Fisher John P. e.a. (ed.) Tissue Engineering

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Tissue Engineering

of the

Temporomandibular

Joint

Mark E.K. Wong

Kyriacos A. Athanasiou

University of Texas Dental Branch

Rice University

Kyle D. Allen

University of Texas Dental Branch

23.1 Introduction.............................................. 23-1

23.2 Gross Anatomy and Function of the TMJ.............. 23-2

23.3 Microscopic Anatomy of the TMJ Disc ................ 23-6

23.4 Biomechanical Behavior and Failure of the Disc ...... 23-7

23.5 Common Conditions Affecting the TMJ............... 23-8

23.6 Current Methods for TMJ Reconstruction............. 23-9

23.7 Tissue Engineering Strategies for TMJ

Reconstruction........................................... 23-15

Tissue Engineering Motivation and Philosophy • Cellular

Issues • Scaffold Issues • Signals and Stimulation Issues •

Speciﬁc Issues Related to Joint Reconstruction • The Future

of Tissue Engineering in the TMJ

References ....................................................... 23-20

23.1 Introduction

Tissue engineering of the temporomandibular joint (TMJ) is very much in its infancy. Similar to efforts

directed at the replacement of other diseased joints, tissue engineering of the TMJ requires a detailed

understanding of anatomy, normal joint activity and various pathologies. The body of knowledge available

for the TMJ is relatively incomplete compared to other joints, which accounts for many of the problems

encountered in previous reconstructive attempts. To date, very little is known about the manner in which

the joint functions and the environment most conducive to its physiology. Even less is known about

the impact of skeletal morphology and the presence or absence of a dentition. However, it is believed

that both these parameters affect the type and range of motion as well as the forces created during

joint function. The manner by which disease affects the TMJ has been derived largely from orthopedic

and rheumatology studies of other diarthrodial joints. As various investigators attempt to apply basic

tissue engineering techniques to produce replacement components for the TMJ, aggressive efforts are

also underway to characterize its normal and abnormal behavior. These studies will provide an essential

23-1

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23-2 Tissue Engineering

basis for the development of successful and lasting tissue engineering techniques for the reconstruction of

the TMJ.

23.2 Gross Anatomy and Function of the TMJ

Movement of the lower jaw, or mandible, can occur through three planes of space as the result of rotation

around a transcranial axis (vertical opening and closure), translation relative to the skull base (protrusion,

retrusion, and side-to-side motion), or a combination of the two actions. These movements are possible,

because of the presence of paired joints that separate the lower jaw from the skull base on either side of

the cranium. The joints are named for the two bones that provide the articulating surfaces, namely the

temporal bone (temporo) which houses the superior articulation in an area known as the glenoid fossa

and articular eminence, and the mandible (mandibular), whose condylar processes provide the inferior

portion of the articulation.

The TMJs are diarthrodial structures, which is to say that within the joint, a complete interpositional

disc creates separate superior and inferior joint spaces. While this nomenclature suggests that the disc is

isolated from its superior and inferior relationships by true “spaces,” under normal functional conditions,

the separations are extremely small and ﬁlled with synovial ﬂuid. Conceptually, it would be more accurate

to characterize these areas as potential spaces, with superior and inferior volumes approximating 1.0 and

0.5 ml, respectively [1]. This arrangement allows the ﬁbrocartilaginous disc to ﬁll the void between the

condylar head and the glenoid fossa, promoting congruity between two dissimilarly shaped and sized

structures [2] (Figure 23.1). Alterations in discal properties as a result of disease, improper position, or

perforation are common precursors to degeneration of the articular surfaces of the joint, as mechanisms

for the dissipation of normal physiological loads are lost. These degenerative conditions provide ample

reasons for employing tissue engineering techniques to fabricate replacements for damaged discs [3] as

well as condylar and fossa surfaces.

The disc sits astride the condylar head and together with its peripheral attachments and surrounding

joint capsule, produces a closed space separating intra- and extra-articular environments. Three morpho-

logical zones have been described for the disc [4] and these are best appreciated in a sagittal view of the

joint (Figure 23.1). The thickest region of the disc is the posterior band, followed by the anterior band.

The intermediate zone represents the thinnest portion of the disc. The junctions between the zones are

indistinct by gross examination and appear to blend with each other. In sagittal section, the disc has been

described as a biconcave structure (Figure 23.1), but this is not a true depiction of its morphology. Instead,

the disc resembles a cap attached along its entire peripheral margin to both the condylar neck and the

skull base through a variety of different connective tissues. The superior attachments are less tenuous and

allow the condylar head to slide forwards and from side to side in relation to the fossa during translatory

movements of the joint. These attachments are composed of reﬂections of the superior surface of the disc,

in association with the synovial membrane anteriorly and the superior laminar of the retrodiscal tissue

(bilaminar zone) posteriorly. The synovial membrane in turn attaches to the skull base anterior to the

articular eminence while the superior laminar of the retrodiscal tissue inserts into the petrous portion of

the temporal bone. Medially and laterally, the superior surface of the disc turns inferiorly, blending with

ﬁbers of the capsule producing medial and lateral gutters. The inferior surface of the disc is more closely

adapted to the condylar head, especially in its medial and lateral aspects. This relationship promotes

rotary movements of the condyle in relation to the disc and glenoid fossa. Anteriorly, inferior reﬂec-

tions of the disc are interspersed with tendinous insertions of the superior head of the lateral pterygoid

muscle, which attach to a concavity in the condylar head termed the pterygoid fovea. Posteriorly, the disc

attaches to the inferior lamina of the retrodiscal tissue, which contains elastic ﬁbers and blood vessels

(Figure 23.2). As a result of these attachments, rotation occurs in the inferior space while translation of

the joint occurs primarily involves the superior joint space. The different movements of the jaw rely upon

the contraction of the lateral pterygoid muscle and its angle of attachment to the mandibular condyle

(Figure 23.3).

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Tissue Engineering of the Temporomandibular Joint 23-3

Posterior band

Intermediate zone

Anterior band

Temporal bone

Mandible

Anterior band

Intermediate zone

Posterior band

Lateral

Medial

Temporal bone

Intermediate zone

Medial region

Mandible

Lateral

region

FIGURE 23.1 Superior, sagittal, and coronal views of the TMJ disc. The TMJ disc divides the joint into superior and

inferior spaces. From a superior view, the disc displays an ellipsoidal shape, being thicker in the mediolateral dimension

than anteroposteriorly. In a sagittal view of the disc, thicker anterior and posterior bands and a substantially thinner

intermediate zone (central regions of the disc) can be appreciated. In coronal sections, the disc presents a similar

biconcave shape, with thicker medial and lateral regions compared with the intermediate zone. However, regional

variations in thickness are less obvious in the coronal plane.

Sagittal view

Capsule

attachments

Joint capsule

Lateral ligament

Stylomandibular

ligament

Sphenomandibular

ligament

Capsule

attachments

Coronal view

FIGURE 23.2 Ligament and capsule attachments in the TMJ. The TMJ capsule and various mandibular ligaments

serve to guide and constrain mandibular movement. The capsule also separates intra- and extra-articular environments

and produces a closed space containing synovial ﬂuid, which serves both metabolic and lubricative functions. Various

specialized neural elements within the capsule provide sensory input to guide joint position and movement.

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23-4 Tissue Engineering

Zygomatic bone

Lateral plate of the

pterygold process

Lateral pterygold

Temporal bone

Medial

pterygold

Buccinator

Mandible

Pterygold

fovea on

the condylar

head

FIGURE 23.3 Lateral pterygoid attachment. Rotary opening and translatory movements of the mandible are the

result of contraction of the superior and inferior bellies of the lateral pterygoid muscle. This muscle originates from

the lateral surface of the lateral pterygoid plate and inserts into the pterygoid fovea, a depression in the anterior surface

of the condylar head.

While the mouth is capable of opening widely, an interincisal opening of greater than 40 mm is the

result of condylar rotation and translation. Most physiological opening movements are the result of smaller

rotations of the condylar head. Under normal conditions, these movements produce complex compressive

loads between the anterior surface of the condyle and the posterior slope of the articular eminence [5].

In the presence of a normally positioned disc, forces in this region are reduced and dissipated by the

interposed intermediate zone of the disc along with the lubricating actions of synovial ﬂuid. Only with

excessive opening are shear forces generated at the interface of the superior surface of the disc and the

glenoid fossa–eminence complex. The temporomandibular joints’ tissues, particularly the TMJ disc,

appear to have been designed to distribute both tensile and compressive forces during jaw movement.

The TMJ is enclosed by a ﬁbrous capsule, which encloses the joint on its medial and lateral aspects. Lat-

erally, the capsule is reinforced by the temporomandibular ligament. As described previously, attachments

between the capsule and disc produce closed superior and inferior joint spaces (Figure 23.2). The capsule

and ligament are highly innervated structures, containing a signiﬁcant number of receptors which are cap-

able of detecting stretch and pressure. Pacinian corpuscles, Rufﬁni nerve endings, Golgi tendon bodies,

and free nerve endings have all been identiﬁed in the joint capsule [6]. These receptors provide important

proprioceptive signals that guide the position of the mandible through neural relays with the muscles of

mastication. While joint sensation is commonly ascribed to the auriculotemporal nerve, the role of other

neurological mechanisms governing joint motion and mandibular position are not well understood. This

lack of characterization contributes to the morbidity associated with reconstructive procedures.

The inner surfaces of the capsule are lined by the synovial membrane, a specialized structure containing

cells and vessels responsible for both the phagocytosis of foreign particles and potentially pathological

organisms and the production of synovial ﬂuid. Synovial ﬂuid serves two principal functions within

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Tissue Engineering of the Temporomandibular Joint 23-5

a joint. As a lubricating ﬂuid, synovial ﬂuid is extremely effective exhibiting a coefﬁcient of friction

of approximately 0.00001. The lubricating action of synovial ﬂuid is complex in itself and involves the

interaction of multiple proteins [7]. Synovial ﬂuid also acts a medium for the transmission of nutrients

and the removal of metabolic waste from the cells present within the joint. As a dialysate of plasma,

it contains all the components of plasma with the exception of large coagulation proteins. This com-

position suggests that synovial ﬂuid is capable of performing most of the physiological functions of

blood and is essential to the viability of joint structures. Tissue engineering products aimed at recon-

struction of the TMJ or its components must be coupled with efforts to restore the functions of the

synovium.

Potential movement of the mandible through three planes of space has already been described.

Of interest is the considerably larger bulk of musculature responsible for closing movements as opposed

to opening and excursive actions. Closure of the mandible is under the inﬂuence of the masseter, tempor-

alis, and medial pterygoid muscles. These muscles form a robust sling around and above the mandible

that generate a considerable amount of force. In contrast, opening movements are produced through

the relatively small contractions of the superior head of the lateral pterygoid and (possibly) suprahyoid

muscles (Figure 23.4). This muscular arrangement suggests that under normal conditions, opening move-

ments constitute relatively passive actions through smaller ranges, while closure of the mandible invokes

a power stroke to resist loads imposed by gravity and the presence of a bolus of food between the teeth.

Consideration of the functional loads imposed upon the TMJ is critical in the design of tissue-engineered

constructs [3]. Constructs must survive joint loading conditions, especially if protective neuromuscular

controls are compromised by disease or surgical reconstructive procedures.

FIGURE 23.4 Muscles of mastication. In contrast to opening and side-to-side movements, mandibular closure is

produced by contraction of three large muscles: the temporalis muscle (B), masseter muscle (C), and medial pterygoid

muscle (D). These muscles, along with the lateral pterygoid (A), are collectively referred to as muscles of mastication

since their principal activity is associated with eating.

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23-6 Tissue Engineering

23.3 Microscopic Anatomy of the TMJ Disc

Extensive histological studies of the TMJ utilizing light and scanning electron microscopy have been

conducted in both human [8,9] and animal specimens [10,11]. Unlike most diarthrodial joints, the artic-

ular surfaces of the TMJ appear to be formed by nonvascularized and noninnervated ﬁbrous connective

tissue instead of hyaline cartilage, but these structures have not been completely characterized. The inter-

positional disc, on the other hand, is the subject of considerable interest in both human and animal models

and these studies conﬁrm that the disc is composed of ﬁbrocartilage with an organic matrix composed

primarily of collagen ﬁbers enclosing a mixed ﬁbroblastic and chondrocytic cell population [12–14].

In studies using porcine disc specimens, the ratio of ﬁbroblasts to ﬁbrochondrocytes is approximately

7 : 3 [14]. The presence of true chondrocytes, which are characteristic of hyaline cartilage, is debatable and

indicative of the difﬁculty in phenotyping cells on the basis of their light microscopic appearance, espe-

cially when artifactual errors are taken into consideration. Using collagen typing, which provides strong

evidence of the type of cell present based on its secretory product, a predominance of type I collagen in

the TMJ disc [12,13,15] implies that the major cellular constituent is derived from a ﬁbroblastic lineage.

Trace amounts of type II collagen and a procollagen precursor have also been detected in human discs

near the superior and inferior surfaces [16]. The cellular population of the disc appears to vary with age

and also with the animal model studied. This is not surprising considering the different functional loads

applied by various dietary patterns present in old and young ruminants and carnivores alike, and suggests

that discal cells possess the ability to differentiate (or dedifferentiate) according to function. In general,

higher cell numbers have been identiﬁed in the anterior and posterior bands relative to the intermedi-

ate zone [14]. The population of cells in the intermediate zone, subjected to greater compressive forces,

appears to be more chondrocytic than the anterior and posterior bands [14]. In the anterior and posterior

attachment regions, ﬁbroblasts and ﬁbrocytes predominate [14]. Smaller amounts of elastin ﬁbers and

other noncollagenous matrix proteins complete the organic structure of the disc [17].

The histological organization of the collagen ﬁbers in the disc shows considerable regional variation

between the intermediate zone and peripheral attachment regions [18]. In the central area of the inter-

mediate zone, the collagen ﬁbers are oriented primarily in an anterior–posterior direction. In areas where

the disc attaches to the condylar neck and skull base, the ﬁbers assume a ring-like structure (Figure 23.5).

The distribution of the elastin ﬁbers also appears to follow a circumferential pattern [17] with smaller

FIGURE 23.5 Collagen ﬁber alignment in the TMJ disc. The collagen ﬁbers of the TMJ disc are arranged in a

ring-like structure around the periphery of the disc. In the intermediate zone, the ﬁbers are predominantly aligned

in an anterior-posterior direction. In transition regions between the intermediate zone and the anterior and posterior

bands, the collagen ﬁbers curve medially, laterally, inferiorly, and superiorly.

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Tissue Engineering of the Temporomandibular Joint 23-7

Chondroitin sulfate

Keratan sulfate

Dermatan sulfate

Hyaluronic acid

<0.1%

0.5%

Lateral

1.5%

<0.1%

10%

0.7%

0.5%

Medial

0.7%

0.5%

<0.1%

Posterior

Approximate GAG distribution

in the porcine TMJ disc

FIGURE 23.6 GAG content and distribution in the TMJ disc. Chondroitin sulfate is the predominant GAG in the

TMJ disc, followed by dermatan sulfate. Keratan sulfate and hyaluronic acid GAGs are also found in the TMJ disc.

Regionally, the medial portion of the disc appears to possess the largest concentration of GAGs followed by the anterior

region. (Data from Detamore, M.S., et al. [2004] Matrix Biol. 24, 45–57. With permission.)

amounts of elastin present near the center of the disc and larger numbers of ﬁbers in the posterior

band [19]. By characterizing the disc according to the orientation of ﬁbers, a different functional view

of the disc is derived. Instead of dividing the disc into the intermediate zone and anterior and posterior

bands, the disc can be regarded as possessing a central zone surrounded by peripheral attachment regions.

The collagen ﬁbers also vary in appearance between the superior and inferior surfaces of the disc. Fibers

within the inferior surface of the disc exhibit a more wavy appearance than those closer to the superior

surface. This arrangement supports the need to dissipate larger compressive forces within the inferior

joint space as opposed to tensile forces in the superior joint space.

Atthe molecular level, the presence, type, and distribution of glycosaminoglycans (GAGs)helps determ-

ine the response of articular tissue to function. The literature is not entirely in agreement regarding the

total amount of GAGs present, the type and relative proportion of GAG, and the zonal distribution of

each GAG [10,20–24]. The variable observations may be the result of differences in the animal model

selected as well as different analytical techniques, which have included inhibition ELISA assays, ion

exchange chromatography, electrophoresis, high-performance liquid chromatography, and colorimetric

analysis [10,20–24].

Most studies suggest that GAGs represent between 0.5 and 10% of the dry weight of the TMJ disc

[10,20–25]. The predominant GAG appears to be either chondroitin sulfate or dermatan sulfate, with

small amounts of keratan sulfate and hyaluronic acid also detected [22,26]. Similar to the knee meniscus,

water content of the disc is high, approximately 70% [27]. Antero-posteriorly, the highest concentration

of chondroitin sulfate and keratan sulfate is found in the intermediate zone [10]. Medio-laterally, a higher

concentration of GAGs is found in the medial regions [10]. The approximate values of GAG content in

the TMJ disc are presented in Figure 23.6.

23.4 Biomechanical Behavior and Failure of the Disc

The TMJ disc under tension and compression exhibits signiﬁcant anisotropy [28–31]. This behavior is

believed to be directly related to the heterogeneous structure and organization of its cellular and molecular