CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE

Degenerative Disorders of the Temporomandibular Joint: Etiology, Diagnosis, and Treatment

E. Tanaka1*, M.S. Detamore2, and L.G. Mercuri3
of Orthodontics and Dentofacial Orthopedics, The University of Tokushima Graduate School of Oral Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan; 2 Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, KS, USA; and 3Department of Surgery, Division of Oral and Maxillofacial Surgery, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL, USA; *corresponding author, etanaka@hiroshima-u.ac.jp
1 Department

INTRODUCTION
n humans, the temporomandibular joint (TMJ) is now generally I considered to be load-bearing during masticatory function. Until 1980, however, this concept was controversial. Wilson (1920) reported that the fibrocartilage of the TMJ condyle was softer than hyaline cartilage, and therefore could not be load-bearing. Hylander and Bays (1979) indirectly measured TMJ condylar loading in the macaque with rosette strain gauges placed on the condylar neck, and found that the condylar bone surface was indeed loaded during function. Brehnan et al. (1981) and Boyd et al. (1990) directly measured the condylar loading in the macaque by means of a piezoelectric foil force transducer, and confirmed that the TMJ was indeed a load-bearing articulation. Other experimental and analytical studies (Smith et al., 1986; Koolstra et al., 1988; Korioth et al., 1992; Beek et al., 2000) have also demonstrated that the human TMJ was load-bearing under function. Although these studies are all simulations, partially performed on data from cadavers, they have shown that the fibrocartilaginous tissues, including the disc and articular cartilage, have important functions in stress distribution. TMJ disorders are characterized by intra-articular positional and/or structural abnormalities. Review studies published in the 1980s showed prevalence rates ranging from 16% to 59% for symptoms and from 33% to 86% for clinical signs (Carlsson and LeResche, 1995), although from 3% to 7% of the adult population has sought care for TMJ pain and dysfunction (Carlsson, 1999). It has been observed that up to 70% of persons with TMJ disorders suffer from displacement of the articular disc, coined 'internal derangement' of the TMJ (Farrar and McCarty, 1979). Meanwhile, the most common joint pathology affecting the TMJ is degenerative joint disease, also known as osteoarthrosis or osteoarthritis. Among individuals with TMJ disorders, 11% had symptoms of TMJ-osteoarthrosis (TMJ-OA) (Mejersj and Hollender, 1984). An epidemiological study, meanwhile, showed that minimal flattening of the condyle and/or eminence was seen in 35% of TMJs in asymptomatic persons (Brooks et al., 1992). More advanced osseous changes were not seen; therefore, it was concluded that minimal flattening was probably of no clinical significance. However, once the breakdown in the joint starts, TMJOA can be crippling, leading to a variety of morphological and functional deformities (Zarb and Carlsson, 1999). This paper is divided into four parts. Part 1 will review the definition and etiology of TMJ disorders. A basic review of the TMJ disorders, their etiologies, and the biomechanical and biochemical factors associated with functional overloading of the joint will also be discussed. Part 2 will discuss the clinical, radiographic, and biochemical analytical findings important in the diagnosis of TMJ-osteoarthrosis. Part 3 will present the noninvasive and invasive modalities utilized in TMJ-osteoarthrosis management. Finally, in Part 4, the possibility of tissue-engineering for treatment of TMJ disorders with degenerative changes will be discussed.

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ABSTRACT
Temporomandibular joint (TMJ) disorders have complex and sometimes controversial etiologies. Also, under similar circumstances, one person's TMJ may appear to deteriorate, while another's does not. However, once degenerative changes start in the TMJ, this pathology can be crippling, leading to a variety of morphological and functional deformities. Primarily, TMJ disorders have a non-inflammatory origin. The pathological process is characterized by deterioration and abrasion of articular cartilage and local thickening. These changes are accompanied by the superimposition of secondary inflammatory changes. Therefore, appreciating the pathophysiology of the TMJ degenerative disorders is important to an understanding of the etiology, diagnosis, and treatment of internal derangement and osteoarthrosis of the TMJ. The degenerative changes in the TMJ are believed to result from dysfunctional remodeling, due to a decreased host-adaptive capacity of the articulating surfaces and/or functional overloading of the joint that exceeds the normal adaptive capacity. This paper reviews etiologies that involve biomechanical and biochemical factors associated with functional overloading of the joint and the clinical, radiographic, and biochemical findings important in the diagnosis of TMJ-osteoarthrosis. In addition, non-invasive and invasive modalities utilized in TMJ-osteoarthrosis management, and the possibility of tissue engineering, are discussed. KEY WORDS: temporomandibular joint, degenerative disease, osteoarthrosis, tissue engineering.

Received April 17, 2007; Last revision January 21, 2008; Accepted January 23, 2008

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DEFINITION AND ETIOLOGY OF TMJ DISORDERS

Classification of TMJ Degenerative Disorders
Unlike rheumatoid arthritis, TMJosteoarthrosis has a non-inflammatory origin. The pathological process is characterized by deterioration and abrasion of articular cartilage and local thickening and remodeling of the underlying bone (Zarb and Carlsson, 1999). These changes are frequently accompanied by the superimposition of secondary inflammatory changes. Therefore, mechanically induced osteo arthrosis may better reflect TMJosteoarthrosis. Internal derangement of the TMJ is defined as an abnormal positional relationship of the disc relative to the mandibular condyle and the articular eminence (Fig. 1). Wilkes (1989) established 5 Figure 1. Magnetic resonance images of TMJ-internal derangement and -osteoarthrosis. Internal derangement of the TMJ is defined as an abnormal positional relationship of the disc relative to the stages based on clinical and mandibular condyle and the articular eminence, while TMJ-osteoarthrosis is characterized by structural imaging criteria. In Stage I, failure of articular cartilage in the early stage and by the deterioration of the cartilage and subchondral clinical observations include bone, resulting in shortening of the mandibular ramus and subsequent mandibular retrusion. Both internal painless clicking and unrestricted derangement and osteoarthrosis of the TMJ are regarded as a frequent cause of pain and/or disturbed mandibular motion. When imaged, mandibular movement. The characteristic radiographic sign of TMJ-osteoarthrosis is dysfunctional remodeling on the mandibular condyle and articular eminence surfaces with osteophyte formation. (A) At the disc is displaced slightly the initial stage, the disc reveals a slight anterior disc displacement but not complete displacement at the forward on opening, although it is intercuspal position. At maximum mouth opening, the disc is located between the condylar and temporal reduced at the maximum mouth bone surfaces, and the condyle and disc move harmoniously. Arrowheads indicate the anterior and opening ('reducing' refers to the posterior ends of the disc. (B) At the intercuspal position, the disc reveals anterior displacement, but not bony remodeling and deformation. On full opening, the disc reduces, usually resulting in 2 noises disc sliding back to a "normal" (reciprocal clicking). Arrowheads indicate the anterior and posterior ends of the disc. (C) Through anatomical position during mouth mandibular movements, the disc is displaced from its normal position, and on full opening, the disc opening, producing the audible deformity occurs because the condyles push the disc forward and downward. In this case, bony changes clicking sound), and the osseous on the condylar surface are not detected. Arrowheads indicate the anterior and posterior ends of the disc. contours appear normal (Fig. 1A). (D) The disc also reveals anterior displacement without reduction, in which the disc is severely deformed on full opening. Arrowheads indicate the anterior and posterior ends of the disc. Furthermore, the osteophyte In Stage II, there are complaints of of the peripheral cortical bone, indicated by arrows, is clearly detected, indicating TMJ-osteoarthrosis. (E) occasional painful clicking, The condyle shows severe bony deformation with flattening and erosion, indicating severe osteoarthrosis of intermittent locking, and the TMJ. Arrows indicate the deformed surface of the mandibular condyle. The disc also reveals anterior headaches. When imaged, the disc displacement without reduction. Arrowheads indicate the anterior and posterior ends of the disc. The individual at this stage is likely to have spontaneous joint pain and movement disability. appears slightly deformed and displaced slightly forward at maximum opening, but still reduces at maximum opening (Fig. displaced (YJ Chen et al. , 2000, 2002). A series of 1B). The osseous contours appear normal. In Stage III, experimental studies with surgical induction of anterior disc clinically, there is frequent joint pain and tenderness, displacement in the rabbit showed that disc displacement led to headaches, locking, and restricted range of mandibular motion, the degenerative changes in the condylar cartilage (Sharawy et as well as painful chewing. When imaged, anterior disc al. , 2000, 2003). In contrast, the apparent radiographic displacement is seen, with moderate thickening (Fig. 1C). This association of articular degeneration with disc displacement has disc reduces early in Stage III, but progresses to non-reducing led to the suggestion that the degenerative process may be a (i.e., locking) on opening in the later stage. The bony contours predisposing factor for disc displacement (Dijkgraaf et al., remain normal in appearance. At the maximum mouth opening, 1995). However, cadaver (Rohlin et al. , 1985), clinical the disc is subjected to deformity, because the condyle pushes (Westesson et al., 1989), and magnetic resonance imaging the disc forward and downward (Fig. 1C). Recent studies, using studies (Kircos et al. , 1987) have demonstrated that disc individual oblique-axial magnetic resonance imaging, have displacement is a common finding in asymptomatic shown that most anteriorly displaced discs were laterally

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individuals. In Stage IV, individuals complain of chronic pain, headache, and restricted mandibular range of motion. When imaged, a markedly thickened disc is anteriorly displaced and does not reduce on opening, and abnormal contours to both the condyle and articular eminence begin to become evident (Fig. 1D). In Stage V, clinically, individuals experience pain, crepitus, and pain with mandibular function. When imaged, the now grossly deformed disc is anteriorly displaced, without reduction, and degenerative changes are present in the osseous components of the articulation (Fig. 1E). The disease process is characterized by deterioration and abrasion of articular cartilage and disc surfaces, and occurrence of thickening and remodeling of the underlying bone. Therefore, osteoarthrosis may be a final common pathway for several joint conditions, including inflammatory, endocrine, metabolic, developmental, and biomechanical disorders (Zarb and Carlsson, 1999).

Etiology of TMJ Degenerative Disorders

Increased loading in the TMJ may stimulate remodeling, involving increased synthesis of extracellular matrices (Stegenga et al., 1989). Remodeling is an essential biological response to normal functional demands, ensuring homeostasis of joint form, and function and occlusal relationships (Smartt et al., 2005). Arnett et al. (1996a,b) proposed an explanation for the pathophysiology of the degenerative changes as one that results from dysfunctional articular remodeling due to (1) a decreased adaptive capacity of the articulating structures of the joint or (2) excessive or sustained physical stress to the TMJ articular structures that exceeds the normal adaptive capacity. The former is the host-adaptive capacity factor, which is associated with the host's general condition. Advancing age, systemic illness, and hormonal factors may define the hostadaptive capacity of the TMJ. This factor may contribute to dysfunctional remodeling of the TMJ, even when the biomechanical stresses are within a normal physiologic range. Age is clearly a predisposing factor, because both frequency and severity of the disease appear to increase with aging. For example, the calcium content of the human disc increases progressively with aging (Takano et al., 1999). This increase in calcification may be caused by aging as such, or by a changed mechanical stress (Jibiki et al. , 1999). Accordingly, the material properties of the disc can also be expected to be related to age (Tanaka et al., 2001). This implies that the disc becomes more stiff and fragile in nature, reducing its capability to handle overload. Articular cartilages can also change with aging. The molecular weight of hyaluronic acid in human articular cartilage decreases from 2000 to 300 kDa between the ages of 2.5 and 86 yrs (Holmes et al., 1988). Hyaluronic acid in articular cartilage is essential for it to maintain its viscosity, and any decrease in molecular weight can lead to reduction of its biorheological property in cartilage. Systemic illness may also influence fibrocartilage metabolism and could affect the adaptive capacity of the TMJ. These illnesses may include autoimmune disorders, endocrine disorders, nutritional disorders, metabolic diseases, and infectious disease. Hormonal factors may also have a marked influence on remodeling of the mandibular condyle. In these cases, the TMJ degenerative disorders may be the result of systemic disease. Mechanical factors can also cause changes in the TMJ structure. Despite host-adaptive capacity, excessive or unbalanced mechanical loading in the TMJ can cause overload

of articular tissues, resulting in the onset and progression of TMJ-osteoarthrosis. Furthermore, internal derangement of the TMJ may be induced by excessive or unbalanced stress in the TMJ. From a review of etiological mechanical events of TMJinternal derangement and -osteoarthrosis, trauma, parafunction, unstable occlusion, functional overloading, and increased joint friction play a role (Stegenga et al., 1989; Arnett et al., 1996a,b; Nitzan, 2001). These factors may occur alone or may be interrelated, interdependent, and/or coexistent. Macrotrauma in the condylar area can cause degeneration of the articular cartilage and production of inflammatory and pain mediators. Trauma has been reported to alter the mechanical properties of the disc (Nickel et al., 2001) and to cause mechanical fatigue of the disc (Beatty et al., 2001, 2003). Furthermore, it may cause cartilage degradation and production of inflammatory and pain mediators. TMJ alterations occurred over time after the macrotrauma, leading to progressive condylar resorption and deformation (Arnett et al., 1996b). However, only about one-third of the individuals with TMJ degenerative changes reportedly suffered previous trauma to the head and neck (Laskin, 1994). The mechanism of delayed condylar resorption and deformation in secondary macrotrauma is not understood, but the clinician should recognize the etiologic importance of the macrotrauma and long-term evaluation of the TMJ form and function after macrotrauma. Parafunction may produce abnormal compression and shear forces capable of initiating disc displacement and condylar and articular eminence degenerative changes (Gallo et al., 2006). Parafunctional hyperactivity of the lateral pterygoid muscle has been considered to lead to masticatory muscle pain (Hiraba et al., 2000; Murray et al., 2001). Since the superior head of the lateral pterygoid muscle attaches partly to the articular capsule of the TMJ and directly or indirectly to its articular disc (Murray et al., 2001), it has been hypothesized that dysfunction of this muscle can lead to TMJ-internal derangement and -osteoarthrosis (Hiraba et al., 2000). Functional overloading and increased joint friction may act together as etiological events for TMJ-internal derangement and -osteoarthrosis. Growing evidence suggests that functional overload with subsequent microtrauma is a crucial event for TMJ-internal derangement and -osteoarthrosis. Milam et al. (1998) proposed the direct mechanical injury and hypoxia/reperfusion injury model, suggesting that the oxidative stress results in the accumulation of free radicals that damage the articular tissues of the TMJ. Several studies have demonstrated the presence of reactive oxidative radical species in synovial fluid from diseased TMJs (Kawai et al., 2000; Takahashi et al., 2003).

Mechanism of Functional Overloading for TMJ Degenerative Disorders (Fig. 2)

In chondrocytes of articular cartilage, cyclic tensile loading upregulated the expression of matrix metalloproteinase (MMP)13 and vascular endothelial growth factor (VEGF) and downregulated the expression of tissue inhibitor of matrix metalloproteinases (TIMP)-1, while cyclic hydrostatic pressure induced opposite effects (Wong et al., 2003). VEGF expression in osteoarthritic cartilage appeared to increase progressively with the applied mechanical overload. Furthermore, VEGF induction in chondrocytes by mechanical overload has been linked to activation of hypoxia-induced transcription factor-1

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(Forsythe et al. , 1996). Recently, Tanaka et al. (2005a) showed that mandibular condylar cartilage in mechanically induced TMJosteoarthrosis expressed abundant VEGF. VEGF regulates the production of MMPs and TIMPs, which are among the effectors of extracellular matrix remodeling (Pufe et al., 2004). Reduction of TIMPs and induction of MMPs result in an imbalance in the turnover of extracellular matrix components, collagens, and proteoglycans, which are degraded more rapidly than they are formed. The loss of balance toward increased extracellular matrix degradation results in the destruction of cartilage (Pufe et al., 2004). The expression of VEGF is also up-regulated in the synovial tissues (Sato et al., 2003) and the TMJ disc Figure 2. The concept of the process of cartilage breakdown in the TMJ. A decreased adaptive (Leonardi et al., 2003) in TMJ-internal capacity of the articulating structures and/or excessive physical stress to the TMJ that exceeds the derangement. This suggests that normal adaptive capacity can induce dysfunctional remodeling. Functional overloading and VEGF expression is involved in the increased joint friction may act together as etiological events for TMJ degenerative changes. development of inflammatory changes Functional overloading can facilitate hypoxia in the TMJ and mediate the destructive processes associated with osteoarthrosis as an autocrine factor. Vascular endothelial growth factor (VEGF) in the TMJ as a reaction to the induction in osteoarthritic cartilage by functional overloading is linked to activation of the hypoxiacytokine. The increased expression of induced transcription factor-1, leading to hypoxia in the joint tissue. Furthermore, VEGF regulates VEGF in the joint tissues might lead to the production of matrix metalloproteinases and tissue-inhibitors of matrix metalloproteinases, which an increase of VEGF in the synovial are among the effectors of extracellular matrix remodeling. Overloading also causes collapse of joint fluid of persons with symptomatic lubrication as the result of the hyaluronic acid degradation by free radicals. The regulation of hyaluronic acid production is controlled by various pro-inflammatory cytokines. Of these cytokines, TMJ-internal derangement (Sato et al., tumor necrosis factor- and interleukin-1 and -6 play crucial roles in the pathogenesis of 2005). Consequently, mechanical osteoarthrosis with respect to the acceleration and progression of cartilage degradation, because overload induces hypoxia-induced they promote bone resorption through the differentiation and activation of osteoclasts. transcription factor-1, and the subsequently generated VEGF activates the chondrocytes in an 1991). Among other effects of reactive oxidative radical autocrine manner to produce MMPs and reduces TIMPs (Pufe species in synovial joints are inhibition of the biosynthesis and et al., 2004). This implies that VEGF is probably induced in degradation of hyaluronic acid, both causing marked reduction chondrocytes by mechanical overload, facilitating hypoxia and in viscosity of synovial fluid (Grootveld et al., 1991). mediating the destructive processes associated with In the healthy TMJ, the co-efficient of friction between the osteoarthrosis as an autocrine factor. cartilage surfaces can be assumed to be almost zero by the Furthermore, in the condylar cartilage with TMJpresence of synovial fluid (Tanaka et al., 2004; Nickel et al., osteoarthrosis, the number of blood vessels and osteoclasts is 2001, 2006). However, after an experimental abrasion of the markedly increased in the area subjacent to the hypertrophic articular cartilage comparable with TMJ-osteoarthrosis, the cocell layer, where several VEGF-expressing chondrocytes are efficient of friction was 3.5 times greater than that in the intact detected (Tanaka et al. , 2005a). Since VEGF plays an joint (Tanaka et al. , 2005b). As the coefficient of friction important role not only in endothelial cell recruitment, but also increases, the shear stresses between the articular surfaces, in osteoclast recruitment (Niida et al. , 1999), VEGF has within the disc, and articular cartilage become greater. Shear overlapping function in the support of osteoclastic bone stress can result in fatigue and damage and irreversibly deform resorption. Then, the increase in osteoclasts stimulated by the TMJ tissues, initiating TMJ-internal derangement and VEGF may induce destruction of cartilage, making vascular osteoarthrosis (Beatty et al., 2003; Tanaka et al., 2003). invasion into the condylar cartilage easier. Hyaluronan degradation is likely to occur in pathologic Overloading also causes collapse of joint lubrication, as the joints because of free-radical de-polymerization of the result of hyaluronan degradation by free radicals (Nitzan, hyaluronic acid chain (McNeil et al., 1985) or the abnormal 2001). With overloading, the increase in intra-articular biosynthesis of hyaluronic acid by type B synovial cells pressure, when it exceeds the capillary perfusion pressure, will (Vuorio et al. , 1982). Free radicals rapidly depolymerize cause temporary hypoxia, which is corrected by re-oxygenation hyaluronic acid in vitro , which may implicate them in the on cessation of degradation by the overloading. Such a degradation of hyaluronic acid in vivo . Furthermore, the hypoxia-reperfusion cycle has been reported to release reactive degradation of hyaluronic acid may lead to cartilage destruction oxidative radical species non-enzymatically (Grootveld et al.,

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Table 1. Classification of Arthritic Conditions Affecting the Joint.

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or high-inflammatory types. Here, the term "osteoarthritis" classically has been defined as a low-inflammatory arthritic condition without pain, Low-inflammatory Arthritic Disorders Degenerative joint disease (Osteoarthritis) either primary or secondary to trauma or other Post-traumatic arthritis acute and/or chronic overload situations, characterized by erosion of articular cartilage, High-inflammatory Arthritic Disorders Infectious arthritis which becomes soft, frayed, and thinned, resulting Rheumatoid arthritic conditions in eburnation of subchondral bone and outgrowth - adult and juvenile of marginal osteophytes. Meanwhile, the term Metabolic arthritic conditions "osteoarthrosis", a synonym for "osteoarthritis" in - gouty arthritis the medical orthopedic literature, has recently - psoriatic arthritis come to be identified in the dental TMJ literature - lupus erythematosus with any non-inflammatory arthritic condition that - ankylosing spondylitis results in degenerative changes similar to those in - Reiters Syndrome "osteoarthritis". However, in the dental TMJ - arthritis associated with ulcerative colitis literature, "osteoarthrosis" has come to be From Mercuri, 2006. identified with the unsuccessful adaptation of the TMJ to the mechanical forces placed on it with disc derangement or disc interference disorders in terms of the enhanced expression of MMPs (Ohno-Nakahara (Stegenga et al., 1989). Since the basic etiology, pathology, and et al., 2004). Since neither healthy nor inflammatory synovial management involved are the same, the terms "osteoarthritis" fluids contain hyaluronidase activity, reactive oxidative radical and "osteoarthrosis" will be used synonymously. species are assumed to cause hyaluronic acid depolymerization Low-inflammatory arthritic conditions begin in the matrix (McNeil et al., 1985). Considering the presence of reactive of the articular surface of the joint, with the subcondylar bone oxidative radical species in synovial fluid from diseased TMJs and capsule secondarily involved (Table 1). The classic types (Kawai et al. , 2000), it is strongly suggested that reactive of low-inflammatory arthritis are (1) degenerative joint disease, oxidative radical species generated in diseased TMJs cause the or primary osteoarthritis, produced by intrinsic degeneration of depolymerization of hyaluronic acid in synovial fluid. articular cartilage, typically the result of age-related functional The process of regulation of hyaluronic acid production is loading, and (2) post-traumatic arthritis. Despite the fact that also controlled by various cytokines, including interleukin-1, these low-inflammatory arthritic conditions often involve the tumor necrosis factor-, interferon-, and transforming growth TMJ, these conditions seldom require invasive surgical factor-. Tanimoto et al. (2004), using rabbit TMJ synovial intervention if they are managed appropriately in their early lining cells, demonstrated that TGF1 enhances the expression stages. Individuals with the low-inflammatory type have low of hyaluronic acid synthase-2 mRNA in the TMJ synovial leukocyte counts in the synovial fluid and laboratory findings membrane fibroblasts and may contribute to the production of consistent with low-level inflammatory activity, and the high-molecular-weight hyaluronic acid in the joint fluid. affected joint shows focal degeneration on imaging. Several pro-inflammatory cytokines have been detected in the High-inflammatory arthritic conditions primarily involve synovial fluid obtained from persons with TMJ-internal the synovial cells and joint bone (Table 1). The classic type of derangement and -osteoarthrosis (Kubota et al., 1998; Hamada high-inflammatory arthritis is rheumatoid arthritis. Other types et al., 2006). of high-inflammatory arthritic conditions include the metabolic Of these cytokines, tumor necrosis factor- and interleukinarthritic conditions, such as gout, arthritis of psoriasis, lupus 1 and -6, produced primarily by stimulated macrophages, play erythematosus, ankylosing spondylitis, infectious arthritis, crucial roles in the pathogenesis of rheumatoid arthritis and Reiter's Syndrome, and the arthritis associated with ulcerative osteoarthrosis, with respect to the acceleration and progression colitis. Although these disorders may be histologically and of cartilage degradation, because they promote bone resorption chemically different, clinical findings and management are through the differentiation and activation of osteoclasts (Boyle often similar. In all instances, the TMJ can be involved, and et al., 2003). A significantly high concentration of interleukin-6 surgical intervention may be required to alleviate symptoms was associated with severe synovitis, although interleukin-1 and correct associated functional and esthetic problems. and interleukin-6 were detected even in asymptomatic TMJs Individuals with high-inflammatory-type arthritis have high (Kubota et al., 1998). Interleukin-10 has also been suggested to leukocyte counts in the synovial fluid and laboratory findings prevent and reverse cartilage degradation in rheumatoid consistent with high-inflammatory activity, and show a more arthritis (van Roon et al., 1996). Recently, interleukin-10 was diffuse degeneration of the involved joints on imaging. detected even in synovial fluid obtained from persons with Signs and Symptoms of Arthritic Changes in the TMJ TMJ-internal derangement (Hamada et al. , 2006). These The most common symptom of any arthritic TMJ condition is findings suggested that cytokines in the synovial fluid might be painful joints. The pain arises from the soft tissues around the responsible for the progression and regulation of the affected joint and the masticatory muscles that are in protective degenerative changes in the TMJ. reflex spasm in accordance with Hilton's law. This orthopedic principle states that the nerves that innervate a joint also DIAGNOSIS innervate the muscles that move that joint and the overlying OF THE TMJ DEGENERATIVE DISORDERS skin. This self-preservation physiologic reflex provides for the TMJ arthritic conditions can be classified as low-inflammatory protection of an injured or pathologically affected joint by

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causing the surrounding Table 2. Classification of Osteoarthrosis Based on Symptoms, Signs, and Imaging with Management Options. musculature to contract reflexively in response to Stage Symptoms Signs Imaging Management Options intra-articular injury or pathology, thus protecting it I Joint/muscle pain Little or no Mild to moderate Non-Invasive from further damage. Pain Early Disease Limited function occlusal or facial erosive changes of or Minimally invasive may also arise from the Crepitus esthetic changes condyle/fossa/eminence subchondral bone that is undergoing destruction as II Little or no joint pain Class II malocclusion Flattened Bone and Joint the result of the arthritic Arrested Disease Muscle pain Apertognathia condyle/eminence Invasive or Salvage process. Some joint dysfunction Other common and Crepitus significant signs and symptoms of TMJ arthritis are III Joint/muscle pain High-angle Class II Gross erosive changes Salvage loss of joint function or lateAdvanced Disease Loss of function malocclusion Loss of condyle and stage ankylosis, joint +/-Crepitus Apertognathia eminence height instability, and facial de Progressive Developing Ankylosis formity due to loss of retrognathia fibrosis/ankylosis Hypertrophy of coronoid posterior mandibular vertiModified from Steinbrocker et al., 1949, and Kent et al., 1986. cal dimension, as pathologic osteolysis decreases the height of the condyle and splint, medications, orthotics, and physical therapy. In the condyloid process, resulting in apertognathia (Mercuri, 2006). clinic, the most common treatment of pain from the TMJ is by Diagnosis occlusal splints. Occlusal splints are an effective device to The diagnosis in late-stage arthritic TMJ disease is usually protect the TMJ from involuntary overloading, and to reduce obvious, especially in the late-stage high-inflammatory arthritic the muscle hyperactivity and articular strain due to bruxism. In diseases, when the disease process is manifest in other joints. a controlled study on the effects of occlusal splint therapy in The problem in diagnosis comes with the uncommon individuals with severe TMJ-osteoarthrosis, a reduction of individual whose arthritic disease first manifests itself as TMJ clinical signs was seen (Kuttila et al., 2002). However, critical pain and mandibular dysfunction. A history of joint overload evaluation of splint therapy has not yet been conducted, due to due to habits (e.g., excessive gum chewing, unilateral chewing) the lack of evidence, and their clinical effectiveness in relieving or parafunction ( e.g. , bruxism, clenching) and clinical pain seems modest when compared with that of pain treatment examination is important, but lacking any correlation between methods in general (Forssell and Kalso, 2004). None of the the signs and symptoms, as well as the history and physical occlusal adjustment studies provided evidence supporting the findings, the best approach to diagnosis may come in turning to use of this treatment method. imaging and laboratory examination. In terms of medications, non-steroidal anti-inflammatory agents, such as ibuprofen, should be used on a timeMANAGEMENT OF THE TMJ contingent basis to take advantage of their pharmacokinetics. DEGENERATIVE DISORDERS Muscle relaxants may be helpful in controlling the reflex masticatory muscle spasm/pain (Dionne, 2006). Oral Principles for Management of TMJ-Osteoarthrosis orthotics, while assisting in the control of parafunctional Management of TMJ-osteoarthrosis may be divided into nonhabits in many persons, also can provide relief from invasive, minimally invasive, and invasive or surgical masticatory muscle spasm/pain and, along with a soft diet, modalities. Finally, in end-stage disease, salvage modalities will decrease the loads delivered across the TMJ articulation must be considered. The decision for surgical management of under function. Reconstruction of the occlusion to provide TMJ-osteoarthrosis must be based on evaluation of the person's bilateral occlusal stability, temporarily during the early stages response to non-invasive management, the person's mandibular of management, also will decrease the potential for unilateral form and function, and the effect the condition has on the joint overload (Clark, 1984). Physical therapeutic modalities person's quality of life (Mercuri, 2006). The management goals act as counter-irritants to reduce inflammation and pain. in TMJ-osteoarthrosis should be: (1) decreasing joint pain, Superficial warm and moist heat or localized cold may relieve swelling, and reflex masticatory muscle spasm/pain; (2) pain sufficiently to permit exercise. Therapeutic exercises are increasing joint function; (3) preventing further joint damage; designed to increase muscle strength, reduce joint and (4) preventing disability and disease-related morbidity. contractures, and maintain a functional range of motion. Using a classification scheme based on clinical signs and Ultrasound, electrogalvanic stimulation, and massage symptoms and imaging, modified from that developed by techniques are also helpful in reducing inflammation and pain Steinbrocker et al. (1949) and Kent et al. (1986), we will (De Laat et al., 2003). present an evidence-based discussion for the management of Active and passive jaw movements, manual therapy TMJ-osteoarthrosis (Table 2). techniques, and relaxation techniques were used in the Non-invasive Management Modalities management of 20 consecutive persons with TMJosteoarthrosis. After treatment (mean, 46 days), pain at rest was The non-invasive modalities of management include occlusal

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reduced in the 20 persons by 80%, and there was no functional impairment in 37% of the 20 persons (seven persons) (Nicolakis et al., 2001).

challenge for management and reconstruction, the authors believe that, to complete the review of the topic, the invasive surgical modalities must be discussed in some detail.

Minimally Invasive Modalities

Injections Hyaluronic acid as an injectable, large, linear glycosaminoglycan has been studied in other body joints. In double-blind studies in other joints after 2 mos, hyaluronic acid has been shown to provide significantly better results than saline. These results were sustained for 1 yr. However, no significant differences were noted in radiographic progression of the disease (Lohmander et al., 1996). An in vivo rabbit study reported that the hyaluronic-acidinjected joints demonstrated limited cartilage change, less fibrillation, and the presence of clusters of chondrocytes in the deficit area, while the prednisolone-treated joint exhibited worsening of the cartilage destruction (Shi et al., 2002). However, to date, hyaluronic acid has not been approved by the United States Food and Drug Administration as a safe and effective medication in the management of arthritic disease in the TMJ. Intra-articular injections of corticosteroids are of limited use in other joints of the body (Gray and Gottlieb, 1983). The main limitations of repeated intra-articular steroid injections are the risks of infection and the destruction of articular cartilage. Repeated intra-articular corticosteroid injections have been implicated in the "chemical condylectomy" phenomenon in the TMJ (Toller, 1977). Intra-articular injections of steroids should be considered only in persons with evidence of acute high inflammation of the joint. Multiple injections of steroids should not be used. In all cases after intra-capsular injection of steroids, decreased activities within pain-free limits should be recommended, to prevent acceleration of the degenerative process from over-activity and joint overload. Arthrocentesis and Arthroscopy Nitzan and Price (2001) presented a 20-month follow-up study of 36 persons with 38 dysfunctional joints that had not responded to non-surgical management, to determine the efficacy of arthrocentesis in restoring functional capacity to the osteoarthrosis joints. They concluded that arthrocentesis is a rapid and safe procedure that may result in the TMJosteoarthrosis returning to a functional state. Failure of arthrocentesis (32%) suggested that painful limitation of TMJ function might be the result of fibrous adhesions or osteophytes that require arthrotomy for management. The value of TMJ arthroscopy may be in the early diagnosis and management of arthritic processes affecting the TMJ, especially early-stage arthritic disease, to avoid the complications of open bite and ankylosis (Holmlund et al., 1986). Holmlund et al. (1986) described the arthroscopic picture as varying widely, depending on when in the stages of the arthritic process the procedure is performed and whether disease-modifying therapeutic agents have been given. Latestage marked fibrosis or ankylosis makes arthroscopy impossible and contraindicates its usefulness. While the majority of persons with TMJ-osteoarthrosis can be successfully managed with non-invasive/minimally invasive procedures, there is a small percentage of persons with osteoarthrosis (< 20%) who have such severe pathology, pain, and dysfunction that invasive surgical management must be considered (Mercuri, 2006). Since the later cases present such a

Invasive Surgical Modalities (Bone and Joint Procedures)

Arthroplasty Reshaping the articular surfaces to eliminate osteophytes, erosions, and irregularities found in osteoarthritis refractory to other modalities of treatment was described by Dingman and Grabb (1966). While this technique reportedly provided pain relief, concerns about the resultant mandibular dysfunctions, dental malocclusions, facial asymmetries, and the potential for development of further bony articular degeneration, disc disorders or loss, and ankylosis led to the development of techniques for interposing autogenous tissues and alloplastic materials. The need for replacement of the articular disc in such cases remains controversial (Merrill, 1986). According to Moriconi et al. (1986), TMJ replacement grafts should fulfill the following criteria: biological compatibility, adequate strength, restoration of biomechanical function, and resistance to the adverse affects of the biological environment. Autogenous Hemi-arthroplasty Several different autogenous tissues have been advocated as a replacement for the TMJ disc (Merrill, 1986); however, the literature on the use of the vascularized local temporalis muscle flap appears to present the most applicable data for the management of the arthritic TMJ (Feinberg and Larsen, 1989). Osteotomy Individuals with active TMJ-osteoarthrosis and either concomitant or resultant maxillofacial skeletal discrepancies, and treated only with orthognathic surgery, often have poor outcomes and significant relapse (Wolford et al., 1994, 2003). Pre-existing TMJ pathology, with or without symptoms that can lead to unfavorable orthognathic surgery outcomes, includes: internal derangement, progressive condylar resorption, osteoarthritis, condylar hyperplasia, osteochondroma, congenital deformities, and non-salvageable joints (Wolford et al., 1994). Since the TMJs are the foundation of orthognathic surgery, the resultant pathology offers a poor base upon which to build any maxillofacial functional skeletal reconstruction in conditions where there are gross erosive changes in the articulating components of both the fossa and condyle, resulting in loss of vertical height. Further, the degenerative and osteolytic changes the joint components are undergoing in these conditions make these components of the TMJ highly susceptible to failure under the new functional loading resulting from orthognathic surgical repositioning of the maxillofacial skeleton. Osseodistraction Van Strijen et al. (2001) advised that, since osteoclastic activity in the TMJ has been reported after gradual distraction of the mandible, distraction osteogenesis may make its own contribution to TMJ-osteoarthrosis and idiopathic condylar resorption. They suggested that, in the future, persons being considered for surgical management of mandibular hypoplasia be critically evaluated for any traumatic, functional, or metabolic risk factors for TMJ-osteoarthrosis and idiopathic condylar resorption.

Salvage ProceduresTotal Joint Replacement

The costochondral graft has been the autogenous bone most

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frequently recommended for the reconstruction of the TMJ, due to its ease of adaptation to the recipient site, its gross anatomical similarity to the mandibular condyle, its low morbidity, its reported low morbidity rate at the donor site, and its demonstrated growth potential in juveniles (MacIntosh, 2000). However, orthopedists recommend alloplastic reconstruction when total joint replacement is required for the management of a non-growing person affected by either low-inflammatory or high-inflammatory arthritic disease (Chapman, 2001). In the TMJ, alloplastic reconstruction has been discussed at length (McBride, 1994; Mercuri, 1998, 1999, 2000). All of these authors agree that when the mandibular condyle is extensively damaged, degenerated, or lost, as in arthritic conditions, replacement with either autogenous graft or alloplastic implant is an acceptable approach to achieve optimal symptomatic and functional improvement. Long-term followup studies include individuals with diagnoses consistent with low- and high-inflammatory arthritic TMJs in their total alloplastic reconstruction datasets (Mercuri et al. , 2002; Mercuri and Giobbe-Hurder, 2004; Mercuri, 2006, 2007). In light of these findings, previously published experience in both orthopedic and oral and maxillofacial surgery, and the literature comparing autogenous with alloplastic total TMJ replacement in arthritic conditions, it appears that total alloplastic TMJ reconstruction should be considered appropriate management for advanced-stage TMJ osteoarthritic disease and idiopathic condylar resorption (Table 2).

group, which collectively supported the use of polyglycolic acid over agarose (Almarza and Athanasiou, 2004), promoted the spinner flask as the preferred seeding method with polyglycolic acid scaffolds (Almarza and Athanasiou, 2004), demonstrated the importance of using growth factors such as insulin-like growth factor-I (Almarza and Athanasiou, 2006b; Detamore and Athanasiou, 2005a), revealed the detrimental effects of passaging and pellet culture (Allen and Athanasiou, 2006b), recommended 25 g/mL as a preferred ascorbic acid concentration (Bean et al., 2006), and investigated the effects of hydrostatic pressure (Almarza and Athanasiou, 2006a) and rotating wall bioreactors (Detamore and Athanasiou, 2005b). Recently, another study has suggested the use of plateletderived growth factor-BB in TMJ disc tissue engineering (Hanaoka et al., 2006). Overall, the TMJ disc tissue-engineering studies to date have utilized various cell sources and biomaterials, evaluating the effects of different bioactive signals and bioreactors. The next major investigations into TMJ disc tissue engineering will be the incorporation of stem cell sources and the evaluation of in vivo performance of engineered TMJ discs.

Mandibular Condyle/Ramus Tissue Engineering

Unlike the TMJ disc, mandibular condyle/ramus tissueengineering studies did not appear in the literature until this decade. The largest contributions, thus far, have come from the groups of Hollister and Mao. Beginning in 2000, Hollister and colleagues developed a strategy for producing person-specific condyle-shaped scaffolds based on computed tomography and/or magnetic resonance images. By using solid free-form fabrication, they have been able to control not only the overall shape, but also the internal architecture, providing for precise control over pore size, porosity, permeability, and mechanical integrity. Solid free-form fabrication methods such as stereolithography and selective layer sintering work by creating scaffolds layer by layer. In this manner, Hollister and colleagues have engineered cylindrical osteochondral constructs (Schek et al. , 2004, 2005) and condyle/ramusshaped bone constructs (Williams et al., 2005), using materials such as hydroxyapatite, polylactic acid, and polycaprolactone and mature cell sources (fibroblasts with bone morphogenic protein-7 gene inserted and/or chondrocytes). In vivo studies collectively demonstrated substantial bone ingrowth and glycosaminoglycan formation (Schek et al. , 2004, 2005; Hollister et al., 2005; Williams et al., 2005). Mao's group (Alhadlaq and Mao, 2003, 2005; Alhadlaq et al., 2004) has taken a different approach, encapsulating marrow-derived mesenchymal stem cells in a polyethylene glycol diacrylate hydrogel to create stratified bone and cartilage layers in the shape of a human condyle. After 12 weeks in vivo, it was shown that osteopontin, osteonectin, and collagen I were localized in the osteogenic layer, and collagen II and glycosaminoglycans were localized in the chondrogenic layer (Alhadlaq and Mao, 2005). Beyond these two primary groups, various different approaches have been used, most of which were in vivo studies using only histology and/or imaging to validate engineered constructs. A pair of studies molded coral into the shape of a human condyle and seeded it with mesenchymal stem cells, then implanted it either with bone morphogenic protein-2 in mice, to demonstrate osteogenesis (YJ Chen et al., 2002), or

LOOKING TO THE FUTURE: TISSUE ENGINEERING

The next generation of TMJ implants will be biological constructs fabricated with tissue-engineering technology. Currently, the TMJ disc and the mandibular condyle have been the focus of tissue-engineering efforts, pursued by only a limited number of groups in the world. In the long term, regenerative therapies may need to combine both of these structures into a single implant, and to expand the focus to include surrounding structures, such as the retrodiscal tissue and the fossa-eminence of the temporal bone (Detamore et al., 2007). However, the disc and condyle are the highest priority for clinical application.

TMJ Disc Tissue Engineering

To date, tissue-engineering investigations of the disc and the condyle have been conducted independent of one another. Both the condyle and disc tissue-engineering communities have made significant advances in recent years, although the disc investigations began much earlier. Four TMJ disc tissueengineering studies were published from 1991 to 2001 (Detamore and Athanasiou, 2003), and while important issues were addressed, such as cell source, biomaterials, and shapespecific scaffolds, the common theme among these pioneering studies was an unfamiliarity with the available characterization data for the TMJ disc in terms of cell content and matrix composition. In 2001, strategies for TMJ tissue engineering, including cell sources, scaffolding materials, and signaling, were reviewed (Glowacki, 2001), and a photopolymerization method for developing a shape-specific TMJ disc scaffold was developed (Poshusta and Anseth, 2001). However, it took 3 years before the next wave of TMJ disc tissue-engineering studies was published, all of which utilized cells derived from the TMJ disc. Most of these studies were from Athanasiou's

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under blood vessels in rabbits, to demonstrate construct vascularization (Chen et al., 2004). Another pair of studies implanted acellular poly(lactic-co-glycolic acid)-based constructs with growth factors in rat mandibular defects, demonstrating either the efficacy of transforming growth factor-1 and insulin-like growth factor-I (Srouji et al., 2005) or the lack of efficacy of bone morphogenic protein-2 (Ueki et al., 2003) under the prescribed conditions. In another case, osteoblasts were seeded into condyle-shaped polyglycolic acid/polylactic acid scaffolds, and chondrocytes were painted on the surface prior to implantation in mice, after which positive histological results were observed (Weng et al., 2001). In a related study, porcine mesenchymal stem cells seeded in condyle-shaped poly(lactic-co-glycolic acid) scaffolds were cultured under osteogenic conditions in a custom-built rotating bioreactor, which also yielded positive histological results (Abukawa et al. , 2003). Finally, a recent study compared human umbilical cord matrix mesenchymal stem cells with porcine condylar cartilage cells for condylar cartilage tissue engineering, showing that the umbilical cord matrix stem cells outperformed the cartilage cells, especially with regard to proliferation and to chondroitin sulfate and overall glycosaminoglycan synthesis (Bailey et al., 2007). The next major step for mandibular condyle/ramus tissue engineering will be demonstrating long-term in vivo efficacy with osteochondral condyle/ramus replacements in larger animals (e.g., pig), which will require an understanding of the growth and mechanics of the native tissue (Herring and Ochareon, 2005).

Future Directions in TMJ Tissue Engineering

Despite its short history and the relatively few published reports, significant advances have already been made in TMJ tissue engineering. At this stage, we are still several years away from bringing tissue-engineering technology to the clinic for individuals with TMJ. Although it would be premature to speculate as to how and when these models can be applied to humans, there are nonetheless areas of pressing clinical interest that have been identified for the near future. In particular, primary issues to be addressed in the coming years include attachment, integration, metaplasia, angiogenesis, the person's age, marketing, and creating a condyle-disc composite scaffold (Detamore et al., 2007). Biomechanical models of the TMJ are becoming highly sophisticated, especially with recent additions to the literature characterizing tissue properties, which will be invaluable in predicting mechanical design requirements for engineered constructs.

to achieve these goals can range from non-invasive therapy, to minimally invasive and invasive surgery. Most people can be managed non-invasively, and one must acknowledge the importance of disease prevention and conservative management in the overall treatment of persons with TMJ. The decision to manage TMJ-osteoarthrosis surgically must be based on evaluation of the person's response to non-invasive management, his/her mandibular form and function, and the effect of the condition on his/her quality of life. To date, although systemic illness, aging processes, hormonal factors, and behavioral factors have been implicated in the etiology of TMJ-osteoarthrosis, growing evidence suggests that mechanical overload may be assumed to be an initiating factor for a series of degenerative changes in the TMJ, resulting in condylar resorption and deformity. Therefore, an evaluation of the biomechanical environment in the TMJ would lead to a better understanding of the inducing mechanism of TMJ pain and disability, which result in proper diagnosis and available treatment planning for TMJ degenerative disorders. A proper understanding of the biomechanical behavior of the joint components and biomechanical environment within the TMJ also provides better focus in the search for and selection of mechanically compatible synthetic or regenerative biomaterials for TMJ reconstruction. While tissue engineering may revolutionize the future of TMJ treatment, it will be absolutely necessary to remember the lessons learned from decades of successes and failures with TMJ implants. Moreover, tissue-engineered joint structures may be doomed to failure unless the etiology of the underlying degenerative processes is identified and managed. Therefore, an understanding of the pathobiology of TMJ degenerative disorders and current clinical treatment, as described in this article, will be essential to the successful integration of tissue engineering into the future surgical management of TMJ pathology.

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CONCLUSIONS
The importance of developing an evidence-based approach to clinical management and treatment must be emphasized. Often, in the past, treatment of clinical disorders has been based purely upon experience and knowledge gained through clinical training. This often resulted in various management modalities for the same condition, as well as in ineffective, expensive, unvalidated, and sometimes potentially harmful interventions. The goal of evidence-based medicine is to move beyond anecdotal clinical experience by bridging the gap between research and clinical practice. With respect to the degenerative pathology of the TMJ, the treatment goals for affected individuals include restored function and pain reduction. The management modalities used

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