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

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components. Furthermore, the disc appears to have much more tensile integrity than compressive; tensile

moduli are 100- to 1000-fold larger than compressive moduli [28,29]. The bands of the disc also show

a larger capacity to resist compressive loading than the central portions of the disc [28]. While the disc

experiences both tensile and compressive loading, its role in the joint appears to be primarily compressive,

yet its material properties under compressive loading are much smaller than other compressive tissues such

as articular cartilage. The material properties of the TMJ disc support the hypothesis that the TMJ disc

operates in a “trampoline-like” fashion. As the disc experiences increased levels of tensile deformation, the

mesh-like collagen ﬁber network increases its resistance to deformations from the mandibular condyle.

The TMJ disc’s material properties vary regionally [28–31]. The posterior and anterior bands appear to

possess the largest resistance to instantaneous compressive loading, while the medial portions of the disc

exhibits a signiﬁcant relaxed resistance [28]. Under antero–posterior loading, the TMJ disc demonstrates

considerable stiffness in all regions, however, the lateral portions of the disc appear to be less stiff than

the central and medial portions [29]. Under medio-lateral tension, the disc behaves very differently. The

anterior and posterior bands each display large resistance to tensile deformation, but the intermediate

zone appears to be much weaker and consequently, more prone to deformation. From this account, we see

strong correlations between a disc’s tensile properties and its collagen ﬁber alignment [29]. Correlations

between the disc’s compressive properties and its matrix constituents are less deﬁned. While GAG content

is believed to increase the hydrostatic pressure within a matrix, and thus its compressive stiffness, the

GAG content of the TMJ disc may not be large enough to account for signiﬁcant variations throughout

the tissue. Other factors, such as the speciﬁc type of GAGs or the size of collagen ﬁbers present, account

for the regional variations [28].

23.5 Common Conditions Affecting the TMJ

Within the context of clinical disease, four categories of pathology have been recognized to affect the TMJ

to the extent that treatment is required. Internal derangement of the TMJ is a condition characterized by

incoordinate movements of the disc relative to the condyle. It is believed to be the result of several inter-

related pathological processes, including softening (chondromalacia) which produces either a deformed

or malpositioned disc (most commonly in an anteromedial direction), disc perforation as a result of

functional loads applied to diseased tissue, intra-articular reparative processes which limit joint and disc

motion (adhesions or scar bands), and an alteration of synovial ﬂuid properties which affect lubrication

and metabolism (synovitis). When a disc is displaced from its normal position, a variety of responses occur

depending on the extent and duration of the displacement. Minimally displaced discs that are capable of

reduction often provokeadaptiveresponseswithin a joint, consisting of remodelingof the articular surfaces

and discal tissue. However, if the disc is displaced signiﬁcantly for a prolonged period, degeneration occurs

as the result of unfavorable loading forces and the consequences of reduced mobility [32].

Degenerative joint disease represents a different state where catabolic loss of articular tissue exceeds

anabolic attempts to restore joint structure. Various etiologies are capable of producing degeneration

and these include excessive and repetitive loading patterns (osteoarthritis) and autoimmune conditions,

where inﬂammatory antibodies against joint matrix proteins destroy the structural organization of the

joint (rheumatoid and psoriatic arthritis). The etiology of osteoarthritis is unknown, but the interaction

of several factors such as heredity, prolonged loading, trauma to a joint, immobility, obesity, joint

instability, and advanced age appear to affect the normal mechanism by which cartilage cells replenish

matrix macromolecules responsible for cartilage integrity [33]. The capacity for internal remodeling of

both the discal and articular cartilage diminishes as a result of changes in matrix composition, biosynthetic

activity of cartilage cells, and responsiveness of these cells to stimulation.

The cause of rheumatoid arthritis is also unknown, and while a strong genetic predisposition has been

suggested by the presence of the HLA-DR4/DR1 epitope in over 90% of patients, the concordance of

disease in monozygotic twins is between 15 and 20%, suggesting the signiﬁcant inﬂuence of nongenetic

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Tissue Engineering of the Temporomandibular Joint 23-9

factors. Macroscopic hallmarks of disease include synovial proliferation (rheumatoid pannus) and uncon-

trolled inﬂammation, reﬂected on a microscopic level by synovial cell hyperplasia and endothelial cell

proliferation. The inﬂammatory process is also associated with activation of various cells of the reticulo-

endothelial system, including CD

T lymphocytes, B cells, phagocytes, and neutrophils. Fibroblast and

osteoclast activation result in both cartilage and bone resorption and thickening of the periarticular

tissue.

Both internal derangement of the TMJ and degenerative joint disease can produce a reduction in the

range of motion of a TMJ. These conditions may also be associated with signiﬁcant pain. The origins of pain

remain controversial, often because of the difﬁculty in localizing the sources of pain. Activation of nerve

endings by inﬂammatory mediators and stimulation of neural elements present within the capsule, TMJ

ligament, synovial membrane, and retrodiscal tissue by distortion or compression have been implicated.

In addition, compromised joint function is capable of altering the normal behavior of the mandibular

musculature. This sequela of joint disease produces reactive muscular responses and the phenomenon

has been characterized as myofascial pain dysfunction (MPD), a condition which includes myospasm

and muscle fatigue. The combination of pain derived from multifactorial origins and reduction in joint

mobility produces the principal signs and symptoms associated with temporomandibular dysfunction

(TMD), a clinical syndrome associated with pain and an inability to achieve normal mandibular motion.

The third category of TMJ disease differs from the preceding conditions, because it reﬂects a disorder

of bone metabolism, rather than cartilage. Here, the local intra- and extra-articular environment favors

the formation of heterotopic bone. When the dystrophic bone bridges the joint space (temporal–condyle

interphase), complete immobility of the joint (and mandible) occurs. This condition is referred to as

ankylosis of the TMJ.

The last category of conditions affecting the TMJ consists of different neoplasms or cysts that affect

the mandible. These diseases rarely affect the joint without involvement of the adjacent mandibular bone

and as such, will not be considered in this discussion on tissue engineering of the TMJ, because the defect

requiring reconstruction usually extends beyond the conﬁnes of the joint.

The successful application of tissue engineering strategies to reconstruct either individual joint com-

ponents or the entire joint mandates a full appreciation of the pathological condition(s) responsible for

the destruction of the joint in the primary instance. Ignoring the etiology of joint disease may result in a

diminished capacity for successful implementation of an engineered construct and an inability of tissue

engineering to fulﬁll its promise as a reconstructive modality.

23.6 Current Methods for TMJ Reconstruction

Reconstruction of the TMJ can involve the replacement of a disc, reconstruction of the superior artic-

ulation (hemi-arthroplasty), or replacement of the superior and inferior articulating surfaces (total joint

reconstruction). A variety of autogenous and alloplastic materials have been used for joint reconstruction

with varying and conﬂicting results. It is beyond the scope of this chapter to discuss comparative outcomes

from these procedures. Analyzing the relative success and failure of each technique or material is com-

plicated by an inability to fully appreciate the normal function of a particular patient’s joint, which has

lead to difﬁculty in gauging outcomes. Criteria used to evaluate treatment of patients with TMJ pathology

usually include a comparison between the mandibular range of motion and pain levels before and after

surgery, which are imprecise measurements fraught with subjective error.

Removal of a diseased or severely displaced disc (discectomy or meniscectomy) is a procedure employed

when repositioning maneuvers of the malposed disc fail or are not possible because of advanced degener-

ation of the disc. Following removal, treatment alternatives include leaving the joint empty, replacement

of the disc with an autogenous fat, fascia (e.g., fascia lata), cartilage (e.g., auricular cartilage), dermal

graft, or rotating a fascia ﬂap (e.g., temporalis fascia) into the defect. Whichever modality is selected, it

appears that the formation of an interarticular scar band either through a de novo process or metaplastic

transformation of grafts and ﬂaps into ﬁbrous tissue provides a common endpoint.

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Experiences with different alloplastic materials for discal replacement have been characterized by a

number of signiﬁcant failures resulting in severe joint resorption, alteration of mandibular skeletal rela-

tionships, compromised motion, pain, and allegations of systemic immune compromise. These surgical

disasters and the resultant lawsuits have unfortunately tainted all forms of TMJ surgery and discouraged

manysurgeons from seeking alternativemethods to reconstruct the joint. Before the controversysurround-

ing the implantation of medical-grade silicone developed, silicone (Silastic) interpositional implants were

available for disc replacement. As permanent replacements, these devices were capable of fragmentation,

but when used as a temporary interpositional implant (“pull-out” technique), they were observed to

provoke the formation of a dense ﬁbrous tissue capsule, which served as an interarticular cushion. Their

relatively successful use following discectomy might be attributed to this reaction.

One of the most litiginous experiences associated with the alloplastic replacement of a disc occurred

with the use of a Teﬂon–Proplast implant in the late 1980s and early 1990s. Produced by the Vitek®

Corporation, fragmentation of the implant under functional and parafunctional loads was associated

with an exuberant foreign body giant cell response and signiﬁcant osteoclastic activity, resulting in the

resorption of condylar and fossa surfaces and severe local inﬂammatory events. The lessons learned

from this experience are essential, and include the signiﬁcance of characterizing the loading patterns

within a joint, and the importance of recognizing the effects of degradation products upon the local joint

environment.

The TMJ hemi-arthroplasty was a procedure popularized by Christensen and Morgan in the 1960s, in

which the superior articulation of the joint was replaced with an implant fabricated out of chrome–cobalt

alloy. The Christensen implant reconstructed both the fossa and articular eminence while the Morgan

implant covered the eminence only. Concerns over accelerated degeneration of the natural condyle artic-

ulating against a less-deformable surface eventually resulted in the replacement of the hemi-arthroplasty

with total joint reconstructive procedures utilizing both prosthetic fossa and condylar components. Several

systems are currently licensed by the Food and Drug Administration (FDA) (ca. 2004) for implantation

into patients, though limitations have been imposed on surgeons wishing to use these devices and the

selection of patient candidates. Stringent follow-up of patients treated with these implants form the basis

of various clinical trials designed to test not only the ability of the procedure to improve a patient’s

condition, but also the integrity of the devices over time.

As an alternative to prosthetic devices, autogenous grafting techniques are available. Reconstruction of

the TMJ with autogenous tissue involves the harvesting of a costochondral graft (fourth to sixth rib) and

attaching the graft to the remaining mandibular ramus following removal of the diseased joint. The rib is

usually placed on the lateral surface of the ramus and ﬁxated with multiple transcortical screws or a bone

plate (Figure 23.7). The rib may also be placed on the posterior border of the ramus so that its widest

dimension occupies the fossa, but ﬁxation with either bone plates or screws becomes a little more difﬁcult.

When the disc is removed along with the condyle, alternatives for discal reconstruction are similar to

those following discectomy and range from leaving the interarticular space empty to using some form of

autogenous soft tissue to ﬁll the void.

In general, reconstruction following joint removal for neoplastic or cystic disease enjoys a higher

rate of success than similar procedures performed in patients with temporomandibular dysfunction.

Several reasons have been proposed for this dichotomy, including persistence of parafunctional load-

ing of the articulation, excessive scarring from multiple operations, the physical and psychological

consequences of chronic illness, and degenerative disease states which are directed against bone and

cartilage.

The principal indications for considering an alloplastic total joint over an autogenous costochondral

graft include the treatment of joints where heterotopic bone formation is a concern (e.g., ankylosis of the

TMJ), joints affected by a resorptive inﬂammatory process (e.g., rheumatoid arthritis or joints affected

by a foreign body response to previously implanted alloplasts), and multiply operated patients where the

soft tissue bed is excessively scarred and relatively avascular. Under these adverse conditions, autogenous

grafts may be compromised by further disease or conditions which do not favor graft survival. The ability

to customize an alloplastic device is also useful for correcting a skeletal discrepancy that may occur in

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Tissue Engineering of the Temporomandibular Joint 23-11

FIGURE 23.7 Autogenous reconstruction of the joint with a costochondral graft.

patients with severe degenerative joint disease, where retrusion and rotation of the mandible is the result

of decreased posterior vertical support (Figure 23.8a,b).

Customized prosthetic devices involve complex surgical techniques. In order to accurately reproduce

the skeletal bases to which the devices will be attached, two separate surgeries are ideally required. During

the ﬁrst procedure, the diseased joint (or failed implant) is removed and the area derided. A temporary

alloplastic space maintaining implant is used to reduce the amount of soft tissue in-growth into the

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(a)

(b)

FIGURE 23.8 Mandibular retrusion secondary to bilateral condylar resorption. (a) Proﬁle view of patient with

severe, bilateral rheumatoid degeneration of the mandibular condyles. Retrusion of the mandible can be appre-

ciated from the posterior position of the chin; (b) stereolithographic model of the same patient demonstrating

the resulting malocclusion created by loss of condylar height. Correction of mandibular skeletal position with

bilateral alloplastic total joint reconstruction. (c) Patient with bilateral degenerative rheumatoid disease of the

mandibular condyles following surgical reconstruction of the joints with alloplastic total joint prosthesis. Note restora-

tion of mandibular projection; and (d) Postero-anterior (PA) skull radiograph demonstrating bilateral alloplastic total

joints.

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Tissue Engineering of the Temporomandibular Joint 23-13

(c)

(d)

FIGURE 23.8 Continued.

resulting space. Following this surgery, a thin-cut Computerized Tomography (CT) scan is obtained

using a protocol devised by companies specializing in the fabrication of stereolithographic models. The

anatomically accurate model is sent to a joint fabrication company where CAD–CAM technology is used

to produce a prototype of the ﬁnal device. Each device is composed of a prosthetic fossa and eminence as

well as a condylar head attached to a ramus component. The prototype is returned to the surgeon who

conﬁrms that the surgical defect has been correctly reconstructed. At this time, minor modiﬁcations to

the skeletal defect may be proposed to better accommodate and ﬁt the implant. Once the customized

implant has been completed, the patient undergoes a second surgery during which time, the surgical

sites are adjusted to match the defect created on the stereolithographic model before the prosthetic fossa

and condyle are attached to their bony bases. The entire process is time-consuming and expensive, but

justiﬁcation for its use lies in the magnitude of the problem requiring correction (Figure 23.8c,d).

Single surgery reconstruction of a joint is also possible with custom devices. In this procedure, a

stereolithographic model of the diseased joint is prepared. If an alloplastic device is already in place,

digital subtraction technology is employed to artiﬁcially remove the prosthesis. Otherwise, the surgeon

creates the anticipated surgical defect on the model and the device is fabricated. Minor adjustments to the

skeletal remnants can be made at the time of implantation to promote a close adaptation of the device to

the defect.

The Christensen total joint system has been available since 1965, though the current device, which

employs a Vitallium fossa articulating against a chrome–cobalt condylar head, is signiﬁcantly modiﬁed

from the original design which used a metallic fossa matched with a condylar head composed of poly-

methylmethacrylate (PMMA) (Figure 23.9a). Concerns over the development of a giant cell mediated

foreign body response to particulate PMMA prompted this change. Both the fossa and condylar pros-

thesis are ﬁxated to the temporal bone and mandibular ramus, respectively, with screws (Figure 23.9b).

Both patient-speciﬁc implants, customized according to computerized tomographic data, as well as stock

devices with different sizes and shapes for the fossa and condyle are available.

Another system currently available is offered by TMJ Concepts® (Figure 23.10). This system utilizes a

chromium–cobalt–molybdenum condylar head attached to a ramus framework made out of titanium alloy

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(a)

(b)

FIGURE 23.9 Christensen® total joint prosthesis with (a) acrylic condyle and (b) metal condyle.

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FIGURE 23.10 TMJ Concepts® total joint prosthesis.

(6AL–4V) and a fossa component composed of ultra-high molecular weight polyethylene (UHMWPE)

with a nonalloy titanium mesh backing. The respective components are customized to the individual

patient’s anatomical defect and are produced with advanced CAD–CAM technology. After fabrication,

the condyle and fossa are attached to their respective skeletal components with multiple screws (titanium

alloy) placed in a nonlinear fashion to promote maximum stability. There are no stock components

available for this system.

The third device is currently available only to surgeons who are formally registered to participate

in an FDA-sanctioned clinical trial for the Lorenz-Biomet prosthetic total joint. The fossa consists of

a UHMWPE articular surface mounted on a metallic base which is used to secure the prosthesis with

screws to the lateral margins of the glenoid fossa. Since this is a stock device available in three sizes,

the patient’s anatomy requires preparation to conform with the prosthetic contours. This is achieved in

part by removing most of the articular eminence and if indicated, ﬁlling the space between the fossa and

device with orthopedic cement (e.g., Simplex P). A signiﬁcant difference between the design of this fossa

prosthesis and those used in the Christensen or TMJ Concepts systems is the thickness of the articular

surface. The Lorenz-Biomet total joint system attempts to shift the center of rotation of the reconstructed

joint inferiorly to simulate translatory movements by increasing the thickness of the UHMWPE to a

minimum of 4 mm. The condylar portion of this device is composed of a cobalt–chromium–molybdenum

alloy and is available in 45, 50, and 55 mm lengths to accommodate various ramus heights. Several design

features have also been incorporated including augmenting the peripheral margin of the fossa prosthesis

to reduce the likelihood of re-ankylosis and the in-setting of the condylar head so that it articulates against

the middle of the fossa instead of the lateral aspect.

23.7 Tissue Engineering Strategies for TMJ Reconstruction

23.7.1 Tissue Engineering Motivation and Philosophy

The motivations for tissue engineering in the TMJ are abundant [3,34]. While surgical removal of diseased

articular surfaces or a pathologically affected disc with or without reconstruction remains a viable treat-

ment option, the resulting articulation is left without the beneﬁt of physiologically adaptive tissues. Tissue

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23-16 Tissue Engineering

Native TMJ disc

Tissue

characterization

Cellular

Biochemical

Biomechanical

In vitro culture

Scaffold

Cells

Signals

Tissue

engineering

approach

Implant

Tissue

engineered

construct

FIGURE 23.11 Developmental approach toward tissue engineering. The combination of cells, scaffolding, and

signals provide the foundations for the creation of a tissue engineered construct. However, before designing such an

implant, the material characteristics of the native tissue should be fully characterized and incorporated into the design.

engineering offers the potential to replace tissues that have been destroyed and removed [3]. Laboratory

fabricated biological constructs would be capable of immediate structural reconstruction, reproducing

normal joint physiology, and reducing the need for multiple surgical procedures. Current tissue engineer-

ing efforts in the TMJ are focused on the replacement of bony, cartilage, and ﬁbrocartilage structures as

separate components. There are currently no documented efforts to reconstruct the capsule or synovium,

which places the ﬁeld at a considerable distance from the engineering of a true total joint system.

The tissue engineering approach to articular reconstruction combines cells, a scaffold, and biological

agents that control the formation and maintenance of tissue with properties comparable to native struc-

tures [3]. Several variations to this general approach include the use of different cell lineages [35], various

scaffold materials and shapes [36], and the methods by which biological signals are applied [37]. In order

for engineered constructs to succeed, characterization of the native tissue properties (cellular, biochem-

ical, and mechanical) must ﬁrst be conducted, such that tissue engineering efforts may be designed to

create constructs which emulate the native tissues’ functions [18]. Figure 23.11 summarizes the progres-

sion and philosophy associated with tissue engineering efforts. Each level of tissue characterization, as

well as general efforts to engineer joint components, is the focus of active research. A comprehensive

understanding of the challenges in these research areas will lead to the development of viable, implantable

tissue engineered construct for TMJ reconstruction.

23.7.2 Cellular Issues

Cells are the factories responsible for the formation and maintenance of replacement tissues. Through the

action of proteins responsible for creating or degrading the surrounding extracellular matrix, cells produce

and remodel tissue structure to comply with functional requirements. Cells for TMJ tissue engineered

constructs are derived from one of three sources: native cells isolated from healthy mature tissue, undiffer-

entiated progenitor cells isolated from a variety of autogenous sites, and cells which inﬁltrate a noncellular,

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implanted scaffold from the surrounding tissue in vivo. Each cell source is associated with distinct advant-

ages balanced against phenotypical limitations. The selection of an appropriate cell source is therefore

based upon the requirements of a particular tissue engineering application.

Several issues govern the selection of cells for tissue engineering in the TMJ. For example, the pres-

ence of a healthy native cell source may be impossible due to joint pathologies. Also, these mature cells

may have fewer propensities to produce ECM proteins. For these reasons, the promotion of an undif-

ferentiated cellular phenotype has been suggested as a possible cell source for diseased joints. However,

this promotion may be unnecessary if healthy, native cells which have retained their phenotype are

available.

Further complicating the selection of the cell source is a tissue’s phenotypic nature. In the case of

the TMJ disc, a heterogeneous group of cells are found throughout the disc, thus native cell harvesting

techniques may yield the best approximation of the disc’s cellular constituency. Mature cells could have a

reduced ability to produce extracellular matrix proteins, but these effects may be a result of other factors

such as passaging effects. In addition to these issues are the multiple phenotypic origins which may assist

in TMJ development. Cell populations in the TMJ have been shown to possess origins associated with

mesenchymal and neural crest derivatives. These lineages may play very different and interrelated roles in

TMJ development [38].

When a reconstruction aims to replace the entire TMJ and not the disc alone, multiple cell lines,

scaffolds, and molecular factors have to be considered. In the most extensive form of joint reconstruction,

it may be necessary to replace bone, cartilage, ﬁbrocartilage, capsule, and synovium simultaneously.

The concurrent regeneration of these different tissues in a single scaffold with multiple cell lines and

specialized molecular signals may prove extremely difﬁcult. An alternative approach would attempt to

engineer components of the joint separately and to combine these elements after they have been formed,

in a process similar to the use of current alloplastic devices.

To complete the reconstruction, an implantable construct may require the incorporation of a neural

network capable of mediating joint neuromuscular responses as well as a vascular supply to support various

metabolic requirements of the reconstructed joint. Current tissue engineering studies are not sufﬁciently

developed to handle this level of complexity and ultimately, this effort might prove unnecessary if the

capsule, synovium, and temporomandibular ligament are preserved and re-attached after the implantation

of the construct. Currently, the focus of TMJ tissue engineering is the separate regeneration of the major

tissue constituents of the joint, namely bone, cartilage, or ﬁbrocartilage, but success in this area does not

necessarily translate into a successful reconstruction of the total joint.

23.7.3 Scaffold Issues

The scaffold is used to support cells while they produce a three-dimensional biological matrix. The choice

of material for the scaffold is based upon how the construct will be utilized. Important considerations

include the characteristics of the tissue being regenerated, the mechanical environment to which the

scaffold is subjected, interactions between cells and the scaffolding material, the biocompatibility of the

scaffold and its degradation products, and the ability of a scaffold to convey various biological signals.

The scaffold should also elicit a minimal immunogenic response to reduce rejection and facilitate the

formation of biological tissue. Current TMJ tissue engineering efforts have focused on scaffolds composed

of hydrogels and meshes fabricated from different natural and synthetic materials [39].

Hydrogels are scaffolds used in current tissue engineering applications for bone, cartilage, and ﬁbrocar-

tilage regeneration. Some of the advantages of hydrogels include controlled rates of degradation, the ability

to be injected, photopolymerization capabilities, and the assembly of protein sequences conducive to cell

attachment [40,41]. Speciﬁc hydrogels such as oligo(poly(ethyleneglycol)fumarate) (OPF) have shown

promise in the regeneration of bone and might prove effective in the promotion of cartilage regenera-

tion [35]. Alginate hydrogels have also been used in the regeneration of the TMJ disc using porcine TMJ

disc ﬁbrochondrocytes [39]. However, the cellular population of the construct was not stable and observed

to decrease with time [39]. The importance of a scaffold to the production of bone and cartilage from cells