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Australian Dental Journal

The official journal of the Australian Dental Association


Australian Dental Journal 2010; 55: 120–127
REVIEW
doi: 10.1111/j.1834-7819.2010.01214.x

The all-ceramic, inlay supported fixed partial denture. Part 1.


Ceramic inlay preparation design: a literature review
MC Thompson,* KM Thompson,  M Swain*
*Faculty of Dentistry, The University of Sydney.
 Faculty of Health Science, The University of Sydney.

ABSTRACT
The effect of cavity design is a controversial and underrated factor in the clinical success of ceramic inlays and inlay
supported prosthesis. Many articles and studies have been conducted into the advantages and disadvantages of isolated
aspects of preparation design, but lacking is a review of the most relevant papers which bring together a consensus on all the
critical features. Hence, a review and analysis of cavity depth, width, preparation taper and internal line angles is warranted
in our attempts to formulate preparation guidelines that will lead to clinically successful, all-ceramic inlay restorations and
ceramic inlay supported prosthesis.
Keywords: All-ceramic, fixed partial denture, inlay supported denture, ceramic fixed partial denture.
Abbreviations and acronyms: FEA = finite element analysis; IWC = intercuspal width; TOC = total occusal convergence.
(Accepted for publication 6 July 2009.)

design whilst Part 2 will present original research into


INTRODUCTION
the fixed partial denture (FPD) design. Three dimen-
Successful restoration of the dentition has historically sional finite element analysis will be used to create an
depended upon simultaneously respecting the three optimum all-ceramic bridge with regards to connector
foundation principles of tooth preparation: mechanical dimensions and embrasure geometry and validated with
preparation to achieve retention and resistance, hence load-to-failure bench-top testing.
ensuring longevity; aesthetic factors such as minimizing
the appearance of margins and display of metal; and
Inlay preparation design
the biological consequences of achieving the first two
factors which concerns the health and ultimate dura- It has become a basic tenet in dentistry that in order to
bility of the tooth and periodontium. replace a missing tooth (pontic) without resorting to the
Growing patient demands for aesthetic ‘‘tooth-like’’ use of removable prosthetics or implants, it becomes
materials and concerns about the deleterious effects of necessary to attach the pontic to the adjacent teeth
metals has added a new consideration for the profession (abutments). Whether or not it is chosen to prepare the
to address. abutments in an effort to improve mechanical resistance
Magne,1 who advocated a new ‘‘biomimetic’’ and retention is a decision that the dentist must weigh
approach for restorative and prosthetic dentistry via up against the loss of tooth structure that accompanies
the use of ceramics and composite resins, heralded not such preparation and hence increased risk of tooth
only a change in techniques, but as stated by Roeters,2 fracture.
a change in treatment philosophy. As a consequence of Little or no preparation to the abutments means
this major paradigm shift, the primary emphasis for relying heavily upon adhesive technology with minimal
dentistry is now not the restoration of the tooth, but mechanical assistance. The advantages are the conser-
rather its reinforcement and preservation. vation of tooth structure and thus the diminishment of
Part 1 of this two-part investigation will review the the pulpal and periodontal consequences discussed
literature with regards to the ideal inlay preparation above. Conversely, if the decision is made to prepare
120 ª 2010 Australian Dental Association
Ceramic inlay preparation design

the abutments in order to impart mechanical resistance and technology applied and ultimately the inherent
and retention to the FPD, then varying degrees of tooth shape of the carious lesion.12
reduction becomes necessary, with the associated Preparation geometry for ceramic restorations in
complications arising with increasing tooth prepara- general, and inlays specifically, must be adapted to the
tion. It is the challenge of replacing missing teeth and specific properties of ceramics. Possessing a low tensile
the restoration of aesthetics and function at minimal strength and high modulus of elasticity, the traditional
biological cost that is of concern to every practising retention ⁄ resistance principles for cast metal restora-
dentist.3 tions must be relaxed and the simplest geometry
Many articles and studies have investigated the employed.13 Low flexural strength is a limiting property
advantages and disadvantages of the various aspects of brittle materials such as ceramics because the failure
of preparation design and its effect on the clinical mechanism most likely is that of tension or impact
success of ceramic inlays. Milleding et al.4 stated that damage rather than compression, a property of which
‘‘the effect of cavity design on the strength of an inlay is ceramics possess highly but is irrelevant in consider-
a factor that is probably underrated’’. ations of rupture and cyclic fatigue.14–17
The main factors of preparation design that influence The literature is conclusive in regards to the effects
the longevity of the inlay ⁄ tooth complex are as follows: of tooth preparation; it further weakens teeth and
cavity depth; cavity ⁄ isthmus width; preparation taper, increases the likelihood of fracture.18 Khera et al.19
and the morphology of internal line angles. Figure 1 examined the effects of cavity depth, isthmus width and
illustrates the idealized form of an MO inlay on the remaining interaxial dentine on MOD cavity prepara-
lower second molar. tions via the use of 3D finite element analysis (FEA). A
Tooth preparation designs advocated for posterior total of eight different cavity designs were prepared on
ceramic restorations have been based upon recommen- human premolars, divided into three groups and
dations made by GV Black (1836–1915) for cast metal compared with normal, unprepared teeth and to other
and amalgam, resulting in considerable tooth structure cavity designs in the same group. It was demonstrated
removal, opposing walls that are too parallel and that the most crucial factor in the weakening of cusps
internal line angles too steep. was cavity depth, with the width of the isthmus alone
Preserving tooth structure is beneficial to the overall being the least important.
health of the tooth and periodontal tissues. The use of Lin et al. studied the mechanical responses of MOD
the minimally invasive bonded restoration results in less preparations on six human second premolars with the
trauma and superior prognosis.5–10 When designing a use of FEA. They concluded that pulpal wall depth was
tooth preparation, be it for restorative or prosthetic the most profound determinant in the likelihood of
reasons, it is imperative to balance the competing cuspal fracture and the deeper the pulpal depth, the
considerations of aesthetics; preservation of tooth greater the risk to the restored tooth.20
structure and the periodontal complex, and maximizing In a similar study, Lin et al.21 examined the
the strength of the restoration.11 Cavity geometry and biomechanics of 30 MOD cavity preparations on
dimensions are dictated by traditions of cavity design, human maxillary second premolars via FEA. Stress
the properties of the restorative material, the techniques levels were correlated to pulpal depth, isthmus width

Fig 1. Ideal ceramic inlay preparation design.


ª 2010 Australian Dental Association 121
MC Thompson et al.

Table 1. Cavity depth recommendations for minimizing tooth fracture in Class II restorations
Author Recommendation for Comments
cavity depth

Banks (1990)15 1.5 to 2 mm Uniformity of depth stressed.


Blaser et al. (1983)22 Shallow floor considered is Cavity depth most important factor. Width does not substantially
1.5 mm weaken teeth if depth is shallow.
Donly et al. (1990)23 1.5 mm 1.5 mm depth conservative Class II preparation has less marginal
leakage than 2.0 mm conventional preparation.
Etemadi et al. (1999)11 1.5 to 2.0 mm Study conducted on resin-bonded porcelain restorations. Rounded
internal line angles recommended.
Goel et al. (1992)24 NSR Unfavourable stresses increased with increasing cavity depth.
Homewood (1998)25 NSR Shallower cavity results in less cusp deflection.
Khera et al. (1991)19 NSR Cavity depth most significant factor in fracture of tooth, isthmus
width the least.
Lin et al. (2001)20 Unfavourable stresses develop exponentially as cavity depth increases.
Malament and 1.5 to 2.0 mm Smooth preparation with no sharp internal line angles recommended.
Grossman (1987)26
Malament (1998)27 1.5 to 2.0 mm Cavity depth recommended for ceramic strength.
Milleding et al. (1995)4 1.5 to 2.0 mm Recommendation made specifically to minimize fracture of ceramic
inlay but authors found that 1.5 mm cavity depth resulted in only
2% cusp fracture rate.
Nadal (1962)28 NSR Shallow floor and narrow occlusal outline recommended.
Rosenstiel et al. (2001)29 1.5 to 2.0 mm Manufacturers recommendation.
Watts et al. (1995)30 Cavity depth of 1/3 to ½ Shallower restoration depth leads to decreased prevalence of tooth
bucco-lingual width. fracture.

NSR ¼ no specific recommendation.

and interaxial thickness (width of the pulpal floor from Habekost et al.32 evaluated the in vitro fracture
axial wall-to-axial wall) with variations of the three resistance of teeth restored with different designs of
design parameters being made and analysed. The results ceramic restorations. One hundred and twenty sound
demonstrated that enlarging the volume of the MOD maxillary premolars were tested in three groups. Each
cavity significantly increased the stresses in enamel, and group was prepared with three indirect restorations
to a lesser extent dentine, with the stress intensity rising consisting of inlays, onlay with only lingual cuspal
exponentially with cavity depth. For enamel, cavity coverage and onlay with buccal and palatal cuspal
depth is the most dominant factor influencing stress. coverage. Twenty intact teeth were selected as controls.
However, for dentine, it appears that the length of the Peak load-to-fracture was measured for each specimen.
interaxial wall could be the most important factor. Results indicated that the fracture resistance of the teeth
Table 1 summarizes a number of studies evaluating was related to the quantity of hard tissue removed and
the role of cavity depth and its relation to restoration inlays showed a significantly higher fracture resistance
and tooth strength. It demonstrates that a depth of 1.5 than onlays. This suggests that unlike in the use of
to 2 mm is ideal in minimizing tooth loss and providing metallic materials and composite resins, where cusp
sufficient thickness of material in order to ensure capping is often viewed as being a preferred means of
adequate functional life. reinforcing a tooth, caution is needed for ceramic
The concurrence of opinions regarding the recom- inlays.
mended depth for cavities in order to minimize the Bonding of inlays to teeth increases the fracture
incidence of tooth fracture is considerable. This needs resistance of the tooth.33–35 However, large MOD
to be balanced with the need to retain adequate bulk in preparations severely undermine cusps to the degree
the restorative material to ensure the long-term viability that adhesive bonding of restorative materials does
of the tooth ⁄ restoration complex. These competing ‘‘not re-establish the fracture resistance of the tooth to
issues influencing material strength can be successfully its original levels.’’16 Hence, minimizing the depth and
answered with current bonded restorations which rely overall width of any tooth preparation to the amount
significantly less on mechanical factors than traditional needed for adequate retention, resistance and conve-
direct and cast restorations. In the case of ceramic inlay nience form must be of primary concern.
systems, the use of a resin cement to both retain the Table 2 summarizes a number of studies evaluating
restoration and support the weakened tooth structure the relationship between enlarged cavity widths (spe-
results in good long-term success.31 Zinc phosphates cifically the intercuspal width defined as the distance
and glass-ionomer cements must be avoided. However, between cusps) and tooth fracture strength. Universally,
the former, because of its inability to bond, and the the consensus is to maintain as narrow cavity width
latter, due to its low modulus of elasticity, increases the as possible whilst maintaining acceptable strength
flexure of the inlay and thus the rate of fracture. in the restorative material; the recommendation is 1/3
122 ª 2010 Australian Dental Association
Ceramic inlay preparation design

Table 2. Cavity isthmus width recommendations for minimizing tooth fracture in Class II restorations
Author Isthmus recommendation Comments
(as a ratio of ICW)

Bader et al. (2004)36 NSR Relationship exists between fracture risk and dentinal support
measured by intercuspal width proportion and restoration depth.
Blaser et al. (1983)22 NSR Width of MOD preparation does not substantially weaken the tooth
if the pulpal depth is shallow.
37
Cavel et al. (1985) £1/3 ICW Wider isthmus and ⁄ or more restored surfaces related to increased
fracture susceptibility.
Christensen (1971)38 £1/3 ICW Inlays with ICW > 1/3 have higher fracture risk.
Re et al. (1982)82 NSR No specific trend found between the fracture strength of restored
teeth and preparations with various sizes of faciolingual width.
Homewood (1998)25 NSR Wider isthmus results in greater cusp deflection.
Joynt et al. (1987)40 1
/3 ICW 1
/3 ICW chosen for study, recognized that narrow ICW associated
with reduced fractures.
Larson et al. (1981)41 £¼ ICW Proportional isthmus width is possibly the most important measure
of lost dentinal support associated with fracture resistance.
Lin et al. (2001)20 NSR Smaller isthmus results in less stress, cavity depth most important
factor.
Mondelli et al. (1980)42 £¼ ICW The narrower the isthmus, the greater the load to cause fracture.
A significant factor in preparation design.
Osborne and Gale (1980)43 £¼ ICW ¼ ICW provides better resistance to fracture than 1/3 ICW.
Vale (1959)44 £¼ ICW Isthmus greater than 1/3 ICW significantly weakened.
Watts et al. (1995)30 <1/3 ICW Narrower cavity width had statistically higher fracture strengths.

NSR ¼ no specific recommendation.

intercuspal width (ICW) or less, with most recommen- increased retention offered by the friction fit of the
dations suggesting ¼ or less. surfaces, whilst Jørgensen49 attributed the increased
Total occlusal convergence (TOC), defined as ‘‘that retention to the limiting of the ‘‘paths of insertion’’ and
angle which is formed between opposing walls of a removal.
preparation’’, is an important factor in cavity design Mack examined the TOC angles of clinically
and yet the aspect associated with the most conten- prepared inlay and crown dies, and compared them to
tion.45 For complete crown preparations, TOC was one those prepared in a laboratory with the use of standard
of the first preparation criteria given a specific quanti- laboratory optical measurement equipment.53 It was
tative value when Prothero in 1923 recommended a concluded that the average TOC achieved in dental
range of between 2 and 5. This was later scientifically practice was about 16.5 – far removed from the
tested by Goodacre et al.44 with the recommendation textbook ideal of 5. He showed that if a dentist looked
increasing to between 6 and 7. over the preparation with a mirror and could sight all
The current practice of minimizing the axial wall the walls, then the minimum taper achieved is 5, 42¢.
convergence or the TOC to between 6 and 7 (or less) An estimate of 12 was also made for the minimum
in the preparation of cast metal restorations47–50 is convergence required in order to ensure an absence of
likely to lead to increased failure rates if used for undercutting clinically.
ceramic restorations, and should be increased to Ceramic restorations are fundamentally different to
approximately 15. cast metal restorations in numerous ways. Chief
Kaufman et al.49 examined the effects of varying the amongst them is their very high modulus of elasticity
TOC angle (1, 5, 10, 15, 20) on complete veneer and presence of numerous micro-flaws on the surface
crowns with controlled variations in height and diam- which renders them fragile in tension, hence highly
eter, and found that as the convergence approached brittle and likely to fracture during the luting procedure
parallelism (at least to within 5), retention increased and under occlusal loading.11,54–56
geometrically – this being related to the simple effects of Qualtrough and Wilson55 stressed the importance of
geometry. No definitive recommendation was made as the bonding procedure to the overall success of the
to a TOC angle as it was acknowledged that many ceramic restoration. Hypothesizing that unlike tradi-
factors influence the retention of a cast restoration (e.g., tional cast metal inlays where the fit was critical to
adaptation of the casting, texture of surfaces, elasticity success, it is the bonding procedure in ceramic systems
of the casting to enable it to resist deformation and that may ultimately determine the longevity of the
hence maintain the cement seal, etc.). restoration, with smaller degrees of divergence between
Livaditis,51 Shillingburg52 and Rosenstiel et al.29 axial walls resulting in greater stress being imparted to
have recommended a TOC of 5–7 for resin-bonded the inlay and the increased likelihood for the need of
cast metal, intracoronal restorations due to the adjustment. Unlike metals, resins and tooth structure,
ª 2010 Australian Dental Association 123
MC Thompson et al.

ceramics are unable to elastically deform to the same angularity within tooth preparations and restorative
extent; hence the build-up of stresses is likely to occur materials give rise to significant stress concentrations.
from the cementation procedure if there are any The pioneering work of Noonan,69 Mahler and
discrepancies of fit, or if the fit is tight. The TOC angle Peyton70 and Haskins et al.,71 as well as others,
must be relaxed in order to accommodate the inlay, concluded that ‘‘rounding of internal line angles [is]
minimizing straining and the build-up of stress.56 the most satisfactory modification of cavity preparation
Table 3 demonstrates the current opinion with with respect to stress within the remaining tooth
regards to increasing the TOC for ceramic inlays from structure’’.72
the traditional 5 to 7 to approximately 20 when The stresses that accumulate within complex shapes
ceramic restorations are utilized. Values are also given is difficult mathematically to analyse. However, the use
for ceramic and metallic crowns as a comparison and a of photoelastic analyses of these complex and deleteri-
guide as to the fluctuating historical opinions. ous stresses has provided useful data to derive optimal
Classic cavity design principles as advocated by GV design parameters for cavity preparations. Photoelas-
Black recommended the use of flat walls and sharp ticity involves the construction of a model of the
internal line angles as the best way of maximizing structure from a photoelastic material, i.e., a trans-
the retention and especially the resistance form of parent material which exhibits birefringence. The
restorations – this is especially true with regards to photoelastic material exhibits birefringence upon the
Class II restorations where traditionally even the application of stress and the magnitude of the stress,
axiopulpal line angle has been left deliberately angular. and each point is displayed via the refractive indices.73
Cavity design evaluation based upon the use of 2D The evaluation of the stresses using this approach has
photoelastic methods has revealed that any areas of immensely helped our understanding of the need for the

Table 3. Total occlusal convergence angle recommendations


Author TOC recommendation Comments
57
Doyle et al. (1990) 15 15 TOC significantly stronger than 5 on all-ceramic, complete
crowns.
Eames et al. (1978)58 20 20 TOC most likely to be seen clinically on complete crowns.
El-Ebrashi et al. (1969)47 2.5 to 6.5 Stress concentration increases slightly from 0 to 15, increases
sharply at 20. Measured from models of complete crowns.
Esquivel-Upshaw et al. (2001)59 5 Inlays with TOC of 5 significantly more fracture resistant than those
at 20.
11
Etemadi et al. (1999) 21 to 40 21 to 40 for internal tapers, 6 to 15 for external tapers, as
measured from clinical models of porcelain inlays and onlays.
Gerami-Panah et al. (2005)60 22 22 TOC results in less stress to the gingival connector area of an
all-ceramic FPD than 12.
48
Gilboe and Teteruck (2005) 2 to 5 Recommendation for cast-metal complete crowns.
Goodacre et al. (2001)46 10 to 20 Recommendation for complete crowns
Jørgensen (1955)61 As parallel as possible Recommendation for complete crowns. 5 TOC is twice as retentive
as 10; 20 is 62% the retention of 10 and 81% that of 5.
Leempoel et al. (1987)62 15.5 to 30.2 Review of working dies from dental laboratory. Crowns were in place
5 to 10 years and still functioning adequately.
Mack (1980)53 5 accepted consensus Whilst he accepts the consensus that the ideal TOC for inlays and
crowns is 5, 16.5 is more commonly seen clinically. 12 is the
minimum required to avoid undercutting.
Milleding et al. (1995)4 NSR Inlay preparation designs must be relaxed from the traditional
recommendations.
Malament and Grossman (1987)26 6 to 8 Recommendation for all-ceramic complete crown.
Nordlander et al. (1988)50 5 to 10 Theoretical ideal for complete crowns, but rarely seen clinically.
Average seen clinically for premolars is 8 and for molars 12.5.
Owen (1986)63 12 Unless special jigs used, not possible to prepare teeth with TOC of less
than 12 TOC. At this angle they still perform well.
Palacios et al. (2006)64 20 Common journal finding for all-ceramic crowns.
Parker et al. (1993)65 8.4 for molars, Calculation of limiting average taper mathematically based on ½ arc
10 for premolars sin (H ⁄ B). Less than this amount results in reduced resistance.
Qualtrough and Wilson (1996)55 NSR Fit must be relaxed for ceramic inlays.
Schwartz (1952)66 Ideally 0 Pulpal and axial walls should be perpendicular.
Sobrinho et al. (1999)67 No difference between TOC of in-ceram crowns had no effect on their fracture strength.
8 and 16 However, luting with zinc phosphate achieved significantly better
results than GIC.
Wilson and Chan (1994)68 6 to 12 For extracoronal retainers, optimum thickness of cement occurs
between 6 and 12. Retention decreases significantly as TOC
reduces from 9. Larger than 25 TOC also results in significant
decrease in retention.

NSR ¼ no specific recommendation.


124 ª 2010 Australian Dental Association
Ceramic inlay preparation design

Table 4. Stress analysis in dental materials and cavity preparations


Author Findings
75
Arola et al. (1999) Subsurface cracks introduced during cavity preparation with conventional burs may
serve as a principle source for premature restoration failure.
13
Arnetzl and Arnetzl (2006) Geometry of cavities for ceramics must be refined and relaxed, with the simplest of
forms to increase their fracture resistance.
Banks (1990)15 The transfer of distribution of stresses in an efficient manner is of equal importance to
the strength and toughness of the restorative system. Preparations for ceramics must
have smooth surfaces and rounded, smooth flowing internal and point angles.
Bell et al. (1982)76 Cuspal failure is often related to fatigue failure of the cusp, initiated from small cracks
propagating under repeated loading. Evidenced from clinical observations and
mathematical modelling.
Braly and Maxwell (1981)77 Recognition that any inlay restoration, in particular MOD inlays weakens the
remaining tooth. Preserving the natural tooth structure, rounding of sharp line angles
and designing castings that don’t extend onto uninvolved parts of the tooth is essential.
Cameron (1964)78 First mention of ‘‘cracked tooth syndrome’’ and its correlation to restoration size and
postulated mechanisms for crack propagation.
Couegnat et al. (2006)74 Restorations not bonded to the tooth structure are most likely to fracture at the internal
line angles. Rounding of internal line angles results in reduced von Mises stress values.
Etemadi et al. (1999)11 Advocates rounding of all internal line angles.
Haskins et al. (1954)71 Pioneering work advocating the rounding of internal line angles.
Kahler et al. (2006)79 Fatigue is considered to be the principle mechanism of tooth fracture. The axiopulpal
line angle in the dentine is the site of high stress concentration, with cracks as small as
25 lm leading to failure.
Malament and Grossman (1987)26 Preparations for ceramics must be smooth and not have sharp line angles. Gingival
margins must be either a chamfer with a rounded gingivoaxial line angle or a rounded
shoulder.
McDonald (2001)80 Emphasis on rounding of internal line angles and a chamfer or rounded shoulder
finish-line for posterior ceramic restorations.
Milleding et al. (1995)4 Smooth supporting surfaces and softly rounded contours reduce the degree of tensile
and bending forces.
Snyder (1976)81 Cavities should be prepared as conservatively as possible.
Soares et al. (2006)56 Sharp angles and knife edge prepared cusps tend to concentrate stress.
Vale (1959)44 Sharp internal line angles result in increased incidence of tooth fracture.

rounding of all internal line angles, with special oping in the dentine along the buccal and lingual
emphasis on the axiopulpal line angle. Interestingly, margins during cavity preparation can significantly
the stress distribution for bonded restorations is reduce fatigue life and may be the principle source for
markedly different, with peak stress values occurring premature restoration failure. The authors opine that it
in the enamel at the site of contact with the opposing is the instruments and techniques used in tooth
cusp. preparation that must be examined closely as cracks
Couegnat et al.74 utilized structural shape optimiza- as small as 25 lm can lead to fracture in 25 years.
tion procedures based on FEA to derive optimized Table 4 demonstrates the findings from a number of
designs for the second upper premolar. This relatively studies with regards to the stresses caused by sharp
new technique allows adaptations to be made to cavity internal line angles to both tooth and restoration.
designs involving the build-up of material at overloaded
zones and the reduction or no build-up of material at
CONCLUSIONS
underloaded zones to be analysed mathematically and
displayed as a scalar function (similar to a photoelastic As a result of the above analysis, it may be concluded
image). Their results indicated that the ‘‘notches’’ that the idealized inlay preparation design should have
which are created at internal line angles are a principle the following dimensions in order to best achieve a
source of stress concentration in non-bonded internal balance between the preservation of tooth structure and
restorations, whereas the principle source of stress for strength of material: cavity depth of between 1.5 and
onlays and other external restorations existed in the 2 mm; isthmus cavity width of »1/3 the intercuspal
restorative material itself. Rounding of all line angles width; TOC of »20, and rounding of all internal line
and the orientation of prepared cusps tips perpendic- angles. However, it should be borne in mind that
ular to the occlusal load is recommended for the clinically, preparations tend to be wider and often
reduction of stresses. deeper than recommended9 and that the presence of
Arola et al. utilized FEA to analyse the stress existing restorations and caries will often dictate
distribution and potential for cyclic fatigue crack preparations much larger than ideal. Hence, the above
growth within Class II amalgam cavities.75 From their dimensions are ideal recommendations that may
results it was concluded that subsurface cracks devel- require changes in clinical settings.
ª 2010 Australian Dental Association 125
MC Thompson et al.

25. Homewood CI. Cracked tooth syndrome–incidence, clinical


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