animals, roughly the same
amount of retrusion and protrusion can be achieved (4 – 6
mm) (Sun et al., in press). As in humans, masticatory
Fig. 7. BrdU immunohistochemistry in parasagittal section, showing
the surface of the articular eminence (A), superior surface of the TMJ
disc (B), and surface of the condyle (C), all near the middle area. Anterior
is to the left. BrdU-positive cells (black) were found almost exclusively in
the subarticular perichondrial layers of the eminence and condyle. No
replicating cells were present in the fibrous articular tissue or the disc,
and very few were found in the cartilage. The cartilage layer of the
eminence is much thinner than that of the condyle and replicating
(BrdU-positive) cells are less numerous.
opening is accompanied by protrusion and masticatory
closing by retrusion (Herring and Scapino, 1973). The
attachment of the disc to the poles of the condyle implies
that, again as in humans, protrusion and retrusion are
TABLE 2. Total counts of BrdU-labeled cells in the
condyle and articular eminence (mean and
standard deviation)
Coronal sections Parasagittal sections Combined
35 ⫾ 24
n ⫽ 13
112 ⫾ 73
n ⫽ 16
P ⬍ 0.02
83 ⫾ 73
n ⫽ 10
182 ⫾ 109
n ⫽ 15
P ⫽ 0.001
128 ⫾ 88
294 ⫾ 146
n ⫽ 15
P ⫽ 0.02
Fig. 8. Relative distribution of BrdU-labeled cells in the TMJ. The
error bars show the mean ranks with 95% confidence intervals. Using
the raw data in Table 1, ranks were assigned for each articular surface in
each plane of section for each subject. The site with the least labeled
cells was assigned the rank of 1, whereas the site with the most labeled
cells was assigned a rank of 3 (for parasagittal sections) or 4 (for coronal
sections). Significant regional differences were found for the condyle in
parasagittal sections and the articular eminence in coronal sections
(Friedman ANOVA followed by post hoc Wilcoxon signed-rank tests).
*, pairs significantly different at P ⬍ 0.05; **, pairs significantly different
at P ⬍ 0.01.
movements of the condyle-plus-disc relative to the articular eminence, whereas opening rotations probably occur
between the disc and the condyle. It seems likely that the
lateral (bony) and medial (ligamentous) reinforcements of
the TMJ would limit transverse condylar movements.
However, lateral excursions are not solely produced by
transverse condylar movements, but also by rotations
arising from asymmetrical condylar protrusion/retrusion
(Sun et al., in press). The elongated jaws of pigs also help
compensate for limited TMJ movement by exaggerating
angular motion. During chewing the incisors undergo lateral excursions of 4 –5 mm (Herring, 1976).
Patterns of Cell Replication and Growth
A number of our histological observations are best explained in the context of growth. While the articular eminence does not contribute to cranial dimensions, the condylar cartilage serves both as an articular surface and as
a major growth site for the mandible. The 11-month-old
pigs in the present study were postpubertal but not full-
grown. Epiphyses of long bones were still open, the dentition was still mixed, and the jaws were presumably still
lengthening. Cell replication was active, as indicated by
the BrdU results. Because the interval between BrdU
injection and animal sacrifice was only 10 hr, it is likely
that only a fraction of the replicating cells had time to
incorporate the label. Nevertheless, the distribution of
labeled cells is probably an accurate depiction of relative
rates of cell division in different parts of the TMJ. The fact
that these rates varied regionally is in itself evidence that
directional growth was taking place, rather than simple
tissue turnover.
The layering of the eminential and condylar articular
surfaces is typical of that seen in humans and other animals at comparable ages. The location of the BrdU label
between the fibrous articular layer and the underlying
cartilage corresponds to the proliferative zone identified
for the condyle (Luder, 1996) and presumably has the
same role in the eminence. A previous BrdU study on the
rat TMJ did not find labeling on the temporal bone articular surface (Sekine et al., 1991), but this may be due to
the absence of an articular eminence in rats. Although
some of the newly replicated cells probably contribute to
the fibrous articular layer, it seems likely that most are
prechondroblasts. A gradual conversion of fibrous tissue
toward a cartilage phenotype has been described for the
(presumed) most loaded surfaces in humans: articular
eminence, intermediate zone of the disc, and anterior aspect of the condyle (Moffett et al., 1964; Luder, 1996,
1998). With the exception of the disc, these were also the
locations of cartilage in the present sample of pigs.
The posterior slope of the condyle displayed some unusual features that probably reflect the posterior-superior
direction of condylar growth. These include thickening of
articular and cartilage layers, invaginations of the perichondrium, and a sudden transition to a noncartilaginous,
trabecular area at the posterior discal attachment. The
number of replicating cells was far higher here than in any
other location in the TMJ (Table 1). Some of these features
are seen in other species, which of course grow in the same
direction. Thickening of the articular layer on the posterior slope of the condyle has been noted in both humans
and monkeys (Luder, 1996); only in this region do humans
retain a cellular intermediate layer (Luder, 1998). The
sudden loss of cartilage at the posterior discal attachment
is also seen in humans (Luder, 1996), although the transition to spindly trabeculae (Fig. 5A) appears to be unique
to pigs. In previous growth studies we have noticed that
these trabeculae elongate at a remarkable rate (0.3– 0.4
mm/day in 4-month-old pigs) (Ferrari and Herring, 1995).
Finally, the prominent invaginations of the posterior perichondrium also have a human equivalent, although only
in fetuses and very young children. Connective tissue invasions of the human fetal TMJ condylar head were described by Vinogradoff (1910) as “crampons.” In Vinogradoff’s opinion the crampons served to fasten the
perichondrium firmly to the cartilage. Later writers have
considered them more as vascular channels, possibly analogous to cartilage canals (summarized by Luder, 1996). In
the pig joints, Vinogradoff’s mechanical explanation
seems more plausible than the nutritional idea; the invaginations we observed were not particularly vascular,
but they were strongly associated with the attachments of
the disc into the condyle. Even more striking, however,
was their association with cell replication. Without excep-
TABLE 3. Mean peak masticatory strains for the animals used for BrdU labeling*
Temporal bone strain (␮ε)
Mean ⫾ S.D.
Condylar strain (␮ε)
200 ⫾ 120
⫺86 ⫾ 67
98° ⫾ 37
155 ⫾ 119
⫺267 ⫾ 231
110° ⫾ 30
*These data are a subset of a previously published sample [Liu & Herring, 2000a]. Left and right chewing cycles (10 –20/
animal) were averaged. Missing data are indicated by dashes. Minimum principal strains were all compressive (expressed as
negative values) and maximum principal strains were all tensile (positive values). The orientation of tensile strain is expressed
as a clockwise angle relative to the occlusal plane with the skull viewed from the left (Fig. 9). Shear strain can be calculated
by summing tensile strain and the absolute value of compressive strain.
Fig. 9. Average bone strain during chewing for the 16 pigs used in
the present study (data in Table 3). The strain gauges were located on
the squamosal part of the temporal bone just lateral to the articular
eminence (see Fig. 3) and on the lateral surface of the condyle (Liu and
Herring, 2000a). The arrows depict the magnitude and orientation of the
peak principal strains. Arrowheads pointing away from the gauge site
indicate tensile strain, whereas arrowheads pointing toward the gauge
site indicate compressive strain. The hatched triangles indicate 1 S.D. for
orientation. Tensile strain, directed approximately vertically, dominates
the temporal bone. For the condyle, compressive strain, oriented anterosuperior to posteroinferior, is dominant.
tion, the invaginations were heavily labeled with BrdU.
Conceivably, the infolded posterior perichondrium reflects
the need for rapid cell replication in this fastest-growing
part of the skull. The dividing cells occupy a layer of a
curved surface but must provide new cells to fill a volume.
Folding this layer would be an effective way to increase its
area and the number of dividing cells without changing
the volume enclosed.
The distribution of BrdU labeling on the eminence (Fig.
8) suggests that the articular eminence was becoming
flatter. The eminence is convex in the parasagittal section
(Fig. 2A), and the tendency for higher replication anteriorly and posteriorly would decrease that convexity. In the
coronal plane the eminence is concave (Fig. 2B), and the
lower replication at the poles would reduce the concavity.
The situation is less clear for the condyle, because the
parasagittal sections are dominated by posterior growth,
and little difference among locations was seen in the coronal plane.
Although BrdU labeling in parasagittal sections of the
condyle clearly indicates growth in the posterior direction,
no such trend was apparent for the eminence (Fig. 8).
Because the eminence becomes repositioned in space by
growth at cranial synchondroses and sutures, there is no
need for oriented expansion of the eminence cartilage. In
the coronal plane, both the eminence and the condyle
move laterally with growth. In the case of the condyle, this
movement probably involves Enlow’s V-principle (Enlow
and Hans, 1996), in which an enlarging V-shape (the
condyle) shows remodeling resorption on its periphery but
apposition centrally. The V-principle leads to the expectation that more central areas on the condylar surface would
have more replicating cells than more polar areas. Our
data (Fig. 8, lower right graph) are in the correct direction
but are very far from statistical significance. Strangely,
the data for the eminence (Fig. 8, upper right graph) do
correspond with the expectation of the V-principle, but the
eminence should not be growing in this manner. Rather,
the eminence is thought to move laterally by simple osseous drift, with resorption on the medial side and apposition on the lateral side. If osseous drift were responsible
TABLE 4. Parametric (Pearson) and nonparametric (Spearman) correlations between BrdU labeling and peak
strain magnitudes during mastication
Temporal bone
Total labeled cells
Articular eminence
Pearson r
Spearman rho
Condylar surface
Pearson r
Spearman rho
Compression and tension are the principal strains illustrated in Figure 9. Shear strain is the sum of tensile strain and the
absolute value of compressive strain.
*P ⬍ 0.05; **P ⬍ 0.01; †0.05 ⬍ P ⬍ 0.10.
Fig. 10. Scatter plots for the best correlations between cell replication and labeling (Table 4). All correlations were negative. BrdU labeling
in the articular eminence correlated best with shear strain in the temporal
bone (asterisks, r ⫽ – 0.87, P ⫽ 0.005), and labeling in the condylar
surface correlated best with compressive strain in the condyle (diamonds, r ⫽ – 0.51, P ⫽ 0.07).
for the pattern of cell replication in the eminence, then we
would expect higher labeling laterally than medially. This
was not seen; in fact, the trend was in the reverse direction. In short, the only aspect of BrdU labeling that
strongly supported a known pattern of growth was that
seen in parasagittal sections, specifically the large number of replicating cells near the posterior attachment on
the condyle. Labeling in the coronal plane did not support
the standard models of growth. This failure may reflect
our lack of understanding of the growth in this plane, or
perhaps our study was too limited in time to reflect a
global picture of that growth. On the other hand, some
aspects of cell replication may be better explained by function than by growth.
TMJ Loading in Relation to Structure and Cell
The compressive loading applied to joints causes both
hydrostatic (shape-preserving) and shear (distortional)
stress. According to Carter and Beaupré (2001), increasing levels of hydrostatic compression should be associated
with thicker articular cartilages (but not necessarily tissue growth), whereas shear loads result in endochondral
ossification. Further, Carter and Beaupré (2001) have argued that hydrostatic compression is always greater in the
convex than in the concave member of a synovial joint and
that this difference causes the convex member to have a
thicker layer of cartilage. Thus, hydrostatic loading may
be the reason for the thicker cartilage and more active cell
replication of the convex condyle than of the concave eminence. However, this explanation is only useful for the
coronal plane. In the parasagittal plane, both elements
are convex.
Functional loading of the TMJ is probably dominated by
shear stress, rather than hydrostatic compression. The
strain gauge results always indicated distortion, i.e., simultaneous compression and tension at right angles to
each other. In dentistry it is believed that increasing the
loading on the condyle will reduce or redirect growth away
from the compressive axis (Proffit, 1986). Thus, where
distortion is present, cell replication is expected to favor
the tensile axis (summarized by Heegaard et al., 1999).
Our original selection of areas for BrdU quantification
was intended to compare regions of ligamentous attachment with more central portions of the articular surfaces.
We reasoned that the attachments would add a tensile
component to the otherwise compressed cartilage and expected that cell labeling would be higher at the attachments. The expectation of higher replication at attachments was clearly wrong. It is supported only by the
parasagittal sections of the eminence (Fig. 8, top left), and
these results were not statistically significant. The high
BrdU counts at the posterior attachment to the condyle
are better explained by growth (see above), and the anterior attachment to the condyle actually had fewer labeled
cells than the middle region (Fig. 8, bottom left). All results from the coronal sections were opposite to the expected findings. Cell replication at the poles was less than
at the bearing surfaces, significantly so for the eminence
(Fig. 8, right). Furthermore, overall density of labeling
was higher in the central third of the joint than in the
more polar lateral or medial thirds. This can be seen by
dividing the counts in Table 1 by the area measured.
Labeling density in the middle region of the parasagittally
sectioned central third was 24 cells/mm2 in the eminence
and 46 cells/mm2 in the condyle, whereas the coronally
sectioned lateral and medial thirds showed labeling densities of 1–3 cells/mm2 in the eminence and 4 cells/mm2 in
the condyle.
In retrospect, the notion that compressive loading would
be reduced at the attachment zones was probably incorrect because the orientations of these two loads would not
coincide. The tensile forces applied by the disc and ligaments would be roughly parallel to the articular surfaces
(Fig. 2), whereas the compressive loading presumably acts
perpendicular to the surfaces. Thus tension applied by the
attachments would not decrease the compressive loading,
but rather would increase the shear stress, inhibiting cell
division. Another possible explanation for the lower replication rates of the polar areas is that these regions
may actually be loaded more heavily in compression
than more central areas. The condyle and eminence are
usually at their closest approach at the poles (Figs. 3C
and 4B); such congruency may increase local loading
and depress cell replication. In the absence of detailed
information about the distribution of stress within the
articular surfaces, it is impossible to test these alternatives rigorously.
Although the distribution of stress within the articular
surfaces is unknown, we do have data relevant to loading
in the parasagittal plane. The present study is unique in
providing bone strain information on the same animals
used for BrdU labeling. The fact that we were able to
establish correlations is in itself remarkable. Both BrdU
labeling and in vivo bone strain have many sources of
experimental variation that mitigate against detecting
relationships. Furthermore, the BrdU results were obtained from the right TMJ and the strain information
from the left TMJ.
Despite these difficulties, the results show clearly that
bone strain is negatively correlated with cell replication.
All correlations were negative, with high significance for
the articular eminence and borderline significance for the
condyle (Table 4, Fig. 10). Thus, individual pigs with high
masticatory loading had low rates of cell division in the
TMJ. This may be a causal relationship; high loading,
especially compressive loading, has been associated with
decreased chondrocyte proliferation in many in vivo and in
vitro studies (Hamrick, 1999; Farnum et al., 2000).
Because the strain data also include information about
orientation in the parasagittal plane, we can also investigate the relationship between the directionality of loading
and of cell replication in parasagittal sections, at least for
the condyle. As discussed above, the articular eminence
did not show directionality of cell replication. Furthermore, the magnitude of compressive strain (thought to be
the main mechanical influence on growth) in the squamosal part of the temporal bone was relatively low, averaging
only – 86 ␮⑀ (Table 3). By contrast, the condyle was
strongly directional in its growth, with the posterior location being far more active than the anterior and middle
areas, and its strain pattern was strongly compressive,
averaging –267 ␮⑀. This compression was directed anterosuperiorly (Fig. 9). Thus, in the condyle, cell replication is
oriented in the direction of tensile strain, posterosuperiorly. This direction is orthogonal to the compressive axis.
This finding is again consistent with the notion that loading (compression) decreases cell division. Even on an individual basis, there are indications that the direction of
condylar compression may be associated with the direction of growth. There were only two pigs in which the
posterior area of the condyle did not have the most BrdUlabeled cells (pigs 215 and 217); both showed slightly
heavier labeling in the middle than in the posterior site
(Table 1). These were also the only two animals that had
an unusually anterior-posterior (⬎1 S.D. from the mean)
orientation of condylar tensile strain (Table 3). Thus the
compressive axis of these two animals was almost vertical,
resulting in a more symmetrically distributed compressive
load over the top of the condyle and a more even spread of
replicating cells.
In summary, these data indicate that individual differences in loading may be a strong influence on growth in
the TMJ. In particular, high strains are associated with
low cell replication rates, and animals with unusual loading orientations have unusual growth patterns as well. In
general, the findings were consistent with the hypothesis
that local replicative activity would be lowest in the direction of the compressive load. However, areas of ligamentous attachment, rather than having high replication
rates as expected, had relatively low numbers of labeled
cells; the mechanical correlates of this difference are still
unknown. Direct mechanical effects on cell replication
provide a mechanism whereby altered function, such as
eating a soft diet, can cause changes in craniofacial dimensions (Ciochon et al., 1997).
We are grateful to Patricia Emry for histological preparation, to Katherine Rafferty, Scott Pedersen, and Christopher Marshall for their help with the experiments, and
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pigsanatomy, temporomandibular, relations, replication, joint, loading, miniature, cells
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