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in Oral Biology & Medicine

Analysis of Pulpal Reactions to Restorative Procedures, Materials, Pulp Capping, and Future Therapies
Peter E. Murray, L. Jack Windsor, Thomas W. Smyth, Abeer A. Hafez and Charles F. Cox
CROBM 2002 13: 509
DOI: 10.1177/154411130201300607

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ANALYSIS OF PULPAL REACTIONS
TO RESTORATIVE PROCEDURES, MATERIALS,
PULP CAPPING, AND FUTURE THERAPIES
Peter E. Murray*
L. Jack Windsor
Department of Oral Biology, Indiana University School of Dentistry, 1121 West Michigan Street, Indianapolis, IN 46202-5186; *corresponding author, petmurra@iupui.edu

Thomas W. Smyth
Department of Dentistry, St. Francis Hospital and Medical Center, Hartford, CT 06105

Abeer A. Hafez
School of Dentistry, University of Southern California, Los Angeles, CA 90089-0641

Charles F. Cox
Department of Restorative Dentistry, School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095-1668

ABSTRACT: Every year, despite the effectiveness of preventive dentistry and dental health care, 290 million fillings are
placed each year in the United States; two-thirds of these involve the replacement of failed restorations. Improvements in
the success of restorative treatments may be possible if caries management strategies, selection of restorative materials,
and their proper use to avoid post-operative complications were investigated from a biological perspective. Consequently,
this review will examine pulp injury and healing reactions to different restorative variables. The application of tissue engi-
neering approaches to restorative dentistry will require the transplantation, replacement, or regeneration of cells, and/or
stimulation of mineralized tissue formation. This might solve major dental problems, by remineralizing caries lesions, vac-
cinating against caries and oral diseases, and restoring injured or replacing lost teeth. However, until these therapies can
be introduced clinically, the avoidance of post-operative complications with conventional therapies requires attention to
numerous aspects of treatment highlighted in this review.

Key words. Cavity preparation, cavity restoration, dental materials, growth factors, inflammation, bacterial microleakage.

(I) Introduction
T he regeneration or replacement of oral tissues affected by
inherited disorders, trauma, and neoplastic or infectious
diseases is expected to solve many dental problems. Within
the next 25 years, unparalleled advances in restorative den-
tistry are set to take place with the availability of artificial
teeth, bone, organs, and oral tissues (Baum and Mooney, 2000;
Baum et al. 2002), as well as the ability of growth factors to
stimulate dental repair (Murray and Smith, 2002), regenerate
lost tissues (Becker, 1994; Smith et al., 2002), produce vaccina-
tions against viruses (Baum and O'Connell, 1995), and geneti-
cally alter disease pathogens to help eradicate caries and peri-
odontitis (Hillman et al., 2000). Patient demand for tissue engi-
neering therapy is staggering in both scope and cost. Each
year, $400 billion is spent treating Americans suffering some
type of tissue loss or end-stage organ failure. This includes
20,000 organ transplants, 500,000 joint replacements, and mil-
lions of dental and oral craniofacial procedures, ranging from
tooth restorations to major reconstruction of facial soft and
mineralized tissues (National Institute of Dental and
Craniofacial Research [NIDCR], 2002).
Two-thirds of all restorative dentistry involves the replace-
ment of failed restorations (Maupome and Sheiham, 1998;
Burke et al., 1999). In the United States, it is estimated that, of
290 million restorations, 200 million are replacements for failed
restorations (Arnst and Carey, 1998). Currently, a high propor-
tion of these teeth develop symptoms requiring endodontic
treatment (Zllner and Gaengler, 2000), and millions of teeth
are extracted, with 1.5 million US restorations requiring root
canal therapy (NIDCR, 2002). This rate of treatment failure sug-
gests that current restorative regimes are not yet optimized and
have a potential for improvement. Often, clinical experience or
empirical evidence is used to diagnose dental problems requir-
ing treatment, because scientific evidence is lacking (Mjr,
2001a). Therefore, it is necessary to evaluate the biological
changes taking place in teeth to help optimize current treat-
ment regimens, and to use, stimulate, or augment natural
regenerative processes to accomplish therapy by tissue engi-
neering. Avoidance of tooth-healing complications requires
examination of surgical trauma and injuries caused by a failure
to use materials and procedures congruent with the natural
regenerative activity of teeth (Murray et al., 2000a). There is lim-
ited information regarding sources of pulp injury, healing
defects, bacterial leakage, and pulp inflammation, although
these factors often create healing problems. Consequently, this
review will investigate those aspects of restorative dentistry

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which may be optimized. It will also discuss how the natural
regeneration of teeth could serve as the basis for tissue engi-
neering approaches to solve common restorative problems.
Tissue engineering is in the early stages of development, and it
is uncertain exactly how this technology might be applied to
solve many common dental problems. Nevertheless, it is
important to formulate tissue-engineering protocols without
delay, because the development phase of these new therapies is
measured in decades.
(II) Treatment of Caries
A caries lesion is initiated when micro-organisms in dental
plaque, commonly mutans streptococci and lactobacilli, fer-
ment carbohydrates (mainly sugars) to produce acid
(Featherstone, 1996). Dental caries is a process that brings
about a progressive acid-demineralization of the inorganic
component of the tooth, accompanied by an enzymatic disinte-
gration of the organic portion. It is primarily a bacterial disease,
but has multifactorial etiology (Glossary of Operative Dentistry
Terms, 1983). The goals of treatment are to reduce the etiologic
microbiota and contributing risk factors to halt the caries decay
process and stimulate remineralization. Caries activity can be
subdivided according to the rate of tooth demineralization. If
demineralization stops, a caries lesion is regarded as "arrested".
Conversely, if the caries lesion is "active", it can be either slow-
ly or rapidly progressing (Bjrndal and Darvann, 1999). The
defense and healing of tooth pulp tissue are more effective in
response to slowly progressing or arrested lesions, and the
pulp injury can be minimal. In contrast, rapidly progressing
lesions can overwhelm pulp-defensive responses and cause
severe pulp injuries (Bjrndal and Mjr, 2001).
(A) OPTIMIZATION OF CARIES LESION TREATMENT
Caries is cited as the most common reason for the need to
restore teeth (Deligeorgi et al., 2000). The goals of restorative
therapy are to restore teeth to a state of health, function, and
esthetic appearance and to prevent the recurrence of caries
(Lutz et al., 1997). However, for the management of caries, it is
difficult to achieve the correct balance between an eagerness to
remove the lesion and the continued monitoring of lesion pro-
gression. The selection of either treatment strategy is relevant
to the risk of creating pulp complications, because the selection
of approach can mediate the quantity of caries excavation, risk
of pulp injury and exposure, size of cavity preparation, and
selection of capping materials. Although pediatric dentists con-
tinue to apply pit-and-fissure sealants to erupting permanent
teeth, this is not done in many general practices. Minimally
invasive procedures to treat small caries lesions are proving
popular, because this approach may be advantageous to pre-
vent lesion progression (White and Eakle, 2000). For larger
penetrating lesions, a step-wise excavation approach may be
used (Bjrndal and Thylstrup, 1998). This can prevent exten-
sive pulp injury by leaving firm but stained carious dentin at
the cavity floor during excavation. This dentin is often re-
mineralizable (ten Cate, 2001), and the stepwise excavation of
carious tissues can provide pulp protection by stimulating the
remineralization of hard carious dentin and reactionary dentin
(Leksell et al., 1996). It is recommended to use caries detector
dyes to distinguish the unstained remineralizable dentin that
should not be excavated (Fusayama and Terachima, 1972), but
the use of these dyes may lead to excessive removal of tooth tis-
sues (I.A. Mjr, personal communication). Furthermore, fluo-
510
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International and American Associations for Dental Research
ride-containing pulp-capping materials, such as resin-modified
glass ionomers, have been observed to remineralize adjacent
caries (Donly and Grandgenett, 1998). However, simple sealing
of caries lesions with composite resin or resin/amalgam tech-
niques has been shown to arrest lesion progression for over 10
years (Mertz-Fairhurst et al., 1998). These developments in
caries treatment planning demonstrate how the natural rem-
ineralizing activity of teeth can be used to optimize restorative
treatment.
(B) GROWTH FACTOR THERAPY TO STIMULATE
TISSUE REGENERATION BENEATH CARIES
If tissue engineering is to have a significant impact on restora-
tive dentistry, it must primarily focus on providing effective
treatments for remineralizing caries lesions and arresting or
reversing tooth decay. Toward this aim, increased understand-
ing of the biological processes mediating tissue repair has
allowed some investigators to mimic or supplement tooth-
reparative responses. Dentin contains many proteins capable of
stimulating tissue responses. Growth factors, especially those
of the transforming growth factor-beta (TGFb) family, are
important in cellular signaling for odontoblast differentiation
and stimulation of dentin matrix secretion. These growth fac-
tors are secreted by odontoblasts and deposited within the
dentin matrix (Roberts-Clark and Smith, 2000), where they
remain protected in an active form through interaction with
other components of the dentin matrix (Smith et al., 1998).
Carious demineralization of the dental tissues can lead to their
release, as can application of cavity-etching agents and restora-
tive materials (Smith et al., 2000). Indeed, it is likely that much
of the therapeutic effect of calcium hydroxide may be due to its
extraction of growth factors from the dentin matrix (Smith et al.,
1995a). Once released, these growth factors may play key roles
in signaling many of the events of tertiary dentinogenesis, a
response of pulp-dentin repair. The addition of purified dentin
protein fractions (Smith et al., 2001), bone morphogenic pro-
teins (Rutherford, 2001), and TGFb1 (Tziafas et al., 1998) follow-
ing cavity preparationall have stimulated an increase in ter-
tiary dentin matrix secretion. This indicates the potential for the
addition of growth factors prior to pulp capping, or incorpo-
rating them into restorative materials to stimulate dentin and
pulp regeneration.
(C) AMELOBLAST STEM CELL THERAPY AND
TRANSPLANTATION OF ENAMEL
The outer enamel layer of teeth is more than 95% mineral.
During formative stages, the enamel consists of a protein
matrix that forms the framework for mineral deposition
(Diekwisch et al., 1995). Amelogenin secreted by ameloblasts
accounts for 90% of the enamel matrix mineral (Zeichner-
David et al., 1995). Other matrix proteins, including tuftelin and
ameloblastin, have recently been identified and cloned
(Takahashi et al., 1998). Isolating ameloblast progenitor cells
and replicating the natural enamel-forming process in three-
dimensional culture by the use of growth factors to stimulate
enamel secretion offer the potential for transplantation.
Transplants of ameloblasts and artificial enamel to the outer
surfaces of teeth could replace the porcelain veneers and den-
tal materials currently applied to restore tooth structure fol-
lowing caries, disease, erosion, and accidental trauma, or for
esthetic reasons (Kihn and Barnes, 1998). The advantage of
Crit Rev Oral Biol Med 13(6):509-520 (2002)
applying artificial enamel and ameloblasts to
teeth is that this procedure provides a natural
regenerative ability to respond to subsequent
erosion, attrition, abrasion, or traumatic losses
of tooth mineral.

(D) GENE THERAPY TO VACCINATE

AGAINST CARIES
The eradication of dental caries or perio-
dontal disease may be successful if gene
transfer therapy can mediate humoral and
cellular immune responses to the pathogenic
bacteria involved in these disease processes
(Slavkin, 1996). This type of gene transfer
therapy is called DNA vaccination, because
DNA-containing antigens which can mediate
an immune response are delivered in a plas-
mid to the target bacteria (Gurunathan et al.,
2000a). Caries vaccine strategies may use the
mucosal immune system in newborn infants,
which is functional prior to the appearance of
their first teeth, as an effective way to induce
immunity against the colonization of teeth by
mutans streptococci and protection against Figure 1. Schematic representation of tooth injury and regeneration. (a) Pulp regenera-
subsequent dental caries (Michalek et al., tion in response to a non-exposed cavity preparation. (b) Pulp regeneration in response
2001). Currently, this approach is years away to an exposed cavity preparation.
from clinical trials, because of the difficulty of
vaccination against intracellular organisms
requiring cell-mediated immunity
(Gurunathan et al., 2000b), and the possibility of inducing tis- This demonstrates the different effects of restorative materi-
sue cross-reactivity (Bleiweis et al., 1992). A promising alter- als on restoration longevity, and the importance of examining
native approach to the eradication of caries may be to replace the effects of cavity preparation and capping materials on
mutans streptococci with genetically altered strains, which pulp injury and regeneration.
have little or no caries-causing potential (Hillman et al., 2000).
The eradication of caries and bacterial disease could reduce (A) IMPORTANCE OF PRESERVING PULP VITALITY
the demand for restorative treatments by up to two-thirds, The preservation of pulp vitality following restorative inter-
which is approximately the annual proportion of restorative vention is dependent on the degree to which the pulpal cell
treatments devoted to the treatment of caries (American populations can survive, as well as the ability of these cells to
Dental Association; in Arnst and Carey, 1998). detect and respond to injury to initiate an appropriate repair
response (Murray et al., 2000b). The most visible repair
(III) Guidelines for Optimizing the Success of response to pulp injury is the deposition of a tertiary dentin
Cavity Preparations matrix. Unlike primary or secondary dentin that forms along
Non-invasive approaches to the sealing of early caries lesions the entire pulp-dentin border, tertiary dentin is focally secret-
with penetrating adhesive resins to arrest tooth demineral- ed by odontoblasts in response to primary and secondary
ization and decay are under development (Robinson et al., dentin injury. The process of tertiary dentin secretion can be
2001). If these techniques become introduced clinically, the classified as being reactionary or reparative in origin,
avoidance of operative intervention should greatly prevent depending on the severity of the initiating response and the
pulp injury. Furthermore, bacterial leakage and secondary conditions under which the newly deposited dentin matrix
caries may also be avoided. In the meantime, it is important was formed. In general, reactionary dentin is secreted by pre-
to investigate pulp reactions to existing treatments. A review existing odontoblasts, and reparative dentin is secreted by
of surveys found that secondary caries and/or discoloration newly differentiated odontoblastoid cells (Smith et al.,
was the most frequent reason for replacement of restorations, 1995b). The secretion of reactionary dentin is the main post-
followed by mechanical failures and various reasons such as operative odontoblast repair response to the presence of a
bacterial leakage and inflammation associated with healing cavity carefully cut into the dentin of a tooth (Fig. 1a).
complications such as hypersensitivity (Deligeorgi et al., Reparative dentin, in contrast, is secreted by a second gener-
2001). Age, diet, and oral hygiene characteristics of patients ation of odontoblastoid cells when irreversible odontoblast
play a considerable role in restoration longevity. Several sur- injury has destroyed these primary cells (Fig. 1b). Reparative
veys have also showed how the placement of one type of dentinogenesis is a much more complex process than reac-
restorative material in preference can make the critical differ- tionary dentinogenesis, and is generally observed following
ence between success and failure within a few years (Mjr et injurious cavity preparation or a pulp exposure situation
al., 1990; Maupome and Sheiham, 1998; Burke et al., 1999). (Mjr, 1985). Minimizing pulp injury during cavity prepara-

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TABLE 1
Sequence of Cavity Preparation and Restoration
Variablesa Correlated to Pulp Injury
Cavity Preparation and Restorative Analysis of
Variable Correlations with Odontoblast Variance
Numbers as a Measure of Pulp Injury (P value)
Cavity remaining dentin thickness
Cavity wall depth
Cavity wall area
Pulpal inflammation related to RDT
Type of restoration material
Total cavity surface area
Etching (cavity conditioning)
Cavity volume
Reactionary dentin area
Sex of patient
Cavity floor width
Patient age
Bacteria within restorations
Cavity floor area
Bacteria in cut dentinal tubules
Time elapsed since operative procedures
a Among the variables most important in the creation of pulp injury were the
cavity remaining dentin thickness and type of restoration material (About et
al., 2001). Reprinted with permission from the Journal of Dentistry.
tion is clinically advantageous, because it maintains pulp cell
function and viability, and reduces the probability of post-
operative pulp complications.
(B) PULP INJURY AND HEALING RESPONSES TO
CAVITY PREPARATION AND RESTORATION
If pulpal viability and function are to be preserved, the poten-
tially injurious effects of cavity cutting, cavity conditioning, and
cavity restoration must be assessed. Following the in vitro cul-
ture of teeth (Murray et al., 2000c), some pulp effects of cavity
preparation and restoration were examined. The most influen-
tial variables in terms of causing pulp injury were the cavity's
remaining dentin thickness (RDT), cavity preparation in the
absence of coolant, and the selection of restorative material if
the pulp tissue is exposed (Murray et al., 2002d). These findings
confirm the observation that heat-energy is the most injurious
event to pulp tissue (Zach, 1972). Some investigations have
found that the amount of intra-pulpal injury generated during
cavity preparation and restoration is determined by the drill
rotation speed (Hatton et al., 1994), size, type, and shape of the
cutting instrument (Ottl and Lauer, 1998), as well as the length
of time the instrument is in contact with the dentin (Ohmoto et
al., 1994), the amount of pressure exerted on the handpiece
(Hatton et al., 1994), the cavity's remaining dentin thickness
(RDT) (Stanley et al., 1975), restoration material temperature
(Anil and Keyf, 1996), and the use of cooling techniques (Lloyd
et al., 1978). Other potential sources of pulp injury during cavi-
ty restoration include: conditioning of the dentin cavity walls
with acid etchants (Murray et al., 2002a) and the choice of cavi-
ty restoration materials (Hilton, 1996). Investigation of pulp
injury in in vivo human teeth confirmed the effects of some of
these variables (Table 1), but also highlighted the importance of
512
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selecting restorative materials which can prevent bacterial
microleakage, to avoid stimulating pulp inflammation which
can further injure the pulp tissue (About et al., 2001), leading to
hypersensitivity and allergic complications (Bergenholtz, 1990).
Pulp repair can be negatively influenced by the absence of
coolant during cavity cutting, and the bur speed (Swerdlow and
Stanley, 1958; Langeland and Langeland, 1968) in addition to
cavity RDT, cavity wall depth, area, volume, inflammation relat-
ed to RDT, type of restorative material, total cavity surface area,
0.0001 cavity conditioning treatment (Table 1), and the presence of bac-
0.0001 teria (Cox et al., 1992) are important considerations. Although
0.0001 other variables were found to be less important (Table 1), this
0.0001
finding is not to say that they lack effect in terms of pulp injury
0.0001
or healing. All aspects of restorative treatment require careful
0.0013
consideration, and the sequence of variables presented in Table
0.0044
0.0069 1 indicates aspects of treatment which are most deserving of
0.0172 attention in an attempt to minimize injury and optimize pulp
0.2063 dentin regeneration.
0.2211
0.2226 (C) PULP REACTIONS TO CAVITYS
0.3892 REMAINING DENTIN THICKNESS
0.6794 Erosion, trauma, caries, and diseases can severely injure teeth;
0.5677 however, it has been frequently observed that greater injuries
0.7557 are sustained following cavity preparation and restoration with
dental materials (Cox et al., 1992; Stanley, 1992; Kim and
Trowbridge, 1998). While the dimensions of cavity prepara-
tions are under the control of the clinician, these are common-
ly determined by the extent and progression of disease, such as
caries, as well as by the cavity preparation form necessary to
retain the filling. Consequently, it is important to understand
pulp reactions to a range of cavity preparation dimensions,
particularly the cavity's remaining dentin thickness (RDT).
Odontoblast survival and reactionary dentin secretion were the
two responses most sensitive to cavity RDT (Murray et al.,
2002b). The relationship between these variables is shown in
Fig. 2. To a lesser degree, pulp inflammation and cavity wall
depth were influenced by cavity RDT, whereas patient vari-
ables and restorative factors had little effect (Murray et al.,
2002b). The effects of RDT on odontoblast survival and reac-
tionary dentin repair activity can be attributed to an increasing
degree of cellular injury, due to reductions in the protective
properties of dentin. Dentin protects pulp cells from potential
sources of injury (Stanley et al., 1975). Deep cavities with small
RDTs leave the pulp tissue less protected from preparation
trauma, and also from the chemical activity of dental materials
(Lee et al., 1992). The ability to understand and predict pulpal
reactions to cavity preparation allows treatment decisions to be
made which exploit the natural repair responses of the tooth.
Deviations from the expected pulp responses to restorative
treatment can be used to identify potential post-operative com-
plications. Practitioners need to have the option to re-attempt
restorative treatment or develop a new treatment plan before
post-operative complications can progress in severity and
become irreversible.
(D) REPAIR OF FILLINGS RATHER THAN
TOTAL REPLACEMENT
An excellent method to conserve RDT is to repair faulty
restorations, because this is less invasive than having to
replace fillings completely. However, most dental schools are
reluctant to teach students how to repair faulty restorations for
Crit Rev Oral Biol Med 13(6):509-520 (2002)
International and American Associations for Dental Research
fear that they would be regarded as second-class restorations
or that severe, extensive decay will be overlooked. This often
leads to the removal and replacement of functional restora-
tions simply to repair a marginal defect affecting perhaps only
10% of the restoration. Part of the problem involves the phi-
losophy of seeking ideal treatment. Another part of the prob-
lem is the clinician's inability to visualize gingival or subgin-
gival marginal areas. However, it is possible to illuminate and
visualize these areas under magnification on a video monitor,
using the same fiber-optic devices that are used in periodon-
tics and endodontics. Together with staining with caries-detec-
tor solutions, this technology allows sufficient image quality
for the removal of carious tooth structure, sealing of the caries-
affected dentin, and repair of the faulty filling according to the
principles of minimally invasive dentistry (D.H. Pashley, per-
sonal communication).

(E) RESTORATIVE MATERIALS FOR NON-EXPOSED

CAVITY PREPARATIONS
Patient confidence is promoted by the placement of long-last-
ing restorations not subject to recurrent caries, pulp inflamma-
tion, allergic sensitization, or symptoms requiring endodontic
treatment. Recognition over the last few years that the largest
proportion of restoration failures arises from secondary (recur-
rent) caries or complications (Deligeorgi et al., 2000, 2001) has
led to technological advancements in dental materials, in an
attempt to reduce their leakage characteristics and improve
their longevity (Kugel and Ferrari, 2000). Operator handling
(Ciucchi et al., 1997; Finger and Balkenhol, 1999) and surgical
skill remain important for influencing treatment success, most
likely due to the need for restorations to be finished with a very
high technical quality (Murray et al., 2001). It is a pity that many
student dentists do not have laboratory exercises where they
can perfect their bonding technique by measuring bond
Figure 2. Summary of human pulp responses to the remaining dentin
strengths to teeth bonded in vitro, before they begin using them thicknesses of cavity preparations. Pulp injury and repair activity
clinically (D.H. Pashley, personal communication). However, increas as the remaining dentin thickness decreases (Murray et al.,
several surveys have showed how the selection and placement 2002c). Reprinted with permission from the American Journal of
of one type of restorative material in preference over another Dentistry.
can make the critical difference between the failure and the suc-
cess of treatment within a few years (Maryniuk and Kaplan,
1986; Burke et al., 1999).
restoration (Zllner and Gaengler, 2000). Cavity preparation
(F) PULP INFLAMMATION AND trauma as well as the chemical activity of restorative materials
can stimulate the release of inflammatory mediators from sen-
BACTERIAL LEAKAGE ASSOCIATED sory nerve fibers (Langeland et al., 1966; Okiji et al., 1997).
WITH RESTORATIVE MATERIALS
However, most restorative materials appear to mediate low
The immune system triggers inflammatory reactions to limit levels of pulp inflammation in teeth with highly permeable
tissue damage from invading or foreign molecules (Jontell et dentin, such as those that are newly erupted, except in the
al., 1998). These inflammatory reactions can injure the pulpal presence of bacterial leakage (Cox et al., 1987; Bergenholtz,
cell populations and lead to pulp complications in response to 2000; Murray et al., 2002c). The selection of restorative materi-
cavity restorations that may initially appear to be successful als has an important influence on bacterial leakage. Zinc oxide
(About et al., 2001). Severe forms of inflammatory activity can eugenol and resin-modified glass ionomer can prevent bacter-
develop into total pulpal necrosis and periapical lesion devel- ial growth in 100% of cavity restorations for up to one year fol-
opment with local bone destruction (Bergenholtz, 1982). In less lowing treatment (Table 2). These observations can be attrib-
severe cases, the inflamed pulp is associated with hypersensi- uted to the antibacterial activity of these agents and the direct
tivity, so that thermal, mechanical, or osmotic stimuli encoun- sealing of cavity walls (Bergenholtz et al., 1982; Tarim et al.,
tered in normal function can cause intense pain (Ngassapa, 1998). The placement of enamel-bonded resin composite and
1996). Inflammation has been shown to produce a down-regu- adhesive-bonded resin composite does not seem to result in a
lation of normal sodium channels in nerves (Waxman et al., perfect seal with cavity walls, because bacteria were detected
1999). These observations explain why immunological inflam- in 24 and 11%, respectively, of these restorations (Table 2). The
matory activity is associated with the high rates of primarily favorable sealing characteristics of resin-modified glass
vital teeth exhibiting pulpal complications following cavity ionomers explain why these materials are recommended for

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TABLE 2 es the pulp tissue to be more sensitive
Pulpal Inflammatory Activity and the Presence to the possible cytotoxic and irritation-
of Bacteria at the Tooth-Restorationa Interface al action of the capping agent (Murray
et al., 2000e). Fourth, operative debris
including dentin fragments, some-
Pulpal Inflammation Bacterial Leakage times called "chipitis" (Stanley, 1998),
(Percentage of Teeth) (Percentage of Teeth) and particles of capping materials may
Restorative Material Absent/Slight Moderate Severe No Yes infiltrate the pulp, causing injury and
inflammatory reactions (Walton and
Composite resin bonded to dentin 32 59 9 89 11 Langeland, 1978; Hrsted et al., 1981).
Composite resin bonded to enamel 38 56 6 76 24 The failure to form tertiary dentin may
Resin-modified glass ionomer 51 49 0 100 0 leave pulp tissues vulnerable to subse-
Zinc oxide eugenol 91 9 0 100 0 quent injury, or the opposite effect: The
Calcium hydroxide 83 17 0 - - excessive formation of tertiary dentin
can be associated with a closure of the
a These restorations were placed in the caries-free teeth of young adult patients. Severe inflammation pulp chamber and root canals (Stanley,
was avoided by the use of materials such as resin-modified glass ionomer and zinc oxide eugenol that
1989), to make future endodontic treat-
prevented bacterial growth (Murray et al., 2001). 2001 American Dental Association. Reprinted by
permission of ADA Publishing, a Division of ADA Business Enterprises, Inc .
ment difficult or impossible.

(A) PULP-CAPPING THERAPY

Class V cavities in caries-prone patients (Bergenholtz et al.,
1982). The detection of bacteria beneath composite resin
restorations demonstrates the continued need for improve-
ment in the adherence and marginal sealing ability of these
materials, by the use of sandwich placement techniques to
reduce composite resin shrinkage during polymerization
(Gallo et al., 2000). The greater prevalence of bacteria in cavi-
ties following use of enamel-bonded resin composite suggests
that inadequate or incomplete bonding to dentin may result in
increased leakage of bacteria at the tooth/restoration interface.
It would seem that restorative materials that form the most
perfect sealing with tooth structure are most able to prevent
bacterial microleakage. The prevention of bacterial microleak-
age will limit the severity of pulp inflammation and help
maintain pulp tissue vitality.
(IV) Guidelines for Optimizing the Success of
Pulp-exposed Cavity Preparations
The difference between the longevity and frequency of compli-
cations associated with exposed and non-exposed pulp restora-
tions means that it is worthwhile to make every effort to avoid
creating pulp exposure. The success of pulp capping depends
on many factors (Mjr, 2002a,b), but it is reported to be 37%
after 5 years and 13% after 10 years (Barthel et al., 2000), while
the success of non-exposed cavity preparation/restorations is
generally much higher and varies with different types of mate-
rials and conditions (Maupome and Sheiham, 1998; Burke et al.,
1999). Nevertheless, there is an 86% success rate for equivalent
teeth over 10 years for teeth that did not have a pulp exposure
prior to restoration (Mertz-Fairhurst et al., 1998).
Pulp exposures are more problematic to restore than non-
exposed pulp cavity preparations for several reasons. First,
during surgery, it is necessary to control hemorrhage that con-
taminates the dentin surface and prevent blood clot formation,
while identifying and removing diseased or infected tissue
(Hafez et al., 2000). Second, mechanical or traumatic injury
compromises the pulp-healing response (Mjr, 2001b). Third,
the presence of dentin restricts the diffusion of potentially inju-
rious agents in deep dentin; only 50% of the dentin surface is
composed of tubules, while the other half is made up of solid
buffer. The loss of dentin beneath the restorative material caus-
Ultimately, after the pulp is exposed,
the clinician must decide whether to place a pulp-capping
material or to undertake pulpotomy. Most dentists will imme-
diately opt for a pulpotomy (Ranly and Garcia-Godoy, 2000).
The most important factor in this decision-making process is
the likelihood of success. Factors which contribute to the likeli-
hood of pulp-capping success include a young patient age,
open tooth apex, good patient health, lack of pre-existing
symptoms, good pulp response to stimuli, small size of expo-
sure, and minor pulpal hemorrhage (Christensen, 1998;
Grecka et al., 2000; Hafez et al., 2000). Tissue engineering may
be able to revitalize pulp tissues by adding new stem cells or by
transplanting new vital tissue. Until such approaches are avail-
able, however, it is important to use direct pulp-capping mate-
rials and placement techniques which will benefit pulp healing
and preserve pulp vitality.
(B) ODONTOBLAST REPLACEMENT
BY ODONTOBLASTOID CELLS
Following pulp exposure, all primary odontoblasts are irre-
versibly injured at the exposure site (Murray et al., 2001). These
post-mitotic, terminally differentiated cells cannot proliferate
to replace subjacent irreversibly injured odontoblasts.
Consequently, these primary cells must be replaced by a new
generation of odontoblastoid cells (Tziafas, 1994, 1995). The
source of these cells has proved to be a source of much specu-
lation. Autoradiographic studies have indicated that new
odontoblastoids proliferate from within other pulp cell popula-
tions by a process of differentiation and migrate toward the site
of pulp exposure, where reparative dentin is secreted
(Fitzgerald et al., 1990). Possible progenitor cell populations for
the new odontoblastoid cells were assumed to be the subjacent
cells of the sub-odontoblast layer or pulp fibroblasts
(Fitzgerald, 1979; Fitzgerald et al., 1990). However, cultures of
pulp fibroblasts did not appear to differentiate into cells with
odontoblast-like phenotypes or secretory characteristics
(Hanks et al., 1998; MacDougall et al., 1998). However, recent
histological investigations have observed the presence of peri-
cyte and myofibroblast transitional cells in pulp tissue (Carlile
et al., 2000; Alliot-Licht et al., 2001). These cells appear to
migrate to the site of pulp exposure and secrete reparative

514 Crit Rev Oral Biol Med 13(6):509-520 (2002)

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International and American Associations for Dental Research

dentin (Murray et al., 2002e). Isolation of these cells in culture
has produced human dentin secretion (About et al., 2000;
Alliot-Licht et al., 2001). These specialized fibroblast-phenotype
pulp cells have the ability to migrate in response to cytokine
signaling molecules (Ellis et al., 1997). The similar phenotype
between normal fibroblasts and odontoblastoid progenitor
cells probably explains why the identification and activity of
these cells have proved difficult to isolate. (A schematic repre-
sentation of these cells is shown in Fig. 1b, step 3.) While these
cells appear to lack some characteristics of true stem cells, they
initially appear to be pluripotent mesenchymal cells with the
potential to express both soft- and hard-tissue phenotypes,
such as smooth muscle (Meyrick et al., 1981), fibroblasts
(Ivarsson et al., 1996), chondroblasts (Diaz-Flores et al., 1981),
and osteoblasts (Schor et al., 1990). Consequently, these cells
offer exciting opportunities for regenerating decayed dentin for
which there are few conservative treatment possibilities
because of the limitations of current treatment options.
(C) DENTIN BRIDGE FORMATION
Dentin bridges are a type of tertiary dentin secreted by odon-
toblastoid cells at the site of pulp exposure (Fig. 1b, step 5). The
secretion of dentin bridges can be influenced by pulp-capping
materials, degree of mechanical injury, and the creation of
dentin debris during operative procedures (Murray et al.,
2002e). Inflammation and bacterial leakage also negatively
influence dentin bridge formation (Cox et al., 1987). A practi-
tioner's attention to minimizing operative debris and carefully
placing pulp-capping materials is postulated to be most bene-
ficial for dentin bridge formation (Cox and Suzuki, 1994).
Growth factor therapy is already used to promote new bone
formation to correct periodontal defects (Heijl et al., 1997). This
same approach should also be applied to stimulate healing of
pulp tissues if pulp-reparative activity is compromisedfor
example, by injury or the age of the patient.
(D) PULP-CAPPING MATERIALS
The selection of direct pulp-capping materials and treatments
has changed little in the past 30 years while, over the same
time, the introduction of new composite resin materials has
provided various options for the restoration of indirect cavity
preparations (Cox and Suzuki, 1994). Calcium hydroxide is the
most commonly used pulp-capping agent (Yoshiba et al., 1994).
Its use is largely based on histological evidence, such as: induc-
ing healing of periradicular lesions, promoting apical closure in
incompletely developed teeth, and preventing or arresting root
resorption (Mjr and Ferrari, 2002). The high pH of calcium
hydroxide provides bactericidal activity and encourages tissue
repair by promoting tertiary dentin secretion (Yoshiba et al.,
1994; Foreman and Barnes, 1990). However, calcium hydroxide
suffers from unstable physical properties that allow material
particles to migrate into pulp tissue, thus causing inflamma-
tion, which may develop into necrosis (Walton and Langeland,
1978). The first generations of calcium-hydroxide-containing
materials had improved physical properties but were still not
insoluble, and they eventually permitted bacterial leakage to
occur (Cox and Suzuki, 1994). Calcium hydroxide may be con-
sidered to be a comparatively primitive material by current
standards. The adhesive systems used to place composite resin
materials appear to have more technological development
potential. Future areas in which these adhesive systems could
13(6):509-520 (2002)
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International and American Associations for Dental Research
be developed include: using bioactive molecules to mediate
pulp repair (Tziafas et al., 2000), adding antibacterial activity
(Imazato et al., 2001), including desensitizer, improving sealing
and bond strengths (Costa et al., 2000), as well as active caries-
prevention activity (Christensen, 2000). Moreover, it must be
recognized that the placement protocols for adhesive systems
are not fully optimized, and improvements are needed to
increase the ease and speed of placement, and to avoid prob-
lems. This is because globules of resin can migrate into pulp tis-
sue and stimulate inflammation (Kitasako et al., 1999). In addi-
tion, polymerization-shrinkage during the placement of these
materials can create marginal gaps to permit bacterial leakage
to occur (Pashley, 1996). Knowing the benefits and problems
associated with these restorative materials is helpful in assess-
ment of the risks and types of post-operative complications.
(E) PULP INFLAMMATION FOLLOWING
DIRECT PULP CAPPING
A comparison between pulp capping with resin composite and
that with calcium hydroxide showed that composite resin was
associated with a lower frequency of bacterial leakage (19.7%
vs. 47.0 %) (Murray et al., 2002e). These findings agree with
reports suggesting that new composite resin products are supe-
rior to their predecessors in having improved sealing proper-
ties. The leakage of bacteria was highly correlated with pulp
inflammation in the teeth of young adults (Murray et al., 2002e).
Both composite resin and calcium hydroxide pulp capping
appeared to have similar effects on pulp inflammation in the
presence and absence of bacteria. Consequently, the selection of
materials with the ability to seal the exposed pulp and prevent
bacterial leakage is perceived as the most important factor in
avoiding and minimizing pulp inflammation.
(F) TUNNEL DEFECTS
The pulp tissue can be protected following exposure by the
deposition of tertiary dentin, referred to as dentin bridge for-
mation (Cox et al., 1987, 1996). To act as an effective barrier
against bacterial leakage and migration of particles from cap-
ping materials, the reparative dentin should not contain any
tunnel defects (Cox et al., 1996). A tunnel defect is a discontinu-
ity in the structure of reparative dentin, which allows for pas-
sage between the exposure site and pulp tissue (Cox et al.,
1996). Recently, it was observed that most tunnel defects are
associated with operative debris or particles of capping materi-
als (Murray et al., 2002e). The presence of operative debris
appears to interfere with the continuity of dentin bridging.
Consequently, for more complete bridging of pulp exposures,
slow bur speeds should be used together with the cleansing of
operative debris from the site of exposure.
(V) Impact of Tissue Engineering
on Restorative Dentistry
(A) THE PROBLEM OF NON-RESTORABLE TEETH
The treatment of caries and periodontal diseases has
improved greatly over the last 50 years and has led to reduc-
tions in the numbers of teeth extracted (Greenberg, 1992). If
teeth require extraction, patients have the option of having
artificial tooth implants fitted or wearing dentures.
Currently, 45 million Americans wear dentures, and 25% of
them are dissatisfied (Lechner and Roessler, 2001). Even
Crit Rev Oral Biol Med 515
TABLE 3
Summary of Tooth Injury and Possible Applications of Tissue-engineering Approaches to Aid Healing

Degree of Some Loss Large Loss Complete Loss

Tooth Injury Minimal Severe of Vital Tissue of Vital Tissue of Vital Tissue

Example of Early non-arrested Arrested Arrested or Partially decayed Decayed tooth,

dental problem caries lesion deep-penetrating slowly progressing or fractured tooth or accidentally
caries lesion caries lesion extending evulsed tooth.
to pulp tissue

Common current Seal fissure or Excavate caries Stepwise excavation Pulp capping, Remove injured tissue
restorative therapy excavate caries and apply of caries lesion, endodontic treatment, and place implant
and apply restorative materials. or pulp capping or tooth extraction or prosthetic teeth.
restorative materials.

Likely objective of Alter oral bacterial Stimulate pulp-dentin Regenerate lost Implant progenitor Use progenitor cells
tissue engineering DNA to arrest healing with tissues and cells to regenerate and growth factors
in restorative and prevent growth factors. dentin repair lost tissue and tooth in 3-dimensional
therapy subsequentenamel with growth factors. mineralized structure. tissue culture to
and dentin caries harvest artificial teeth
demineralization. for implantation.

with the implementation of tissue-engineering procedures in (VI) Summary

restorative dentistry, there will always be some teeth that are
too severely damaged to be restorable, and these will still
require extraction and replacement. Recent developments in
tissue-culturing technology and improvements in control-
ling oral cell activity have facilitated the growth of teeth in
organ culture (Murray et al., 2000c, 2002d) and human
dentin to be synthesized and secreted in vitro (About et al.,
2000). The next stage in this process will be to grow and har-
vest artificially grown teeth as a substitute for implants and
prosthodontic devices once teeth have been extracted. But
injury to original tooth-supporting structures from disease
and tooth extraction will likely compromise the success of
tooth transplantation. However, studies are under way with
proteins to improve gingival adhesion to implants (Tamura
et al., 1997). It is hoped that this research will also benefit
tooth implantation.
(B) POTENTIAL APPLICATIONS OF TISSUE
ENGINEERING TO REPLACE EXISTING THERAPIES
There appears to be no certainty regarding the introduction of
any particular aspect of tissue-engineering therapy into
restorative dentistry, and there is no way of knowing how suc-
cessful these therapies will eventually prove to be. This
explains a general reluctance of authors to be specific and spec-
ulate on how tissue engineering will transform individual
aspects of restorative dentistry (Ranly and Garcia-Godoy, 2000;
Mjr, 2002a,b). However, in any review of this type, the issue of
using therapies in situations where they are likely to prove
most beneficial should be addressed. Although restorative den-
tistry is too highly dependent on clinical opinion to be an exact
scientific discipline (Mjr, 2001a), if we examine restorative
dentistry by the degree of tooth injury requiring restoration,
then some obvious applications of the tissue engineering dis-
cussed previously in this review become apparent. Examples of
tooth injury with common restorative treatments vs. likely tis-
sue-engineering therapies are shown in Table 3.
Restorative dentistry is an intricate form of microsurgery.
When removing caries, it is often difficult for clinicians to
know how, when, and where to start, and vice versa for
when to stop. Yet there are biological indicators as well as
records of longevity for restorations, radiographs, stimuli
testing, and patient opinions to be used for predicting the
outcomes of different caries-treatment strategies, cavity-
cutting methods, and restorative materials. From the bio-
logical perspective, each restorative variable has some effect
on pulp vitality, injury, and regeneration. Deviations from
normal pulp regeneration may be used to diagnose the
onset of complications, such as bacterial leakage and pulp
inflammation. Minimizing pulp injury during cavity prepa-
ration and placing materials which prevent bacterial
microleakage will preserve pulp vitality. Furthermore, pulp
regeneration will be used as the basis for tissue engineering
to radically alter restorative dentistry and the prognosis of
restored teeth. To avoid the need for operative dentistry,
DNA vaccines may be used to arrest or prevent the devel-
opment of caries lesions. Restorative materials may contain
a "cocktail" of growth factors, delivered in a slow-release
vehicle to regenerate replacement dentin from intra-coronal
pulp matrix. In cases of partially decayed or fractured teeth,
pluripotent cells may be implanted to regenerate tooth
structure. Eventually, non-restorable or lost and missing
teeth might be replaced by artificial implants of tooth tis-
sues grown synthetically in an in vitro culture.
Conclusion
Tissue-engineering therapies offer exciting treatment possibili-
ties, but health hazards, technical problems, and high costs will
delay their routine introduction for years to come. In the mean-
time, restorative dentistry will rely on the optimization of con-
ventional therapies. The following guidelines are intended to
avoid the need for restorative treatment, avoid the creation of
pulp exposures, and optimize restorative outcomes.

516 Crit Rev Oral Biol Med 13(6):509-520 (2002)

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International and American Associations for Dental Research

 (1) Monitor tooth lesions to distinguish between active and
arrested caries. Only active caries should require treat-
ment except for esthetic reasons.
(2) Soft caries should be excavated, but sometimes there
appears to be no need to remove caries-affected dentin
from the cavity floor; although this dentin is often discol-
ored and stains with caries-detector dyes, it is usually
remineralizable.
(3) Deep-penetrating caries lesions should be treated by slow
stepwise excavation techniques to allow for dentin re-
mineralization, regeneration, and pulp healing.
(4) Prior to replacing fillings, clinicians should consider
repair possibilities rather than complete removal.
(5) Dental materials should be selected which reduce bacter-
ial leakage. Prime examples include the use of long-last-
ing amalgam restorations for filling posterior teeth, resin-
modified glass ionomers in non-load-bearing premolar
teeth, and adhesive systems which often require less
removal of tooth structure for filling retention.
(6) Clinicians not experiencing problems with existing
restorative materials should continue with tried and test-
ed approaches. If problems are encountered, aspects of
operator handling should be evaluated, because this can
influence the effects of materials.
(7) Direct pulp capping must be restricted to teeth with a
good prognosis, young patients in good health, lack of
pre-existing symptoms, fresh non-carious exposure, good
pulp response to stimuli, small size of exposure, and
minor pulp hemorrhage; otherwise, pulpotomy or tooth
extraction is indicated.
(8) Minimizing the creation of operative debris with low-
speed cutting, and cleansing away of all visible debris
prior to pulp capping, will reduce pulp injury and permit
the increased continuity of tertiary dentin formation.
Acknowledgments
The authors thank Dr. David H. Pashley and Dr. Ivar A. Mjr for their review
and personal communications.
REFERENCES
About I, Bottero M-J, de Denato P, Camps J, Franquin J-C, Mitsiadis
TA (2000). Human dentin production in vitro. Exp Cell Res
258:33-41.
About I, Murray PE, Franquin J-C, Remusat M, Smith AJ (2001).
Pulpal inflammation responses following non-carious class V
restorations. Oper Dent 26:336-342.
Alliot-Licht B, Hurtrel D, Gregoire M (2001). Characterization of
smooth muscle actin positive cells in mineralized human den-
tal pulp cultures. Arch Oral Biol 46:221-228.
Anil N, Keyf F (1996). Temperature change in the pulp chamber
during the application of heat to composite and amalgam cores
and its returning time to oral heat. Int Dent J 46:362-366.
Arnst C, Carey J (1998). Biotech bodies. Businessweek July,
1998:42-49.
Barthel CR, Rosenkranz B, Levenberg A, Roulet JF (2000). Pulp cap-
ping of carious exposures: treatment outcome after 5 and 10
years: a retrospective study. J Endod 26:525-528.
Baum BJ, Mooney DJ (2000). The impact of tissue engineering on
dentistry. J Am Dent Assoc 131:309-318.
Baum BJ, O'Connell BC (1995). The impact of gene therapy on den-
tistry. J Am Dent Assoc 126:179-189.
Baum BJ, Kok M, Tran SD, Yamano S (2002). The impact of gene
13(6):509-520 (2002)
Downloaded from cro.sagepub.com by guest on June 11, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research
therapy on dentistry. J Am Dent Assoc 133:35-44.
Becker W (1994). Guided tissue regeneration for periodontal
defects. In: Periodontal regeneration: current status and direc-
tions. Polson AM, editor. Chicago: Quintessence Publishing. pp.
137-150.
Bergenholtz G (1982). Effects of bacterial products on inflammato-
ry reactions in the dental pulp. Scand J Dent Res 85:122-129.
Bergenholtz G (1990). Pathogenic mechanisms in pulpal disease. J
Endod 16:98-101.
Bergenholtz G (2000). Evidence for bacterial causation of adverse
pulpal responses in resin-based dental restorations. Crit Rev
Oral Biol Med 11:467-480.
Bergenholtz G, Cox CF, Loesche WJ, Syed SA (1982). Bacterial leak-
age around dental restorations: its effect on the dental pulp. J
Oral Pathol 11:439-450.
Bjrndal L, Darvann T (1999). A light microscopic study of odonto-
blastic and non-odontoblastic cells involved in tertiary dentino-
genesis in well-defined cavitated carious lesions. Caries Res
33:50-60.
Bjrndal L. Mjr IA (2001). Pulp-dentin biology in restorative den-
tistry. Part 4: Dental cariescharacteristics of lesions and pul-
pal reactions. Quintessence Int 32:717-736.
Bjrndal L, Thylstrup A (1998). A practice-based study on stepwise
excavation of deep carious lesions in permanent teeth. A 1-year
follow-up study. Community Dent Oral Epidemiol 26:122-128.
Bleiweis AS, Oyston PC, Brady LJ (1992). Molecular, immunologi-
cal and functional characterization of the major surface adhesin
of Streptococcus mutans. Adv Exp Med Biol 327:229-241.
Burke FJ, Cheung SW, Mjr IA, Wilson NH (1999). Reasons for the
placement and replacement of restorations in vocational train-
ing practices. Primary Dent Care 6:17-20.
Carlile MJ, Sturrock MG, Chisholm DM, Ogden GR, Schor AM
(2000). The presence of pericytes and transitional cells in the
vasculature of the human dental pulp: an ultrastructural study.
Histochem J 32:239-245.
Christensen GJ (1998). Pulp capping 1998. J Am Dent Assoc
129:1297-1299.
Christensen GJ (2000). The need for caries-preventive restorative
materials. J Am Dent Assoc 131:1347-1349.
Ciucchi B, Bouillaguet S, Hotz J (1997). The battle of the bonds. Rev
Suisse Odont Rev 107:32-36.
Costa CA, Hebling J, Hanks CT (2000). Current status of pulp cap-
ping with dentin adhesive systems: a review. Dent Mater 16:188-
197.
Cox CF, Suzuki S (1994). Re-evaluating pulp protection: calcium
hydroxide liners versus cohesive hybridization. J Am Dent
Assoc 125:823-831.
Cox CF, Keall CL, Keall HJ, Ostro E, Bergenholtz G (1987).
Biocompatibility of surface-sealed dental materials against
exposed pulps. J Prosthet Dent 57:1-8.
Cox CF, White KC, Ramus DL, Farmer JB, Snuggs HM (1992).
Reparative dentin: factors influencing pulpal response to cavi-
ty preparations. Quintessence Int 23:257-270.
Cox CF, Sbay RK, Ostro E, Suzuki S (1996). Tunnel defects in
dentin bridges: their formation following direct pulp capping.
Oper Dent 21:4-11.
Deligeorgi V, Wilson NH, Fouzas D, Kouklaki E, Burke FJ, Mjr IA
(2000). Reasons for placement and replacement of restorations
in student clinics in Manchester and Athens. Eur J Dent Educat
4:153-159.
Deligeorgi V, Mjr IA, Wilson NH (2001). An overview of reasons
for the placement and replacement of restorations. Primary Dent
Care 8:5-11.
Diaz-Flores L, Gutierrez R, Gonzalez R, Verela H (1981). Inducible
perivascular cells contribute to the neochondrogenesis in graft-
Crit Rev Oral Biol Med 517
 ed perichondrium. Anat Rec 229:1-8.
Diekwisch TG, Berman BJ, Gentner S, Slavkin HC (1995). Initial
enamel crystals are not spatially associated with mineralized
dentine. Cell Tissue Res 279:149-167.
Donly KJ, Grandgenett C (1998). Dentin demineralization inhibi-
tion at restoration margins of Vitremer, Dyract and
Compoglass. Am J Dent 11:245-248.
Ellis I, Banyard J, Schor SL (1997). Differential response of fetal and
adult fibroblasts to cytokines: cell migration and hyaluronan
synthesis. Development 124:1593-1600.
Featherstone JDB (1996). Clinical implications: new strategies for
caries prevention. In: Early detection of dental caries.
Stookey GK, editor. Proceedings of the 1st Annual Indiana
Conference. Indianapolis: Indiana University School of
Dentistry, pp. 287-295.
Finger WJ, Balkenhol M (1999). Practitioner variability effects on
dentin bonding with an acetone-based one-bottle adhesive. J
Adhes Dent 1:311-314.
Fitzgerald M (1979). Cellular mechanisms of dentinal bridge repair
using 3H-thymidine. J Dent Res 58:2198-2206.
Fitzgerald M, Chiego DJ Jr, Heys DR (1990). Autoradiographic
analysis of odontoblast replacement following pulp exposure in
primate teeth. Arch Oral Biol 35:707-715.
Foreman PC, Barnes IE (1990). Review of calcium hydroxide. Int
Endod J 23:283-297.
Fusayama T, Terachima S (1972). Differentiation of two layers of
carious dentin by staining. J Dent Res 51:866.
Gallo JR 3rd, Bates ML, Burgess JO (2000). Microleakage and adap-
tation of Class II packable resin-based composites using incre-
mental or bulk filling techniques. Am J Dent 13:205-208.
Glossary of Operative Dentistry Terms (1983). 1st ed. Washington,
DC: Academy of Operative Dentistry.
Grecka V, Suliborski S, Biskupski T (2000). Direct pulp capping
with a dentin adhesive resin system in children's permanent
teeth after traumatic injuries: case reports. Quintessence Int
31:241-248.
Greenberg D (1992). The uncelebrated triumph of dental health.
Lancet 340:359-360.
Gurunathan S, Wu CY, Freidag BL, Seder RA (2000a). DNA vac-
cines: a key for inducing long-term cellular immunity. Curr
Opin Immunol 12:442-447.
Gurunathan S, Klinman DM, Seder RA (2000b). DNA vaccines:
immunology, application, and optimization. Ann Rev Immunol
18:927-974.
Hafez AA, Kopel HM, Cox CF (2000). Pulpotomy reconsidered:
application of an adhesive system to pulpotomized permanent
primate pulps. Quintessence Int 31:579-589.
Hanks CT, Fang D, Sun Z, Edwards CA, Butler WT (1998). Dentine-
specific proteins in the MDPC-23 cell line. Eur J Oral Sci
106(Suppl 1):S260-S266.
Hatton JF, Holtzmann DJ, Ferrillo PJ Jr, Stewart GP (1994). Effect of
handpiece pressure and speed on intrapulpal temperature rise.
Am J Dent Res 7:108-110.
Heijl L, Heden G, Svardstrom G, Ostgren A (1997). Enamel matrix
derivative (Emdogain) in the treatment of intrabony perio-
dontal defects. J Clin Periodontol 24:705-714.
Hillman JD, Brooks TA, Michalek SM, Harmon CC, Snoep JL, van
Der Weijden CC (2000). Construction and characterization of an
effector strain of Streptococcus mutans for replacement therapy
of dental caries. Infect Immun 68:543-549.
Hilton TJ (1996). Cavity sealers, liners, and bases: current philoso-
phies and indications for use. Oper Dent 21:134-146.
Hrsted P, El-Attar K, Langeland K (1981). Capping of monkey
pulps with Dycal and a Ca-eugenol cement. Oral Surg Oral Med
Oral Pathol 52:531-553.
518
Downloaded from cro.sagepub.com by guest on June 11, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research
Imazato S, Torii Y, Yakatuska T, Inoue K, Ebi N, Ebisu S (2001).
Bactericidal effect of dentin primer containing antibacterial
monomer methacryloyloxydodecylpyridinium bromide
(MDPB) against bacteria in human carious dentin. J Oral Rehabil
28:314-319.
Ivarsson M, Sundberg C, Farrokhina N, Pertoft H, Rubin K, Gerdin
B (1996). Recruitment of type I collagen producing cells from
the microvasculature in vitro. Exp Cell Res 229:336-349.
Jontell M, Ukiji T, Dahlgren U, Bergenholtz G (1998). Immune
defense mechanisms of the dental pulp. Crit Rev Oral Biol Med
9:179-200.
Kihn PW, Barnes DM (1998). The clinical longevity of porcelain
veneers: a 48 month clinical evaluation. J Am Dent Assoc
129:747-752.
Kim S, Trowbridge HO (1998). Pulpal reaction to caries and dental
procedures. In: Pathways of the pulp. 7th ed. Cohen S, Burns
RC, editors. St. Louis, MO: Mosby, Inc., pp. 532-551.
Kitasako Y, Inokoshi S, Tagami J (1999). Effects of direct resin pulp
capping techniques on short-term response of mechanically
exposed pulps. J Dent 27:257-263.
Kugel G, Ferrari M (2000). The science of bonding: from first to
sixth generation. J Am Dent Assoc 131:20S-25S.
Langeland K, Langeland LK (1968). Cutting procedures with mini-
mized trauma. J Am Dent Assoc 76:991-1005.
Langeland JC, Guttusco J, Jerome DR, Langeland K (1966).
Histological and clinical comparisons of Addent with silicate
cements and cold-curing materials. J Am Dent Assoc 72:373-384.
Lechner SK, Roessler D (2001). Strategies for complete denture suc-
cess: beyond technical excellence. Compend Contin Educ Dent
22:553-559.
Lee SJ, Walton RE, Osborne JW (1992). Pulp response to bases and
cavity depths. Am J Dent 5:64-68.
Leksell E, Ridell K, Cvek M, Mejre I (1996). Pulp exposure after
stepwise versus direct complete excavation of deep carious
lesions in young posterior permanent teeth. Endod Dent
Tramatol 12:192-196.
Lloyd BA, Rich JA, Brown WS (1978). Effect of cooling techniques
on temperature control and cutting rate for high-speed dental
drills. J Dent Res 57:675-684.
Lutz FU, Krejci I, Besek M (1997). Operative dentistry: the missing
clinical standards. Pract Periodont Aesthet Dent 9:541-548.
MacDougall M, Selden JK, Hydegger JR, Carnes DL (1998).
Immortalised mouse odontoblast cell line M06-G3 applica-
tion for in vitro biocompatibility testing. Am J Dent
11(Suppl):S11-S16.
Maryniuk GA, Kaplan SH (1986). Longevity of restorations: survey
results of dentists' estimates and attitudes. J Am Dent Assoc
112:39-46.
Maupome G, Sheiham A (1998). Criteria for restoration replace-
ment and restoration life-span estimates in an educational envi-
ronment. J Oral Rehabil 25:896-901.
Mertz-Fairhurst EJ, Curtis JW, Ergle JW, Rueggeberg FA, Adair SM
(1998). Ultraconservative and cariostatic sealed restorations:
results at year 10. J Am Dent Assoc 129:55-66.
Meyrick B, Fujiwara K, Reid L (1981). Smooth muscle myosin in pre-
cursor and mature smooth muscle cells in normal pulmonary
arteries and the effect of hypoxia. Exp Lung Res 2:303-313.
Michalek SM, Katz J, Childers NK (2001). A vaccine against dental
caries: an overview. Biodrugs 15:501-508.
Mjr IA (1985). Biological and clinical properties. In: Dental mate-
rials, biological properties and clinical evaluation. Mjr IA, edi-
tor. Boca Raton: CRC Press, pp. 91-121.
Mjr IA (2001a). The basis for everyday real-life operative dentistry.
Oper Dent 26:521-524.
Mjr IA (2001b). Pulp-dentin biology in restorative dentistry. Part 2:
Crit Rev Oral Biol Med 13(6):509-520 (2002)
 Initial reactions to preparation of teeth for restorative proce-
dures. Quintessence Int 32:537-551.
Mjr IA (2002a). Pulp-dentin biology in restorative dentistry. Part 7:
The exposed pulp. Quintessence Int 33:113-135.
Mjr IA (2002b). Pulp-dentin biology in restorative dentistry.
London, UK: Quintessence Publishing.
Mjr IA, Ferrari M (2002). Pulp-dentin biology in restorative den-
tistry. Part 6: Reactions to restorative materials, tooth restora-
tion interfaces, and adhesive techniques. Quintessence Int
33:35-63.
Mjr IA, Jokstad A, Qvist V (1990). Longevity of posterior restora-
tions. Int Dent J 40:11-17.
Murray PE, Smith AJ (2002). Saving pulpsa biological basis. An
overview. Primary Dent Care 9:21-26.
Murray PE, About I, Lumley PJ, Smith G, Franquin J-C, Smith AJ
(2000a). Postoperative pulpal and repair responses. J Am Dent
Assoc 131:321-329.
Murray PE, About I, Lumley PJ, Franquin J-C, Remusat M, Smith
AJ (2000b). Human odontoblast cell numbers after dental
injury. J Dent 28:277-285.
Murray PE, Lumley PJ, Ross HF, Smith AJ (2000c). Tooth slice organ
culture for cytotoxicity assessment of dental materials.
Biomaterials 21:1711-1721.
Murray PE, About I, Franquin J-C, Remusat M, Smith AJ (2001).
Restorative pulpal and repair responses. J Am Dent Assoc
132:482-491.
Murray PE, Smyth TW, About I, Remusat R, Franquin J-C, Smith AJ
(2002a). The effect of etching on bacterial micoleakage of an
adhesive composite restoration. J Dent 30:29-36.
Murray PE, About I, Lumley PJ, Franquin J-C, Remusat M, Smith
AJ (2002b). Cavity remaining dentin thickness and pulpal activ-
ity. Am J Dent 15:41-46.
Murray PE, Lumley PJ, Smith AJ (2002c). Comparison of operative
procedure variables on in vitro pulpal viability. Am J Dent (in
press).
Murray PE, Hafez AA, Smith AJ, Cox CF (2002d). Hierarchy of
pulp capping and repair activities responsible for dentin bridge
formation. Am J Dent (in press).
Murray PE, Hafez AA, Smith AJ, Cox CF (2002e). Bacterial
microleakage and pulp inflammation associated with various
restorative materials. Dent Mater 18:470-478.
National Institute of Dental and Craniofacial Research (2002).
Biomimetics and tissue engineering. Bethesda, MD: National
Institutes of Health.
Ngassapa D (1996). Neurophysiological basis, aetiology and clini-
cal aspects of hypersensitive teeth. East African Med J 73:775-
778.
Ohmoto K, Taira M, Shintani H, Yamaki M (1994). Studies on den-
tal high-speed cutting with carbide burs used on bovine dentin.
J Prosthet Dent 71:319-323.
Okiji T, Jontell M, Belichenko P, Dahlgren U, Bergenholtz G,
Dahlstrm A (1997). Structural and functional association
between substance P and calcitonin gene related peptide-
immunoreactive nerves and accessory cells in the rat dental
pulp. J Dent Res 76:1818-1824.
Ottl P, Lauer HC (1998). Temperature response in the pulp chamber
during ultrahigh-speed tooth preparation with diamond burs
of different grit. J Prosthet Dent 80:12-19.
Pashley DH (1996). Dynamics of the pulp-dentin complex. Crit Rev
Oral Biol Med 7:104-133.
Ranly DM, Garcia-Godoy F (2000). Current and potential pulp
therapies for primary and young permanent teeth. J Dent
28:153-161.
Roberts-Clark D, Smith AJ (2000). Angiogenic growth factors in
human dentine matrix. Arch Oral Biol 45:1013-1016.
13(6):509-520 (2002)
Downloaded from cro.sagepub.com by guest on June 11, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research
Robinson C, Brooks SJ, Kirkham J, Wood SR, Shore RC (2001). In
vitro studies of the penetration of adhesive resins into artificial
caries-like lesions. Caries Res 35:136-141.
Rutherford RB (2001). BMP-7 gene transfer to inflamed ferret den-
tal pulps. Eur J Oral Sci 109:422-424.
Schor AM, Allen TD, Canfield AE, Sloan P, Schor SL (1990).
Pericytes derived from the retinal microvasculature undergo
calcification in vitro. J Cell Sci 97:449-461.
Slavkin HC (1996). And the next 50 years? The future of recombi-
nant DNA technology in oral medicine. J Public Health Dent
56(Spec Iss):278-285.
Smith AJ, Garde C, Cassidy N, Ruch JV, Lesot H (1995a).
Solubilization of dentine extracellular matrix by calcium
hydroxide (abstract). J Dent Res 74:829.
Smith AJ, Cassidy N, Perry H, Bgue-Kirn C, Ruch JV, Lesot H
(1995b). Reactionary dentinogenesis. Int J Dev Biol 39:273-280.
Smith AJ, Matthews JB, Hall RC (1998). Transforming growth fac-
tor-B1 (TGF-B1) in dentine matrix: ligand activation and recep-
tor expression. Eur J Oral Sci 106:179-184.
Smith AJ, Sloan AJ, Matthews JB, Murray PE, Lumley PJ (2000).
Reparative processes in dentine and pulp. In: Tooth wear and
sensitivity. Addy M, Embery G, Edgar WM, Orchardson R, edi-
tors. London: Martin Dunitz, pp. 53-66.
Smith AJ, Tobias RS, Murray PE (2001). Transdentinal stimulation
of reactionary dentinogenesis in ferrets by dentine matrix pro-
teins. J Dent 29:341-346.
Smith AJ, Murray PE, Lumley PJ (2002). Preserving the vital pulp
in operative dentistry: 1. A biological approach. Dent Update
29:64-69.
Stanley HR (1989). Pulp capping: conserving the dental pulpCan it
be done? Is it worth it? Oral Surg Oral Med Oral Pathol 68:628-639.
Stanley HR (1992). Biological evaluation of dental materials. Int
Dent J 42:37-46.
Stanley HR (1998). Criteria for standardizing and increasing credi-
bility of direct pulp capping studies. Am J Dent 11:17-34.
Stanley HR, Conti AJ, Graham C (1975). Conservation of human
research teeth by controlling cavity depth. Oral Surg Oral Med
Oral Pathol 39:151-156.
Swerdlow H, Stanley HR (1958). Reaction of the human dental
pulp to cavity preparation. 1. Effect of water spray at 20,000
rpm. J Am Dent Assoc 56:317-329.
Takahashi K, Yamane A, Bringas P, Caton J, Slavkin HC, Zeichner-
David M (1998). Induction of amelogenin and ameloblastin by
insulin and insulin-like growth factors (IGF-I and IGF-II) dur-
ing embryonic mouse tooth development in vitro. Connect
Tissue Res 38:269-278.
Tamura RN, Oda D, Quaranta V, Plopper G, Lambert R, Glaser S, et
al. (1997). Coating of titanium alloy with soluble laminin-5 pro-
motes cell attachment and hemidesmosone assembly in gingi-
val epithelial cells: potential application to dental implants. J
Periodontal Res 32:287-294.
Tarim B, Hafez AA, Cox CF (1998). Pulpal response to a resin-mod-
ified glass ionomer material on non-exposed and exposed mon-
key pulps. Quintessence Int 29:535-542.
ten Cate JM (2001). Remineralization of caries lesions extending
into dentin. J Dent Res 80:407-411.
Tziafas D (1994). Mechanisms controlling secondary initiation of
dentinogenesis: a review. Int Endod J 27:61-74.
Tziafas D (1995). Basic mechanisms of cytodifferentiation and
dentinogenesis during dental tissue repair. Int J Dev Biol
39:281-290.
Tziafas D, Alvanou A, Komnenou A, Gasic J, Papadimitriou S (1998).
Effects of basic fibroblast growth factor, insulin-like growth fac-
tor-II and transforming growth factor B1 on dental pulp cells
after implantation in dog teeth. Arch Oral Biol 43:431-444.
Crit Rev Oral Biol Med 519
Tziafas D, Smith AJ, Lesot H (2000). Designing new treatment
strategies in vital pulp therapy. J Dent 28:77-92.
Walton RE, Langeland K (1978). Migration of materials in the den-
tal pulp of monkeys. J Endod 4:167-177.
Waxman SG, Cummins TR, Dilo-Hajj S, Fjell J, Black A (1999).
Sodium channels, excitability of primary sensory neurons, and
the molecular basis of pain. Muscle Nerve 22:1177-1187.
White JM, Eakle WS (2000). Rationale and treatment approach in
minimally invasive dentistry. J Am Dent Assoc 131(Suppl):13S-
19S.
Yoshiba K, Yoshiba N, Iwaku M (1994). Histological observations of
hard tissue barrier formation in amputated dental pulp capped
with tricalcium phosphate containing hydroxide. Endod Dent
Traumatol 10:113-120.
Zach L (1972). Pulp liability and repair: effect of restorative proce-
dures. Oral Surg Oral Med Oral Pathol 33:111-121.
Zeichner-David M, Diekwisch T, Fincham A, Lau E, MacDougall
M, Moradian-Oldak J, et al. (1995). Control of ameloblast differ-
entiation. Int J Dev Biol 39:69-92.
Zllner A, Gaengler P (2000). Pulp reactions to different prepara-
tion techniques on teeth exhibiting periodontal disease. J Oral
Rehabil 27:93-102.

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