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Int J Oral Maxillofac Implants. Author manuscript; available in PMC 2015 March 04.
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Published in final edited form as:

Int J Oral Maxillofac Implants. 2013 ; 28(6): e393–e414.
Temporomandibular Joint Disorders: A Review of Etiology,

Clinical Management, and Tissue Engineering Strategies
Meghan K. Murphy, BEa, Regina F. MacBarb, BSa, Mark E. Wong, DDSb, and Kyriacos A.
Athanasiou, PhD, PEa,*
Meghan K. Murphy: [email protected]; Regina F. MacBarb: [email protected]; Mark E. Wong:
[email protected]
aUC Davis, Department of Biomedical Engineering, Davis, CA, USA, One Shields Ave, Davis, CA
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95616, Phone: 530 754 6645, Fax: 530 754 5739

bDepartment of Oral and Maxillofacial Surgery, The University of Texas School of Dentistry at
Houston, Houston, TX, USA, 6516 MD Anderson Blvd. Houston, TX 77030, Phone: 713 500 4125
Abstract
Epidemiology reports state temporomandibular joint disorders (TMD) affect up to 25% of the
population, yet their etiology and progression are poorly understood. As a result, treatment options
are limited and fail to meet the long-term demands of the relatively young patient population.
TMD are a class of degenerative musculoskeletal conditions associated with morphological and
functional deformities. In up to 70% of cases, TMD are accompanied by malpositioning of the
TMJ disc, termed “internal derangement.” Though onset is not well characterized, correlations
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between internal derangement and osteoarthritic change have been identified. Due to the complex
and unique nature of each TMD case, diagnosis requires patient-specific analysis accompanied by
various diagnostic modalities. Likewise, treatment requires customized plans to address the
specific characteristics of each patient’s disease. In the mechanically demanding and
biochemically active environment of the TMJ, therapeutic approaches capable of restoring joint
functionality while responding to changes in the joint have become a necessity. Capable of
integration and adaptation in the TMJ, one such approach, tissue engineering, carries significant
potential in the development of repair and replacement tissues. The following review presents a
synopsis of etiology, current treatment methods, and the future of tissue engineering for repairing
and/or replacing diseased joint components, specifically the mandibular condyle and TMJ disc.
Preceding the current trends in tissue engineering is an analysis of native tissue characterization,
toward identifying tissue engineering objectives and validation metrics for restoring healthy and
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functional structures of the TMJ.
Keywords
TMJ; TMD; TMJ Disc; Condyle; Cartilage; Tissue Engineering
*
Corresponding author: K.A. Athanasiou, Phone: 530 754 6645, Fax: 530 754 5739, [email protected].
Murphy et al. Page 2
INTRODUCTION
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The temporomandibular articulation is composed of bilateral, diarthrodial,

temporomandibular joints (TMJs). Each joint is formed by a mandibular condyle and its
corresponding temporal cavity (glenoid fossa and articular eminence), as seen in Fig. 1. The
TMJ and its associated structures play an essential role in guiding mandibular motion and
distributing stresses produced by everyday tasks, such as chewing, swallowing, and
speaking. TMJ disorders (TMD) are a class of degenerative musculoskeletal conditions
associated with morphological and functional deformities.1, 2 TMD include abnormalities of
the intra-articular discal position and/or structure as well as dysfunction of the associated
musculature.3 Symptoms and signs include painful joint sounds, restricted or deviating
range of motion, and cranial and/or muscular pain known as orofacial pain.
While up to 25% of the population may experience symptoms of TMD,4 only a small
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percentage of afflicted individuals seek treatment. For instance, studies in the 1980s detected
TMD symptoms in 16% to 59% of the population,5 although only 3% to 7% of the adult
population actually sought care for pain and dysfunction associated with TMD.6
Furthermore, TMD symptoms occur disproportionately between the sexes with a much
higher incidence reported in females; female to male ratios range between 2:1–8:1.4, 7–9
Most patients presenting symptoms are between 20 and 50 yrs of age,9–11 an unusual
distribution for a disease that is considered a degenerative disorder.11
Up to 70% of TMD patients suffer from pathology or malpositioning of the TMJ disc,
termed “internal derangement” (ID).12 While disease progression is poorly understood, the
primary pathology appears to be a degenerative condition, known as osteoarthritis (OA) or
osteoarthrosis, depending on whether inflammatory or non-inflammatory states exist,
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respectively. In a study of patients presenting unilateral TMD pain symptoms during

function, palpation, and assisted or unassisted mandibular opening (n=131), it was reported
that 54.2% of individuals showed osteoarthritis in the affected joint.13 Asymptomatic
patients, whose discs are identified by magnetic resonance imaging (MRI) in the “normal”
anatomical position, show minimal morphological change in the condyle and articular
eminence in light of normal adaptive processes. In contrast, substantial osseous change is
observed in symptomatic patients with ID.14 Osteoarthritic changes observed during TMD
include deterioration and abrasion of articular cartilage, and thickening and remodeling of
underlying bone.1 In TMD patients, it is readily apparent that once joint breakdown
commences, OA can be crippling, leading to morphological deformity and functional
obstruction.1
As related to Wilkes’ stages of internal derangement of the TMJ,9 management options vary
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with respect to the severity of degeneration. Non-invasive and minimally invasive options
exist for patients in the early stage of ID progression. Minimally invasive and sub-total
reconstruction options exist for intermediate stage patients. Fully invasive, total joint
replacements are the only option currently available for patients in late stage ID progression.
Unfortunately however, many patients require repeat or follow-up surgery, indicating little
promise for the long-term success of this management option.
The following review presents disease etiology, diagnosis, and management with an
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emphasis on the future of tissue engineering for joint reconstruction. Inherently, a discussion
of native TMJ tissue characterization precedes review of the current progress in tissue
engineering, as native tissue characterization is essential to identifying design objectives and
validating progress.
DISEASE ETIOLOGY AND DIAGNOSIS

Remodeling of the load-bearing joints is an essential adaptation process needed for
appropriate stress distribution and function. It has been established that, while progressive
and regressive, mechanically-induced remodeling is a normal process early on. When the
capacity for the joint to remodel has been exceeded, remodeling merges into
osteoarthritis.15, 16 Characteristic osteoarthritic changes observed in the TMJ include
alterations in shape and overall size of joint components, specifically, flattened fossa, less
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pronounced articular eminence, decreased condylar volume and thickened disc, see Fig. 2.15
Degenerative remodeling present in pathologic TMJs may result from either decreased
adaptive capacity in the articulating structures or from excessive or sustained physical stress
to the articulating structures.3, 17, 18 Important to our understanding of TMD etiology, such
degenerative changes have been correlated with internal derangement of the TMJ disc.
While the simultaneous or subsequent progression of ID and OA is not completely

understood, it is established that a correlation exists between the two. In the previously
mentioned study of patients reporting unilateral orofacial pain referred to or within the TMJ
during palpation, function, and assisted or unassisted mandibular opening, a significant
relationship was identified between MRI diagnosis of TMJ ID and TMJ OA.13 In light of the
degenerative changes observed most commonly, including erosion of the articulating
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surfaces, followed by flattening and reformation, it is considered more plausible that ID

precedes OA, rather than the reverse.9, 19, 20 Corroborating this hypothesis, a series of rabbit
studies showed surgically induced ID led to degenerative changes in the condylar
cartilage.21 In a third possibility, ID and OA are initiated simultaneously in response to a
causative event. This possibility has been explored, and it was shown that excessive loading
produced by postero-superior displacement of the rabbit mandible can cause simultaneous
ID and OA onset in the rabbit TMJ.22 Though studies have yet to determine the cause and
effect relationship, a clear correlation exists between displacement of the TMJ disc and
development of OA. Until progression is better understood, treatment modalities must
address all possible scenarios.
Although the onset of TMD is poorly understood, Wilkes9 has established a five stage
system for classifying the progression of internal derangement based on clinical and imaging
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criteria. A schematic depicting anterior disc displacement, as described by Wilkes’ stages,

may be seen in Fig. 3. In Stage I, clinical observations include painless clicking early in
opening and late in closing with unrestricted mandibular motion. Imaging observations
indicate slight forward displacement of the disc, with passive incoordination as the disc
returns to the “normal” anatomical position (ID-reducing). Osseous contours appear normal.
In Stage II, symptoms include occasional pain with clicking, intermittent locking, and
orofacial pain. Imaging shows slight deformation of the disc and slight forward
displacement but as in Stage I, the disc reduces to the “normal” position at maximal
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opening. Osseous contours again appear normal. Stage III, on the other hand, is associated
with frequent orofacial pain as locking becomes more frequent and mandibular motion
becomes restricted. When imaged, the disc is clearly displaced anteriorly to its “normal”
anatomical position. Moderate disc thickening is also apparent. Early in Stage III the disc
reduces at maximal opening but fails to do so as the stage progresses (ID-non-reducing). In
this case, at maximal opening (terminal translation) the disc deforms in response to the
condyle pushing forward and downward on it. The osseous contours, however, remain
normal in appearance. In Stage IV, contours begin to change. Clinical symptoms include
chronic pain and restricted mandibular motion. Observed during imaging, the displaced disc
is markedly thickened and does not reduce upon maximal opening. Imaging also shows
evidence of abnormal bony contours on the condyle and articular eminence. Stage V, the
most advanced stage, is associated with similar clinical and imaging observations as Stage
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IV, but with more significant progression. Patients with Stage V degeneration experience
chronic pain, crepitus, and significantly restricted range of motion. Imaging shows gross
deformation and thickening of the non-reducing, anteriorly displaced disc, as well as
degenerative changes. These changes include abrasion of the articular cartilage and disc
surfaces, as well as thickening and remodeling of the underlying bone.
Clinical observations demonstrate that numerous factors may play a role in the progression
of TMD and associated degenerative changes. Thus, each TMD case much be treated
uniquely. Such factors include the independent or interrelated roles of trauma, parafunction,
unstable occlusion, functional overloading, and increased joint friction.3, 17, 18, 23, 24 The
respective roles of each of these potential components are controversial, however, as direct
cause and effect relationships have not been determined with consistency. For example,
overloading the joint through excessive or unbalanced stress may result in the onset and
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progression of OA as well as ID. However, contributions are difficult to establish due to the
significant time necessary for degeneration to occur in the face of small changes in loads.
Also demonstrating the lack of causal relationships, while some patients with dental
malocclusions do progress to clinically significant TMD, many do not. It is clear that little is
known about the independent or interrelated roles of each of these factors. If treatment is to
include reconstruction with biological tissues, we must attempt to recognize and address all
factors potentially contributing to joint degeneration. Consequently, each patient needs to be
analyzed uniquely and treatment approaches customized to address specific characteristics
of the disease.
Resulting from the diverse nature of TMD symptoms, patient evaluation often requires a
physical examination along with various imaging modalities. As previously mentioned,
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there exists a population of individuals experiencing unilateral or bilateral disc displacement

(presence or absence of joint noises) and minimal osseous change, but these individuals
have not progressed to clinically relevant TMD.14, 26–28 Therefore, various diagnostic
modalities, including clinical and radiological examination, may be necessary to identify the
stage of degeneration in patients presenting with possible TMD symptoms. Steadfast rules
remain to be established regarding imaging for TMD diagnosis under the current Research
Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). As result, TMD
identification may involve any combination of the following modalities: MRI, conventional
and computed tomography (CT), plain and panoramic radiography, arthrography, a thorough
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history, and physical examination. CT is considered most beneficial for imaging bone and
OA, while MRI is considered most beneficial in imaging soft tissues, including the disc and
its joint relation.25, 26 Patient evaluation, together with various imaging modalities, may help
to elucidate a patient’s stage of degeneration, aiding in diagnosis and treatment planning.
CLINICAL MANAGEMENT
For patients seeking management of TMD symptoms, it has been established that non-
invasive modalities should first be explored. However, the complicated nature of the TMJ,
along with the debilitating nature of late stage disease, has created a demand for more
invasive solutions. An analysis of current non-invasive, minimally invasive, and fully
invasive management options now follows. The ultimate goals of the presented modalities
are to: 1) increase mandibular range of motion, 2) decrease joint and masticatory muscle
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pain and inflammation, and 3) prevent further degenerative change in articulating tissues,
including direct or indirect joint damage.3
Non-Invasive
The non-invasive modalities implemented most commonly include physical therapy,
occlusal splints and/or adjustments, and pharmacologics. Beginning first with physical
therapy, electrophysical modalities and manual/exercise techniques are used to relieve pain
in the joint and masticatory muscles, and improve range of motion.27 Physical therapists
may complement these techniques with behavioral changes by drawing awareness to the
patient’s posture, diet, and stress-related habits. Electrophysical modalities include
transcutaneous electric nerve stimulation (TENS), ultrasound, and laser.28 Such modalities
are implemented to reduce inflammation, increase local blood flow, and promote muscle
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relaxation.28 Current research does not point to any significant decrease in pain in
electrophysically treated patients. In fact, one study of 23 bruxists showed a significant
increase in range of motion and a decrease in muscular activity with muscular awareness
relaxation training over the TENS treatment group.29 Manual therapies designed to increase
mobility and reduce pain have shown promise and are often used in conjunction with
exercise techniques. Such exercise techniques work to strengthen and improve mobility in
the masticatory and cervical spine muscles.30 Furthermore, these techniques offer the
potential to “re-teach” and rehabilitate the musculature. This observation is especially noted
in patients exhibiting stress-related habits.31 Along with exercise techniques, postural
exercises may aid in alignment of the craniomandibular system. Intended to relieve pain
associated with TMD and improve range of motion, physical therapy treatment plans must
be patient-specific and may involve a combination of modalities.
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Also non-invasive, occlusal splints and occlusal adjustments work to establish balance in the
occlusion and TMJs. The occlusion, or bite position, is a third and important element in the
joint system and is the element often addressed by general dentists. Adjustments and splints
may be used to achieve the most stable and least joint- traumatizing bite position. The
ultimate goal of splints and adjustments is to minimize pain in the joint and masticatory
muscles by establishing stability. Furthermore, as reviewed by Ingawale and Goswami,32
splints may be used to control bruxism, which has been associated with tooth attrition,
malocclusion, myofacial pain, and masticatory muscle strain, fatigue, and fibrosis. The
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literature has shown mixed results associated with splint use. These results are not surprising
considering that the role of malocclusion in TMD progression remains poorly understood.
Occlusal splints and adjustments may be suggested to reestablish balance in the joint system,
but the long-term effectiveness of this therapy remains controversial.32
Regarding pharmacologic agents, commonly prescribed non-steroidal anti-inflammatory

drugs (NSAIDs) offer advantages in reducing inflammation. Research, however, is needed
to exploit long-term use and to identify whether the advantages in management of pain and
inflammation outweigh the negative side effects.33 Muscle relaxants may also be prescribed
for treatment of muscle pain and/or spasm.34 However, studies have failed to demonstrate
that muscle relaxants are any more effective in pain relief than NSAIDs.35 To improve their
benefit, muscle relaxants are often used in combination with NSAIDs. NSAIDs may
therefore be recommended for their anti-inflammatory and analgesic benefits yet further
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research is needed to elucidate the benefits and risks of both short and long-term use.
Minimally Invasive
Minimally invasive modalities for management of TMD symptoms include sodium
hyaluronate and corticosteroid injections, arthrocentesis, and arthroscopy. Injections of
corticosteroids and high molecular weight sodium hyaluronate in the superior joint space are
designed to treat osteoarthritic symptoms. With research indicating both regenerative and
degenerative responses to such injections, their use remains controversial.34 The
pathophysiology of the disease indicates there may be more significant potential for these
injections in early stages of degeneration when inflammation first begins to exacerbate
tissue catabolism.3, 36
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Similar to intra-articular injections, arthrocentesis and arthroscopic surgery are minimally

invasive techniques requiring entrance into the joint capsule to lubricate articulating surfaces
and reduce inflammation. During arthrocentesis, a sterile needle is used to drain fluid from
the joint.37 After draining, the joint is flushed of debris and inflammatory cytokines using a
sterile solution.37 During the procedure, the physician may also attempt to restore some
range of motion with mandible manipulation.38 Through arthroscopic surgery, a slightly
more invasive procedure, the surgeon may break intra-articular adhesions that may be
preventing disc reduction in ID patients.39 With joint visualization during surgery,
arthroscopy offers advantages in TMD stage diagnosis and identification of OA. While
arthroscopic surgery and arthrocentesis may be used to lubricate joint surfaces and reduce
inflammation, further research is needed to identify long-term advantages especially in the
absence of disc repositioning or replacement.38, 40
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Invasive
For the 5% of TMD patients whose nonsurgical methods fail, open joint surgery may be
necessary to restore mandibular motion and mitigate orofacial pain.41 Most commonly, open
joint surgery may include discectomy, reshaping or reconstruction of the articulating
surfaces, and implantation of autologous or alloplastic materials.42 Total joint replacement,
the most invasive option, may become necessary when joint degeneration and pain exceed
the potentials of the less invasive surgical methods. Condylar replacements in clinical use
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include autologous costochondral grafts, but autologous full joint replacements are not
currently available. Alloplastic joint replacement systems, including total joint prostheses
and hemiarthroplasties, have been in development since the 1960s. The currently available
systems have, however, seen substantial modifications since their inception.
Discectomy and Disc Replacement—In TMD patients presenting with limited range
of motion, discectomy offers one means of regaining mandibular motion and reducing
orofacial pain, and may be followed by disc replacement. Discectomy has been shown in 5
and 10 yr post-operative follow-ups to increase mandibular motion in patients previously
showing no improvement with non-invasive management modalities.43, 44 Radiographic
changes in these long-term studies indicate evidence of osteophytes and flattening of
articular surfaces in such joints.43–45 Though the mechanism is poorly understood, some
authors conclude such changes are indicators of adaptive change rather than degenerative
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disorders.43–45 In some patients, however, OA-like changes continue to exacerbate,

necessitating the development of autologous and alloplastic disc substitutes. Such
substitutes, including subcutaneous fat grafts and alloplasts, are aimed at providing a
protective cushion for the articulating surfaces of the joint during rotation and translation.
Unfortunately, previous attempts with alloplastic disc replacements have often failed.46, 47
Likewise, fat grafts may not sufficiently protect the articulating surfaces. Often, following
implantation, the graft is displaced posterior to the condyle.48 The lack of clinical success
associated with disc replacement therapies may be the result of varying responses to the
respective materials used. For example, with certain alloplasts, most notably the composite
Teflon-Proplast implant, degradation of the implant material led to particulate debris that
stimulated an osteolytic local foreign body reaction. It was observed that this response
eventually led to resorption of the condylar head and fossa, producing perforations in the
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middle cranial fossa. Other more inert materials, such as silicone-based disc implants,
produced a fibrotic response resulting in capsule formation around the implant. Progression
of this reaction led to restricted movement of the joint due to the development of an intra-
articular scar band. A similar response has also been noted with the use of interpositional fat
grafts. If the fat becomes de-vitalized, it undergoes replacement with fibrous tissue and the
resultant scar reduces movement of the joint. Patient experience with disc replacement
demonstrates the unanswered need for autologous tissue replacements, capable of function
in the complex loading environment of the TMJ. While discectomy may be implemented to
improve mandibular range of motion, patients experiencing continued joint degeneration
reveal the need for a functional, non-pathogenic disc replacement.
Joint Reconstruction—Several techniques have been proposed for reconstruction of

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portions of the joint or the entire joint itself. For sub-total reconstruction, a hemiarthroplasty
may be used to replace the superior articulating joint surface.47 During reconstruction, joint
adhesions are lysed and a vitallium alloy fossa-eminence prosthesis, manufactured by TMJ
Implants, is implanted to replace the temporal component of the joint. As reviewed by
McLeod et al.,49 a hemiarthroplasty can produce successful results in patients where the
condyle is unaffected by severe degenerative changes. Importantly though, condylar change
often accompanies degenerative change in the temporal component of articulation. In this

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case, total joint reconstruction may be necessary.
Total Joint Reconstruction—Reconstruction of the entire joint is indicated when a

substantial portion of the joint is lost. Such loss can result from joint removal due to
pathology, joint destruction due to trauma, or significant degeneration in the articulating
surfaces of the joint, resulting in skeletal changes and malocclusion. Severe degeneration is
seen in acute, local osteoarthritis, and in patients with systemic conditions such as
rheumatoid disease, where progressive bone and cartilage loss occurs. If immune-mediated
processes are not present, a costochondral graft permits a comprehensive reconstructive
option in which autologous costochondral segments replace the condyle with a biological
graft. The costochondral graft has histological and morphological similarities to the condyle.
Further, as a native tissue, its inherent adaptability and lack of immunogenic potential offer
significant advantages over alloplastic materials.50–52 The results of costochondral grafting,
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however, are varied. When used to treat defects caused by pathology or trauma, excellent
functional results are seen, even in the presence of significant long-term resorption of the
graft. It appears that compensatory changes in the associated musculature and the dentition
accommodate for loss of the graft. When costochondral grafts are used to reconstruct
patients with TMD, on the other hand, results are less than ideal. Loss of vertical height
produced by graft resorption leads to a recurrence of both joint and muscle pain. Alloplastic
alternatives appear to be better suited for the treatment of these patients and those with
immune-mediated degenerative processes. The three currently available FDA approved
alloplastic total joint replacement systems include The Christensen Total Joint system, the
TMJ Concepts system, and the Biomet Microfixation prosthetic total joint. A review of the
history and current use of alloplastic devices is available in the literature.53 Implant lifetimes
are in the range of 10–15 yrs,32 and considering the average age of TMD patients, secondary
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surgery is often necessary. Specifically, early degradation and local debris may require
follow-up or repeat surgery. When a substantial portion of the joint is lost, costochondral or
alloplastic systems may be used for reconstruction, but, the young patient population and the
dynamic environment of the TMJ necessitate improved treatment options. Based on
previous experiences, an ideal replacement system will meet the functional demands of the
joint system and maintain its integrity and functionality throughout the duration of the
patient’s lifetime.
Currently, the repair and replacement of pathologic TMJ tissues remains an unmet need and
tissue engineering presents long-term promise for meeting this demand. Considering the
absence of symptoms in some ID patients, and the success of costochondral grafts despite
graft resorption in certain patients, it is clear that the TMJ and associated musculature
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represent an adaptive environment capable of constant remodeling. While in the past 10 yrs
significant strides have been taken in the development of joint reconstruction systems, the
need remains for tissue replacements capable of adaptation, possessing the biochemical,
biomechanical, and geometric properties of healthy TMJ tissues. This challenge may be met
using tissue engineering techniques to produce joint components with the ability to adapt to
mechanical and chemical stimuli produced by functional articulation.
CURRENT PROGRESS IN TISSUE ENGINEERING

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Engineering tissue replacements for the diseased structures of the TMJ may offer a
permanent, natural solution to regain function in the joint and eliminate problematic and
often painful TMD symptoms. Though tissue engineering of the TMJ is in its infancy,
significant steps have been taken toward understanding appropriate cell sources,
biochemical and biomechanical signals, and scaffolding for developing condylar and discal
cartilage. Engineering tissues matching the native geometric, biochemical, and
biomechanical properties of healthy joint tissues requires a thorough understanding of native
tissue characteristics. The following sections will outline design objectives and current
strategies for condylar as well as discal tissue engineering, as depicted in Fig. 4.
Condylar Cartilage Characterization

Thus far, research in tissue engineering of condylar cartilage has exploited a variety of cell
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sources, bioactive signals, and shape-specific scaffolds. To-date shape-specific

osteochondral condyle tissue replacements have been validated in vivo in small animal
models.54–57 However, the future of condyle/ramus and osteochondral tissue replacements
will require demonstrating long-term efficacy in large animal models. As reflected by the
literature, validation of such engineered replacement tissues is based upon comparison with
native biochemical and biomechanical tissue properties. The following section contains a
review of native condyle anatomy, cell type, extracellular matrix (ECM) composition and
biomechanical properties, followed by a synopsis of current condylar tissue engineering
strategies.
From an anatomical standpoint, the condyle is longer mediolaterally than anteroposteriorly,

forming an ellipse in the transverse plane. Fibrous connective tissue extends from the
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periphery of the disc, securing the disc to the condyle inferiorly and to the temporal bone
superiorly. This arrangement of connective tissue forms a fluid-filled joint capsule with two
discrete compartments. Anteriorly and posteriorly, the condyle connects to the TMJ disc via
the capsular ligaments while mediolaterally, the condyle connects to the disc via the
collateral ligaments. This arrangement ensures close contact between the disc and condyle
during joint movement. The condyle is formed by the condylar process of the mandibular
bone and is covered superiorly by a layer of zonal cartilage. The mandibular bone is
comprised of cancellous bone and a layer of compact cortical bone. Generally speaking, the
cartilage may be described by four distinct zones: fibrous, proliferative, mature, and
hypertrophic. The proliferative zone separates the fibrocartilage of the fibrous zone from the
hyaline cartilage of the mature and hypertrophic zones.58 Anteroposteriorly, the cartilage
layer is thickest in the central superior region: 0.4–0.5 mm in the human.59 As the
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anatomical nature of this tissue is better characterized, engineering efforts may more
successfully develop shape-specific, layered (osteochondral) implants.
Histological and biochemical evidence of cell type and ECM characteristics demonstrate the
mandibular condyle is composed of a fibrocartilage, rich in type I collagen. The cellularity
and biochemical content will now be described by zone, beginning most superiorly. This
arrangement may be seen schematically in Fig. 5. The fibrous zone is cellularly composed
primarily of low density fibrochondrocytes. The primary ECM component identified in
rats60–62 and pigs63 is type I collagen, while type II collagen is minimally

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observed.60, 61, 63, 64 An anisotropic, anteroposterior fiber organization has been observed,
similar to that of the disc.65, 66 Porcine67 and rat68 studies have identified the primary
proteogylcan comprising this zone to be similar in nature to versican, consisting almost
exclusively of chondroitin sulfate GAGs. Inferior to the fibrous zone is the proliferative
zone. This zone acts as a cell reservoir containing mesenchymal chondrocyte precursor cells.
To this effect, the proliferative zone is highly cellularized and the matrix is minimally
developed. Type I collagen has been detected in this zone, observed most often as scattered
fibers.62, 69 Similar to the fibrous zone, immunohistochemistry has identified versican-like
chondroitin sulfate as the primary proteogylcan in the proliferative zone.67 The mature and
hypertrophic zones are similar to one another in their cellularity and ECM composition.
These two layers are cellularized by mature chondrocytes. Chondrocytes of the hypertrophic
zone, however, are larger. The ECM in both zones is comprised primarily of type II
collagen,60 yet type I and X have also been identified.64 Collagen organization in the mature
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and hypertrophic zones is isotropic, showing random bundle orientation.62, 70 Furthermore,

aggrecan has been identified as the primary proteogylcan in these zones in porcine67 and
rat64 models. Significantly, the articulating surface of the mandibular condyles is largely
fibrous (rich in type I collagen), which is in contrast to the hyaline nature of other
articulating surfaces, such as those found in the knee and hip.
Illustrating a structure-function relationship, biomechanical evidence suggests the condyle is

stiffer under tension in the anteroposterior direction than in the mediolateral direction. In the
porcine model, Young’s modulus has been measured as 9.0±1.7 MPa in the anteroposterior
direction and 6.6±1.2 MPa in the mediolateral direction under axial tension to failure
(n=8).71 This mechanical behavior agrees with Singh and Detamore’s66 work which
identified anisotropic collagen alignment. This group also obtained moduli ranging from 22–
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29 MPa in the anteroposterior direction and 8–11 MPa in the mediolateral direction.66 Shear
studies have likewise confirmed the anisotropy of mechanical behavior. Storage moduli in
dynamic shear experiments at 2 Hz frequency range from 1.50–2.03 MPa in the
anteroposterior direction, yet range from 0.33–0.55 MPa in the mediolateral direction
(n=17).72 The anisotropic collagen orientation, tensile, and shear properties of the
mandibular condyle suggest anteroposterior loading, matching the loading patterns observed
during translation and rotation of the mandible in vivo.
Though compressive structure-function relationships have yet to be revealed for the condyle,
regional variability has been established and likely contributes to specific condylar function.
Compressive properties have been examined via atomic force microscopy (AFM),
indentation testing, and unconfined compression. In one study of regional variability, rabbit
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condylar cartilage was divided into four regions and tested in compression using AFM.73
Young’s modulus and Poisson’s ratio were both revealed to decrease in magnitude as
follows: greatest in the anteromedial region, followed by the anterolateral, then by the
posteromedial, and finally lowest in posterolateral region. Notably, results suggest the
condylar cartilage is stiffer medially than laterally.73 It has also been shown that porcine
condylar cartilage deforms significantly less under intermittent compression than sustained
compression,74 an expected result in light of the dynamic nature of the joint. In two other
studies, aggregate moduli from in situ creep testing75 and equilibrium moduli from
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unconfined compression testing76 were reported. Creep testing demonstrated the greatest
aggregate moduli in the central and medial positions, with the aggregate modulus of the
medial position significantly greater than that of the lateral and anterior positions.
Equilibrium moduli obtained during unconfined testing demonstrated the greatest stiffness
in the posterior region and the greatest compliance in the anterior region.76 Although a
consensus regarding the specific regional biomechanical variability remains to be
established, these data suggest that the joint sustains significant load in the medial and
posterior regions in vivo and more successfully resists cyclic, rather than sustained loading, a
factor that may contribute to TMD progression.
Tissue Engineering Condylar Cartilage

Tissue engineering initiatives attempting to recapitulate the native condylar cartilage follow
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a three-part approach considering cell sourcing, biomaterials for construct scaffolding, and
bioactive stimuli. Beginning first with cell sourcing, adult condylar cartilage cells have been
explored in most detail in the literature. However, it is important to note the significant
donor site morbidity and potential pathology in TMD patients associated with this cell
source. As research progresses, it is expected that alternative primary and stem cells will
receive more significant attention. Nonetheless, due to their appropriate phenotype, condylar
chondrocytes offer an effective starting point for condylar cartilage engineering strategies.
Among others, two distinct strategies have been established for acquiring primary condylar
cartilage cells. The more common strategy for obtaining primary cells involves harvesting,
mincing, and isolating condylar cells via a collagenase treatment.77 In contrast, a second
procedure allows the cells to migrate out of the fibrous zone of condylar tissue onto surgical
sponges yielding fibroblast-like cells upon isolation.78 Considering alternative cell sources,
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most recently, ankle hyaline cartilage cells have been determined to outperform condylar
cartilage cells in terms of biosynthesis and cell proliferation when seeded in three
dimensional non-woven polyglycolic acid (PGA) meshes,63 though the authors cited non-
adherence of condylar cells as a possible factor in their relatively poor performance. The
hyaline cartilage-seeded scaffolds yielded a more fibrocartilaginous tissue with both type I
and II collagen. In contrast, condylar cartilage-seeded scaffolds yielded a more fibrous tissue
which predominantly stained positive for type I collagen.63 This is not a surprising result
considering the hyaline nature of the articulating cartilage of the ankle as compared to the
fibrous nature of the cartilage of the TMJ condyle. Prior to this work, the same group
explored human umbilical cord matrix stem cells (HUCMs). HUCM constructs were found
to yield 55% and 200% higher cellularity at week 0 and 4 wks, respectively, as well as
higher GAG content over condylar cartilage constructs.79 Due to donor site morbidity and
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tissue engineering challenges associated with condylar cartilage cell sourcing, it is apparent
that researchers have begun to turn their attention toward alternative sources. More work is
needed to exploit these potential sources, but promise exists in the arena of progenitor,
mesenchymal, embryonic, and induced pluripotent stem cells.
Research in scaffold selections primarily surrounds the idea of developing shape-specific

scaffolds. For example, the Hollister group80 has demonstrated polycaprolactone (PCL),
bioresorbable scaffolds may be constructed by solid free-form fabrication techniques based
on CT (or alternatively MRI) imaging data to generate an anatomically-shaped mandibular

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condyle scaffold that attaches to the ramus via a collar. Seeded with bone morphogenetic
protein-7 transformed fibroblasts, the group obtained compressive moduli and yield
strengths in the lower range of reports for human trabecular bone.80 A second study from the
same group demonstrated that biphasic PCL scaffolds may be differentially seeded with
transformed fibroblasts and fully differentiated chondrocytes.57 This strategy yielded
differential tissues with a mineralized interface when implanted subcutaneously.57 More
recently, the presence of blood vessels, marrow stroma, and adipose tissue was demonstrated
in the ceramic phase of these scaffolds, representing the region seeded with transformed
fibroblasts.56 In an alternative strategy for developing shape-specific scaffolds, the Mao
group54, 55 has demonstrated the potentials of sequential photopolymerization of
poly(ethylene glycol) hydrogels. This strategy was used to obtain osteochondral constructs
with shape and dimensions matching those of a human cadaveric mandibular condyle
model.55 Importantly, this group has demonstrated the potentials of inducing differentiation
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of primary bone-marrow derived mesenchymal stem cells into chondrocyte and bone
lineages for the development of stratified bone and cartilage layers.54, 55 As can be seen,
there is a plethora of biomaterials that may be implemented for condylar tissue engineering,
some offering patient-specific morphology.
In vitro culture techniques may include the application of biomechanical stimulation

intended to mimic physiological loading conditions and therefore influence ECM
architecture. Current efforts with bioreactors and direct stimulation have attempted to do so,
specifically with the intention of encouraging cell growth and recreating the ECM
architecture of healthy condylar cartilage. For example, mass transfer bioreactors can be
used in culture toward obtaining a homogeneous cell distribution and improved nutrient and
waste transport over static cultures. Rotating wall bioreactors stimulate cell proliferation and
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biosynthesis without causing cell damage, by exposing cells to a low shear force via laminar
flow. Similarly, spinner flasks accelerate the exchange of oxygen and nutrients in the
interior of scaffolds, improving cell proliferation and matrix synthesis. Hydrostatic and
direct compression loading schemes may potentially be used to stimulate matrix deposition,
improving mechanical properties of engineered condylar cartilage.81 With in vitro
characterization identifying the tissue to deform significantly less under intermittent
compression than sustained compression74 and in consideration of the native, dynamic
loading patterns in the TMJ, Nicodemus et al.82 obtained surprising results in response to
dynamic compressive strains. Bovine condylar chondrocytes were encapsulated in
photopolymerized PEG hydrogels and constructs were exposed to dynamic loading at 0.3 Hz
and 15% amplitude. Dynamic stimulation led to suppression in gene expression, cell
proliferation and proteoglycan synthesis over unloaded controls.82 This work recognizes the
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need to further investigate the potential role of mechanical stimulation, via various loading
schemes, in construct development.
Bioactive signals may also be used to encourage cell proliferation and biosynthesis with
cellular responses depending on the specific signal or combination of signals. Addressing
first the role of proliferative agents for condylar cartilage cells, bFGF has been found to
have the greatest stimulatory effect on the proliferation of second passage human
mandibular condylar chondrocytes over IGF-I and TGF-β1 treatments in monolayer

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culture.83 Studies exploring biosynthesis as well as proliferation have observed an inhibitory

effect of bFGF on GAG and collagen synthesis84 in contrast to the enhancing effect of IGF-I
on biosynthesis.85, 86 Specifically, an inhibition of GAG and collagen synthesis in rat
condylar cartilage explants was observed in the presence of bFGF following 2 wks of
culture.84 An increase in GAG and collagen synthesis, on the other hand, was observed in
explants treated with IGF-I alone or in combination with bFGF, with bFGF downregulating
IGF-I’s biosynthetic effects when used in combination. Considering next epidermal growth
factor (EGF), Tsubai et al.,78 whose isolation technique was previously mentioned, explored
EGF treatment in fibroblast-like condylar cells obtained from fetal rats. EGF was shown to
bring cells into the s-phase of the cell cycle more quickly and to increase cell number over
controls. Both measures indicate an increase in cellular proliferation.78 The authors also
noted the role of EGF in matrix deposition, with tissue volume increasing toward the end of
the culture period (21 days).78 As research moves toward alternative cell sources, our
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understanding of bioactive signals must be translatable. Notably, early work by Copray et

al. 87 demonstrated that most of the factors enhancing proliferation explored in their study,
including EGF, similarly enhanced proliferation in secondary mandibular condylar cartilage
as well as primary costal chondrocytes. However, results must be validated in the specific
culture system under review, considering not only the cell source but also the scaffold-type
and mechanical stimulation.
Combined mechanical and bioactive stimulation has revealed interrelated roles of

biochemical and biomechanical effectors. A study of rat condylar cartilage cells explored the
effects of TGF-β1 and static tension-stress (5kPa) on cellular proliferation.88 It was
demonstrated that TGF-β1 had a mitogenic effect at all concentrations under review (0.1, 1
and 10 ng/ml), but an additive effect was observed in the group treated with both TGF-β1
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and static tension-stress. As various cell sources and culture systems are explored, this result
illustrates the need for continued exploration of exogenous stimulation, both chemical and
mechanical, throughout cell culture, toward developing shape-specific condylar
replacements.
Glenoid Fossa and Articular Eminence

In attempts to repair or replace pathologic TMJ tissues, it is essential to continue with a
discussion of the superior articulating surface of the joint, including the articular eminence
and glenoid fossa. Together, the superior and inferior surfaces transmit loads experienced by
the joint, through the TMJ disc. Important to note is the incongruence existing between the
superior and inferior surfaces. The TMJ disc and the synovial fluid contained within the
joint capsule fill this gap, ensuring smooth articulation. As previously mentioned, joint
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pathology, including OA and ID, can significantly affect this structure-function relationship.
Of the salient tissues in the joint, the glenoid fossa and articular eminence are the least
characterized in terms of biochemical and biomechanical properties. The surface of the fossa
has been described as a dense, fibrous tissue,89 though more specific characterization is still
needed. As expected, the primary component of this fibrous tissue has been identified as
collagen.90 Biomechanical evaluation of the glenoid fossa and articular eminence has
demonstrated the aggregate moduli to be greater in the medial and posterior regions (42.6
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and 58.9 kPa, respectively), and lower in the anterior, central, and lateral regions, all in the
range of 35 kPa.89
With limited characterization information available, design criteria and validation metrics
have yet to be established for engineering tissue replacements for the superior articulating
surfaces. To our knowledge, tissue engineering efforts have not yet addressed this tissue.
However, as research progresses toward the development of condylar and TMJ discal tissue
replacements, the glenoid fossa and articular eminence must also be considered.
TMJ Disc Characterization

The following section briefly outlines the anatomy, structure, and function of the TMJ disc.
More detailed reports by may be found in the literature.91–94 From a superior view, the
human disc takes on a biconcave, elliptical shape and is longer mediolaterally (~23mm) than
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anteroposteriorly (~14mm),95 similar to the shape of the condyle. The disc may be divided
into three zones: anterior band, intermediate zone, and posterior band.91 In the sagittal view
of a human TMJ, seen in Fig. 6, the posterior band is thicker than the anterior band and the
intermediate zone is the thinnest region. As described previously, the disc is attached along
its periphery to the condyle and temporal bone via fibrous connective tissue. Anteriorly, the
disc is attached to the articular eminence and to the condyle at the pterygoid fovea, via
capsular ligaments. Posteriorly, the disc blends with the bilaminar zone, a network of fibro-
elastic tissue, connecting superiorly to the glenoid fossa and inferiorly to the condyle. When
the joint is in the neutral position, the disc is situated between the condyle and the glenoid
fossa. With joint motion, less-tenuous superior attachments allow the superior surface of the
disc to translate anteroposteriorly, and to a lesser extent mediolaterally, with respect to the
fossa. The inferior surface of the disc, in contrast, remains in close proximity to the condyle.
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The shape and motion of the disc imparts its function: to separate the incongruent
articulating surfaces and to transmit force between them.
The TMJ disc is composed of a heterogeneous distribution of cells with characteristics of

chondrocytes and fibroblasts, together termed TMJ disc cells. More specifically, the porcine
disc has been be described by a non-uniform distribution of approximately 70% fibroblast-
like cells and 30% chondrocyte-like cells.96 While both cell types are distributed throughout
the disc, cells in the central portion of the intermediate zone tend to be more chondrocyte-
like, while cells in the periphery of the disc tend to be more fibroblast-like.96–98 Across
species, cellularity is higher in the anterior and posterior bands than in the intermediate
zone. 96, 99 More specific variations in band cellularity appear to exist between species,95
and it has been reported that, with age, the disc becomes more fibrous100 and acellular.101
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In terms of its biochemical composition, the disc is highly fibrous, illustrated by low GAG
content and high type I collagen content. Water content has been reported in the range of
66–80% for bovine and porcine models.102–104 The primary ECM component is collagen,
which comprises 30% of the disc by wet weight105 and 50% by volume.100, 106 The disc
shows ring-like collagen alignment along the periphery and anteroposterior alignment
through the central region. This anisotropy contributes to the structure-function relationship
of the disc, with anteroposterior alignment supporting the tensile forces imposed on the disc
during translation.107–109 With the condyle demonstrating a similar structure-function

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relationship, it is apparent that these two structures work closely together to distribute loads
experienced by the joint. Unlike hyaline cartilages, which are composed primarily of type II
collagen, the TMJ disc is composed primarily of type I collagen.110 Studies have also
identified the presence of collage types III in trace amounts,111, 112 as well as collagen VI,
IX, XIII in bovine113 and leporine models114. Cross-linked elastin fibers of relatively small
diameter (0.5 μm)115 are also distributed throughout the disc and comprise 1–2% of the
tissue by mass.112 There is a greater distribution of elastin in the superior surface than in the
inferior surface116 and a significantly greater distribution in the peripheral bands than in the
intermediate zone.110, 116, 117 Through its highly compliant nature, elastin likely plays a role
in restoring the disc’s original shape following loading.97, 115, 118 GAGs, including
chondroitin-6-sulfate, chondroitin-4-sulfate, dermatan-sulfate, keratin-sulfate and to a lesser
extent hyaluronan, together comprise less than 5% of the disc.103, 104, 110, 119, 120 The
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proteoglycans identified throughout the tissue are chondroitin-sulfate proteoglycans (CSPG),

likely aggrecan or versican, and dermatan-sulfate proteoglycans (DSPG), including decorin
and biglycan.110 Overall, the low GAG content and high proportion of type I collagen in the
disc exemplify fibrocartilage characteristics, closely resembling the superior articulating
surface of the condyle.119
The mechanical properties of the TMJ disc show regional and interspecies variability, and
can be best understood in light of the structure’s viscoelastic (time dependent)
characteristics. In a study on the regional mechanical properties of the human TMJ disc,
tissue behavior was shown to depend on the amplitude, rate, location, and time of
deformation using a dynamic indentation apparatus.121 An overview of species and region-
dependent tensile and compressive properties is presented in Table 1 and Table 2,
respectively. Due to the rate- and history- dependence of the mechanical properties, careful
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attention should be paid to testing parameters as reported. Notably, an interspecies study by

Kalpakci et al.95 aimed to quantify variability between species and to relate regional
mechanical properties to biochemical content within the disc. The authors successfully
associated the mechanical properties and biochemical content of the disc to loading schemes
of herbivores (cow, goat, and rabbit- primarily translational motion) and omnivores (human
and pig- both rotational and translational motion). Additionally, the authors concluded that
the pig TMJ disc offers the best animal model for the human TMJ disc with the most
statistical similarities in dimensions, collagen content, GAG content, and compressive
properties.95 While GAG content has historically been correlated with compressive
properties, and collagen content/organization has been correlated with tensile properties,
evidence suggests collagen density and organization may be a primary determinant of both
tensile and compressive properties.95 This is because a higher correlation with tensile
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properties has been found with collagen density and alignment, than with GAG distribution
and density, in region-specific comparisons.95 However, GAGs, such as decorin, may play
an indirect role, as they have been found to influence collagen alignment and orientation.122
Tissue Engineering TMJ Disc

While early studies exploring tissue engineering of the TMJ disc have laid the foundation
and demonstrated the potential for today’s efforts, early work lacked the characterization
information needed for validation and progress in optimizing design criteria. Considering
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Fig. 4 and Tables 1 and 2, the TMJ disc shows biomechanical properties that may be
matched more easily in tissue engineered constructs, this in contrast to other musculoskeletal
soft tissues that are substantially stiffer and stronger.
Considering first the exploration of cell sourcing, TMJ disc cells, articular chondrocytes,
and, most recently, costal chondrocytes have been studied in detail with the latter showing
clinical relevance and promise. Similar to the progression in cell source selection for
condylar cartilage engineering, TMJ disc cells were first explored. In isolating and seeding
second passage leporine disc cells on type I collagen scaffolds, it was observed that the
constructs reduced significantly in size over 2 wks, from 16 mm to 12 mm.123 However, this
early work demonstrated the ability to generate constructs possessing cells of a more
chondrocytic phenotype, with rounded morphology and positive staining for proteoglycans,
as compared to monolayer controls which showed a more fibroblastic phenotype.123
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Considering possible variability between species and cell sources within the TMJ, second
passage cells from human and porcine TMJ disc and articular eminence were explored with
various scaffolds: polyamide, expanded polytetrafluorethylene (ePTFE), PGA, natural bone
mineral blocks, and glass.124 Results demonstrated no significant differences between
constructs seeded with human or porcine cells and cells from the disc or articular eminence.
A predominantly chondrocyte-like cellularity was suggested by rounded cell morphology
and the prevalence of type II collagen. Notably, in their conclusions, the authors pointed to
functional loading and oxygen pressure as determinants of fibroblast or chondrocyte-like
phenotypes. More recently, the Athanasiou group performed a series of studies aiming to
refine construct development for a porcine disc cell source; selected results of this work will
be addressed in the following sections. With regards to articular chondrocytes, cells obtained
from the shoulder of newborn calves were seeded in TMJ disc shaped- polylactic acid
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(PLA)/PGA scaffolds and after 1 wk of scaffold incubation, the constructs were implanted
subcutaneously in nude mice.125 Though the goal was to develop shape-specific replacement
tissue for the TMJ disc, this technique yielded a shape-specific construct reminiscent of
hyaline cartilage with positive sulfated GAG and type II collagen staining. In an alternative
strategy for developing disc replacements, isolated mandibular chondro-progenitor cells
from the condyle (unspecified zone of origin) of adult marmosets were suspended in
unpolymerized type I collagen and fibrinogen, and seeded on type I collagen scaffolds.126
Biochemical analysis demonstrated that 3 to 9 days following initial culture, about 66% of
the collagen was type I while the remaining 33% was type II. This time point represented the
most disc-like properties.126 With further culture, the tissue began to take on more hyaline
characteristics. At 21 days, collagen was identified as primarily type II and at 35 days,
nearly 80% of the collagen was found to be type II. Most recently, it was demonstrated that
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costal chondrocytes (CCs) isolated from goat rib tissue show significant promise as a cell
source.127–130 Notably, comparing primary and passaged CCs to primary and passaged disc-
cells, it was demonstrated that CC scaffoldless constructs could be generated with cellularity
and GAG content nearly an order of magnitude greater than the respective disc-cell
constructs, see staining in Fig. 7 (top).127 Moreover, the CC constructs retained their size
and shape. Primary CC constructs, stained positively for types I and II collagen while TMJ
disc constructs stained positively for type I collagen exclusively, see staining in Fig. 7
(bottom).127 Though disc and articular chondrocytes have been explored in more detail
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historically, these results are particularly exciting due to the clinical relevance of the CC cell
source, used by craniofacial surgeons in condylar rib grafts, as well as the lack of donor site
morbidity.
Various scaffolds have been explored across cell sources for TMJ disc construct
development. Synthetic scaffolds are advantageous for their ease of modification.
Modifiable characteristics include shape, size, porosity, mechanical properties, degradation
rate, and hydrophilicity. PLA and PGA are two biodegradable and biocompatible materials
relevant for chondrocyte seeding. In attempts to optimize porcine disc cell culture, PGA
nonwoven meshes were seeded using a spinner flask, orbital shaker, and novel pelleting
seeding technique.131 Greatest type I collagen production was observed on PGA scaffolds
seeded via spinner flask. In a subsequent study, poly-L-lactic acid (PLLA) was selected for
exploration due to its slower degradation, the rationale being slower degradation would
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allow for greater matrix secretion and reduced construct contraction.132 Results, seen in Fig.
8, demonstrated PGA and PLLA constructs exhibit similar cell proliferation and matrix
deposition at 4 wks, but PLLA constructs did not show the shrinking observed in PGA
constructs.132 Considering native biomaterials, type I collagen is an extensively studied
scaffold material for cartilage tissue engineering. Collagen may be used as a seeding vehicle
either intact or following proteolytic digestion for gel encapsulation. Importantly, it has been
demonstrated that collagen synthesis is enhanced in constructs seeded on collagen
scaffolds.133 Electrospinning collagen scaffolds may potentially be used to encourage
collagen synthesis and organization toward recapitulating aforementioned native tissue
characteristics. In attempting to develop disc replacements, it is likely that a type I collagen
sponge would yield constructs with morphology more similar to that of the disc, as
compared to gel encapsulation. Gels, however, may be better suited for filling defects.
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Decellularized tissues present another scaffold option. For example, the porcine disc has
been explored as a xenogeneic scaffold.134 Addressing the mechanical integrity of scaffolds
following various decellularizing treatments, dodecyl sulfate treated tissues have been
identified as potential seeding vehicles for TMJ disc engineering.134 Aside from their
inherent potential immunogenicity, several disadvantages exist for decellularized tissues,
including the inability to control scaffold size/shape and difficulty in reseeding the tissue.
A novel and promising method for tissue engineering the TMJ soft tissues involves self-
assembly of constructs using a scaffoldless approach. It has been demonstrated that self-
assembled articular cartilage constructs may be developed with aggregate moduli
approaching that of native tissue with clinically relevant dimensions.135–137 Scaffoldless
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constructs eliminate the problem of scaffold-induced stress shielding, permitting important

mechanotransductive events during tissue development and biosynthesis. Furthermore, self-
assembled constructs circumvent disadvantages of scaffold use: hindrance of cell-to-cell
communication, immunogenicity, and the potentially deleterious effects of byproducts of
degradation. Thus, while numerous seeding vehicles have been explored, a scaffoldless
technique holds significant potential for engineered TMJ disc replacements.
Considering bioactive signals, anabolic agents have been explored in greater detail, but
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catabolic treatments should also be noted as mediators in construct development. Anabolic

growth factors explored toward the development of TMJ disc constructs include: TGF-β,
platelet derived growth factor (PDGF), bFGF, and IGF-I. Beginning first with the
exploration of TGF-β, it was observed that TGF-β enhanced proliferation in bovine disc
cells by 250% in monolayer culture.113 More recently, in a study exploring PDGF, bFGF,
and IGF-I treatments to TMJ disc cells on a 2D surface, bFGF was found to be the most
beneficial mediator of proliferation, GAG synthesis, and collagen synthesis.138 Additionally,
PDGF and bFGF were found to be the most potent upregulators of GAG synthesis, while
IGF-I was most successful in upregulating collagen production 4.5x over the control.138 In a
second study, the response of TMJ disc cells seeded on PGA scaffolds to TGF-β1, IGF-I,
and bFGF was compared. 139 While all growth factors improved mechanical properties over
controls, IGF-I and TGF-β1 were most effective in promoting collagen synthesis. Catabolic
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treatments such as chondroitinase-ABC may also be used to control matrix modification. By

temporarily depleting GAG side chains and thereafter encouraging development of newly
synthesized, organized ECM, chondroitinase-ABC has been shown to increase tensile
properties in self-assembled articular cartilage constructs.140 Thus, bioactive signals, both
catabolic and anabolic, may be used for various purposes in TMJ disc engineering.
Though not considered an anabolic or catabolic agent, intercellular signaling has also been
explored as a mediator of construct development. Seeding density is one means by which
intercellular signaling is indirectly affected in tissue engineering. For example, seeding
density has been shown to affect morphology, collagen and GAG content, and permeability
in PGA scaffolds seeded with TMJ disc cells.141 Results have suggested a maximum
seeding density of 75 million cells/mL scaffold volume.141 Likewise, in the self-assembly
process it has been shown that a minimum seeding density of 2 million cells/construct yields
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constructs possessing morphological, biochemical, and biomechanical properties

approaching those of native tissue.142 With properties improving as density increases toward
upward limit, an optimal seeding density of 3.75 million cells/construct has been identified,
based on morphological, histological, biochemical and biomechanical results.142 Thus,
controlling the initial cell seeding density is a powerful modulator of the tissue engineering
process.
Mechanical stimulation is of particular relevance for tissue engineering avascular cartilage,

as loading facilitates nutrient delivery, waste removal, and biosynthesis in vivo. TMJ disc
engineering efforts have thus far explored the application of hydrostatic pressure and low
shear forces in a rotating wall bioreactor. Both stimuli implement loading schemes
reminiscent of loading patterns experienced in vivo. It is important to note that while the
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development of synovial fluid pressure has been observed in vivo during operator-induced
mandibular motion of the pig TMJ,143 hydrostatic loading, implemented for the purpose of
tissue engineering, may exceed the magnitude and frequency of that experienced by the disc
in vivo.144 Despite this fact, engineering efforts have demonstrated that static hydrostatic
pressure increases collagen content over unloaded controls, improving the mechanical
integrity of constructs.144 Specifically, in exploring the role of hydrostatic pressure in
monolayer culture and on 3D PGA scaffolds seeded with porcine TMJ disc cells, static
loading at 10 MPa for 4 hrs was found to be most beneficial in promoting biosynthesis. In
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monolayer culture, and similarly on 3D scaffolds, the static loading group yielded the
highest amount of collagen, and specifically, more type I collagen than type II compared to
control and cyclic loading groups.144 In light of the biochemical content of the native disc,
this result demonstrates static loading may be a suitable regimen.
Considering shear stimulation, shear stress is experienced in vivo by the disc during joint
rotation and translation and may be recapitulated in culture via a rotating wall bioreactor.
Toward this end, TMJ disc cells were seeded in a spinner flask on nonwoven PGA scaffolds
and constructs were cultured either statically or in a low-shear rotating bioreactor.145
Scaffolds cultured in the bioreactor contracted earlier, yielding a denser matrix with higher
collagen II content over static controls. Overall, however, the authors found no notable
benefit to using bioreactor culture, as no significant differences were observed in matrix
composition and construct stiffness compared to static culture. Though counterintuitive,
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these results seem to corroborate the results obtained by Nicodemus et al.82 demonstrating
the beneficial application of static over dynamic compressive loading for condylar tissue
engineering. Further investigation is needed to elucidate the potential independent benefit of
mechanical stimulation and the interrelated benefits of mechanical and biochemical stimuli
for both discal and condylar cartilage engineering. With further comprehension of the in
vivo loading environment in healthy joints, bioreactors may potentially be designed to more
accurately recapitulate the native mechanical environment experienced during tissue
development.
Conclusions
To address the mechanically demanding and biochemically active environment of the TMJ,
tissue engineering is emerging as a suitable option for replacing diseased, displaced, or
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degenerated tissues. Characterizing the biochemical and biomechanical properties of the

joint structures, including the condyle, TMJ disc, superior articulating surface, and disc
attachments, in both healthy and diseased cases, continues to facilitate the development and
validation of tissue engineering strategies. Simultaneously, characterization efforts are
aiding researchers and clinicians in developing their understanding of TMD etiology and
progression. Thus far, native tissue characterization studies have identified distinct
differences between the biochemical and biomechanical properties of the TMJ disc and
condyle, thus calling for concurrent, yet independent, tissue engineering strategies. With
refined design objectives and validation metrics, and with a growing awareness of TMD as a
pathology in need of clinical action, it can be expected that tissue engineering for both the
mandibular condyle and TMJ disc will progress significantly over the next decade.
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Acknowledgments
This work was supported by grant R01DE019666 from the National Institute of Health.
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147. Tanaka E, Tanaka M, Hattori Y, Aoyama J, Watanabe M, Sasaki A, et al. Biomechanical
behaviour of bovine temporomandibular articular discs with age. Arch Oral Biol. 2001; 46:997–
1003. [PubMed: 11543706]
148. Tanaka E, Shibaguchi T, Tanaka M, Tanne K. Viscoelastic properties of the human
temporomandibular joint disc in patients with internal derangement. J Oral Maxillofac Surg.
2000; 58:997–1002. [PubMed: 10981980]
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149. Beatty MW, Bruno MJ, Iwasaki LR, Nickel JC. Strain rate dependent orthotropic properties of
pristine and impulsively loaded porcine temporomandibular joint disk. J Biomed Mater Res.
2001; 57:25–34. [PubMed: 11416845]
150. del Pozo R, Tanaka E, Tanaka M, Okazaki M, Tanne K. The regional difference of viscoelastic
property of bovine temporomandibular joint disc in compressive stress-relaxation. Med Eng
Phys. 2002; 24:165–71. [PubMed: 12062175]
151. Allen KD, Athanasiou KA. Viscoelastic characterization of the porcine temporomandibular joint
disc under unconfined compression. J Biomech. 2006; 39:312–22. [PubMed: 16321633]
152. Tanaka E, Tanaka M, Miyawaki Y, Tanne K. Viscoelastic properties of canine

temporomandibular joint disc in compressive load-relaxation. Arch Oral Biol. 1999; 44:1021–6.
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[PubMed: 10669080]
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Figure 1.
Temporomandibular joint sagittal schematic.
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Figure 2.
Bilateral TMJ degeneration. Coronal TMJ CT scan depicting signs of osteoarthritis.
Superficial erosions and osteophytes present in the left joint (right side) and a sub-chondral
cyst present in the right joint (left side).
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Figure 3.
Internal derangement of the TMJ. Normal: Normal anatomical position of articulating disc
with respect to condyle and surfaces of articulation. ID-Reducing: Anteriorly displaced disc
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returning to normal anatomical position upon maximal opening (Wilkes Stage II-early Stage
III). ID-Non-reducing: Anteriorly displaced disc during closed and maximal opening
positions with disc thickening present (Wilkes late Stage III-Stage IV).
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Figure 4.
TMJ tissue engineering strategy. Tissue engineering approach to repairing or replacing the
mandibular condyle and TMJ disc.
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Figure 5.
Zonal condylar cartilage schematic. Fibrous zone: anisotropic, anteroposterior fiber
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orientation (predominantly type I collagen and versican-like proteoglycans). Proliferative

zone: predominantly cellular with minimal matrix. Mature and hypertrophic zones:
isotropic, random fiber orientation (predominantly type II collagen and aggrecan
proteoglycans).
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Figure 6.
Sagittal TMJ histology. Articulating structures (blue) and discal attachments (green) of a
non-pathological TMJ.
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Figure 7.
Primary and passaged costal chondrocytes in scaffoldless TMJ disc engineering. (top)
Primary CC (P0) constructs stained uniformly for collagen, GAG, and cells. TMJ disc cell
(TMJ) constructs did not stain for GAG, but stained uniformly for collagen and cells.
Passaged CCs (P1, P3, P5) formed fluid-filled spheres, with only an outer ring staining for
cells and ECM. (bottom) All constructs stained positive for type I collagen. Only CC
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constructs stained positive for type II collagen, the most intense staining around the outside
of constructs and within fluid-filled centers. Controls: f- knee meniscus tissue and l-
articular cartilage tissue. http://www.springerlink.com/content/gv8266l31307t815/.
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Figure 8.
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Comparisons of PLLA and PGA scaffolds for TMJ disc engineering. (A) PGA constructs
experienced at least a 90% reduction in volume over 4 wks while PLLA constructs
experienced negligible volume change. (B) Cellular, collagen, and GAG content of PLLA
and PGA constructs were similar at 0 and 4 wks. (C) Under compression, PLLA constructs
had larger relaxation moduli relative to PGA constructs at wk 0. PGA constructs at wk 0 had
higher viscosity than PLLA constructs at 0 and 4 wks. Under tension, PLLA constructs at
both time points were stiffer and stronger than PGA constructs at wk 0. http://
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jdr.sagepub.com/content/87/2/180.full.pdf+html.
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Table 1
Biomechanical properties of the TMJ disc under tension.
Region Species Relaxed or Instantaneous Modulus (MPa) (age where provided) Stress/Strain Range (direction) Reference
Murphy et al.
Lateral Canine Instantaneous 39.5 0–1.5 MPa (AP) Tanne et al.146
Canine Instantaneous 83.7 1.5–4.0 MPa (AP) Tanne et al.146
Bovine Instantaneous 22.5 (3 yr), 21.7 (7 yr), 24.0 (10 yr) Tanaka et al.147
Bovine Relaxed, Creep 12.4 (3 yr), 11.9 (7 yr), 10.2 (10 yr) 1.5 MPa Tanaka et al.147
Central Canine Instantaneous 50.2 0–1.5 MPa (AP) Tanne et al.146
Human Instantaneous 44.0 (53.3 for ID) 0–2% strain Tanaka et al.148
Human Instantaneous 95.7 (95.7 for ID) 2–4% strain Tanaka et al.148
Human Relaxed, SR 29.9 (41.0 for ID) 0–2% strain Tanaka et al.148
Human Relaxed, SR 61.2 (59.2 for ID) 2–4% strain Tanaka et al.148
Porcine Instantaneous 76.4 (AP) Beatty et al.149
Porcine Instantaneous 3.2 (ML) Beatty et al.149
Medial Canine Instantaneous 43.3 0–1.5 MPa (AP) Tanne et al.146
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Table 2
Biomechanical properties of the TMJ disc under compression.
Region Species Relaxed or Instantaneous Modulus (kPa) (surface where provided) Strain Range Authors
Murphy et al.
Lateral Bovine Instantaneous 14.6E3 del Pozo et al.150
Porcine Relaxed, Creep 16.3 (superior) Kim et al.89
Porcine Relaxed, SR 99.0 (inferior) 15–30% Allen et al.151
Porcine Instantaneous 371.0 (inferior) 15–30% Allen et al.151
Central Bovine Instantaneous 15.5E3 del Pozo et al.150
Canine Instantaneous 30.9E3 Tanaka et al.152
Medial Porcine Relaxed, Creep 28.9 (superior) Kim et al.89
Bovine Instantaneous 14.7E3 del Pozo et al.150
Anterior Porcine Relaxed, Creep 18.8 (superior) Kim et al.89
Bovine Instantaneous 17.3E3 del Pozo et al.150
Porcine Instantaneous 1.42E3 (inferior) 15–30% Allen et al.151
Posterior Bovine Instantaneous 15.5E3 del Pozo et al.150
Porcine Instantaneous 1.92E3 (inferior) 15–30% Allen et al.151

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Temporomandibular Joint Disorders: A Review of Etiology,

95616, Phone: 530 754 6645, Fax: 530 754 5739

functional structures of the TMJ.

The temporomandibular articulation is composed of bilateral, diarthrodial,

respectively. In a study of patients presenting unilateral TMD pain symptoms during

DISEASE ETIOLOGY AND DIAGNOSIS

While the simultaneous or subsequent progression of ID and OA is not completely

surfaces, followed by flattening and reformation, it is considered more plausible that ID

criteria. A schematic depicting anterior disc displacement, as described by Wilkes’ stages,

there exists a population of individuals experiencing unilateral or bilateral disc displacement

Regarding pharmacologic agents, commonly prescribed non-steroidal anti-inflammatory

Similar to intra-articular injections, arthrocentesis and arthroscopic surgery are minimally

disorders.43–45 In some patients, however, OA-like changes continue to exacerbate,

Joint Reconstruction—Several techniques have been proposed for reconstruction of

often accompanies degenerative change in the temporal component of articulation. In this

case, total joint reconstruction may be necessary.

Total Joint Reconstruction—Reconstruction of the entire joint is indicated when a

CURRENT PROGRESS IN TISSUE ENGINEERING

Condylar Cartilage Characterization

sources, bioactive signals, and shape-specific scaffolds. To-date shape-specific

From an anatomical standpoint, the condyle is longer mediolaterally than anteroposteriorly,

rats60–62 and pigs63 is type I collagen, while type II collagen is minimally

and hypertrophic zones is isotropic, showing random bundle orientation.62, 70 Furthermore,

Illustrating a structure-function relationship, biomechanical evidence suggests the condyle is

Tissue Engineering Condylar Cartilage

Research in scaffold selections primarily surrounds the idea of developing shape-specific

on CT (or alternatively MRI) imaging data to generate an anatomically-shaped mandibular

In vitro culture techniques may include the application of biomechanical stimulation

mandibular condylar chondrocytes over IGF-I and TGF-β1 treatments in monolayer

culture.83 Studies exploring biosynthesis as well as proliferation have observed an inhibitory

understanding of bioactive signals must be translatable. Notably, early work by Copray et

Combined mechanical and bioactive stimulation has revealed interrelated roles of

Glenoid Fossa and Articular Eminence

TMJ Disc Characterization

The TMJ disc is composed of a heterogeneous distribution of cells with characteristics of

during translation.107–109 With the condyle demonstrating a similar structure-function

proteoglycans identified throughout the tissue are chondroitin-sulfate proteoglycans (CSPG),

attention should be paid to testing parameters as reported. Notably, an interspecies study by

Tissue Engineering TMJ Disc

constructs eliminate the problem of scaffold-induced stress shielding, permitting important

catabolic treatments should also be noted as mediators in construct development. Anabolic

treatments such as chondroitinase-ABC may also be used to control matrix modification. By

constructs possessing morphological, biochemical, and biomechanical properties

Mechanical stimulation is of particular relevance for tissue engineering avascular cartilage,

degenerated tissues. Characterizing the biochemical and biomechanical properties of the

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152. Tanaka E, Tanaka M, Miyawaki Y, Tanne K. Viscoelastic properties of canine

orientation (predominantly type I collagen and versican-like proteoglycans). Proliferative

Biomechanical properties of the TMJ disc under tension.