2. BIOCOMPATIBILITY
General definition:
The ability of a biomaterial to perform its desired
function with respect to a medical (or dental)
therapy, without eliciting any undesirable local or
systemic effects in the recipient or beneficiary of
that therapy, but generating the most appropriate
beneficial cellular or tissue response in that
specific situation, and optimizing the clinically
relevant performance of that therapy
(Williams, 2008) .
4. HISTORICAL
PERSPECTIVE
Since ancient times, a wide variety of relatively inert materials
have been placed or implanted in humans to replace or repair
missing, damaged, or defective body tissues. Bone, seashells,
animal teeth, human teeth, metals, resin materials, inorganic
compounds, and other tooth replacement materials have
been used for replacement of missing teeth. For the restoration
of damaged or decayed teeth, metals and nonmetals have
also been used, with outcomes that have varied from short term
failure to limited success in certain individuals. Many
of these treatments reflected situations in which the risks
were far greater than the anticipated benefits. Some of these
materials have caused immediate or delayed adverse reactions
because of their allergenic or toxic potentials.
6. IN GENERAL
Biological testing of materials has evolved significantly over the past 50 years. Since
the 1980s, testing has focused on:
Primary tests for cytotoxicity , hemolytic , Styles’ cell transformation,
the Ames test, the dominant lethal response, oral LD50, intraperitoneal (IP) LD50, and
the acute inhalation test.
Secondary tests are also used; include the mucous membrane irritation test (in
hamsters’ cheek pouches),
dermal toxicity from repeated exposures, responses to subcutaneous
implantation (e.g., in rats), and sensitization (of
guinea pigs).
Testing of dental materials also includes tests for
pulp irritation responses, pulp capping effects, endodontic
applications, and dental implant performance.
7. INFLUENCE OF THE AMERICAN DENTAL
ASSOCIATION
In 1930, the American Dental Association (ADA) formed
1. Council on Dental Therapeutics to oversee the evaluation of dental products.
2. Council established the ADA’s Seal of Acceptance program to promote the
safety and effectiveness of dental products.
In 2005, the ADA decided to phase out the Seal of Acceptance program for
professional products. Instead, decided to publish a product evaluation
newsletter for ADA member dentists .
This newsletter, called the Professional Product Review, was initiated in July 2006 .
The final phase-out of the ADA seal for professional products
occurred on December 31, 2007.
The major accomplishments
of the ADA was the development and acceptance
of ANSI/ADA Specification No. 41. Recommended Standard
Practices for Biological Evaluation of Dental Materials.
8. ADVERSE EFFECT FROM EXPOSURE TO
DENTAL MATERIALS
Local effects might occur in the
pulp tissue, in the
periodontium, at the root
apex, or in nearby oral tissues
such as the buccal mucosa or
tongue .
These local effects are a
function of
(1) the ability of substances to
be distributed to these sites,
(2) their concentrations, and
(3) exposure times, which may
range from seconds to years.
Systemic effects from dental
materials are also a function of
the distribution of substances
released from dental materials.
Their routes of entry into the
body include the following
sources:
(1) ingestion & absorption;
(2) inhalation of vapor;
(3) Leakage through the tooth
apex; and
(4) absorption through the oral
mucosa.
9. INFLAMMATORY AND ALLERGIC
RESPONSES
The inflammatory response involves the
activation of the host’s immune system
to ward off some challenge or threat.
Inflammation may result from trauma (excessive
force, laceration, and abrasion), allergy, or
toxicity.
Histological, the inflammatory response is
characterized by edema of the tissue caused
initially by an infiltration of inflammatory cells
such as neutrophils and, later in the chronic stage,
to the action of monocytes and lymphocytic cells.
10. Three potential sites for allergic reactions to
nickel-containing metals: watchband
buckle , fixed metal ceramic prostheses with
copings and framework made from nickel-
alloy and severe reaction of lips to nickel-
containing wire.
Bilateral lichenoid mucositis lesions on the
buccal mucosa adjacent to gold alloy
crowns.
Latex, can cause allergy directly by
activating antibodies to the material.
11. PRECURSORS FOR ADVERSE REACTIONS
A metal restoration can release metal ions as a result of
chemical reactions through high pH (HCl regurgitation),
electrochemical forces through dissimilar metal restorations,
or mechanical forces during brushing(abrasion).
For some materials, such as ceramics and resin-based
composites, cyclical stresses contribute to the breakdown
of the material and release of components.
Thus, the biocompatibility of the
material is controlled by the degradation process.
12. Another factor that increases the potential for the release
of potential allergens, mutagens, or toxins is the surface
roughness of a restoration or prosthesis.
For metals, rough surface promotes corrosion, which
increases the release of ions that may lead to adverse
effects.
Several types of beverages (high pH) have caused
degradation of dental ceramics.
Plaque accumulation also increases on roughened surfaces
and this may contribute to periodontal disease or caries.
13. IMMUNOTOXICITY
Principal concept of immunotoxicity is that
The substances leached from materials can alter immune
system cells, resulting in enormous biological
consequences because of the amplifying nature of
immune cells.
Monocytes control chronic inflammatory and immune
responses .Thus, if substances leached from a
biomaterial change the monocyte’s ability to secrete
these substances, the biological response can be greatly
influenced and this may greatly impair cellular defense
mechanisms against bacteria .
14. Mercury ions are known to increase the glutathione
content of human monocytes in cell culture, whereas
palladium ions decrease the cells glutathione content. {Glutathione
is important in maintaining oxidative stress in cells,
and any change in its concentration can alter cell function.}
Higher concentrations of mercury can also decrease glutathione
as the ion concentration becomes more toxic.
Small amounts of HEMA released from bonding
adhesives or resin-based composites can alter the normal
functions of monocytes, thereby contributing to the potential
Immunotoxicity of some resin-based products.
15. PULPAL AND PERIODONTAL EFFECTS
The postoperative discomfort or pain caused by dental materials may result
from any of several factors, including thermal trauma, chemical injury,
microleakage, and allergy.
It is well known that dentin permeability increases substantially in areas
closer to the pulp chamber. Thus, the damaging effect of a material, is
strongly influenced by the remaining thickness of dentin between the
material and the pulp chamber.
The cervical margins of many dental restorations are near the periodontal
attachment area, the biocompatibility of these materials may influence
the body’s ability to defend against bacteria that cause periodontal
disease.
Further, the periodontal pocket, or gingival sulcus, may accumulate
significant concentrations of leached or dissolved substances in sub
gingival areas, substances that are leached from root canal filling
materials may accumulate next to the apical foramen.
16. INTERFACES WITH DENTAL MATERIALS
The dentin–cement or dentin–resin interfaces are the most important
in transition areas for transfer of leached substances into dentinal
fluid.
Resin material does not penetrate the collagenous network or
debonds from it as the resin shrinks during polymerization, a
microscopic gap will form between the resin and dentin.
Incomplete bonding or resin penetration into the collagen mesh of
acid-etched dentin can lead to fluid ingress along gaps wider than
1 μm, which is referred to as microleakage
17. INFLUENCE OF BIOCOMPATIBILITY ON THE
OSSEOINTEGRATION OF IMPLANTS
The success of endosseous dental implants is
based on the biocompatibility of the implant
surface and the in growth of new bone into
the surface through the process of
osseointegration.
They tend to form surface oxides that enhances
bony approximation.
Some materials such as bioglass ceramics
promote a perfect osseointegration of the
bone.
The general process of biointegration involves
the adaptation of bone or other tissue to
the implanted material without any
intervening space along the tissue-material
interface
18. METHACRYLATES AND RESIN-BASED
COMPOSITES
The best screening substance for methacrylate allergy
caused by dental material products is HEMA. This result
confirms previous findings (Goon et al., 2006),
which revealed that HEMA alone picked up 96.7% of the
patients with methacrylate allergy and
100% of the dental personnel with methacrylate allergy.
19. ESTROGENICITY
In 1996, a research group claimed that dental sealants released estrogenic
substances in sufficient quantities to warrant concern (Olea et al., 1996).
Since then, the estrogenicity of dental composites has also been
questioned, particularly for use in children.
The substance is called xenoestrogen.
The concern about estrogens in dentistry centers around a chemical called
bisphenol A (BPA), which is a synthetic starting point for bis-GMA
(bisphenol-A-glycidyldimethacrylate)composites in dentistry as well as
many other plastics.
However, these studies have also shown that BPA is probably 1000-fold
less potent as an estrogen than the native estrogen hormone.
One test commonly used to assess xenoestrogenic activity is the E-screen
assay. (In vitro test relies on the growth response of breast cancer cells,
which are sensitive to potential estrogenic compounds) which is not
reliable.
20. OTHER BIOLOGICAL CONSIDERATIONS
FOR RESINS
The explosion in the use of resin-based composites for restorative work has
raised questions about the biological safety of these materials.
The primary risk of resin based composite materials appears to be allergy
related, and the risk is highest for dental personnel because of frequent
exposure to non polymerized materials.
The allergenicity of methylmethacrylate is well documented, and the use of
gloves is not effective in preventing contact because most resin
monomers pass easily through gloves.
The allergic reactions occur primarily as contact dermatitis, with the resins
acting as haptens via delayed hypersensitivity (Type IV) mechanisms. In
rare cases, anaphylactic responses have been reported, and dermatitis
may be so severe as to be disabling.
Resin components have also been shown to traverse dentin, and newer
techniques that advocate direct pulp capping with resins expose pulp
directly to these materials.(have significant toxic effects, which are
clearly demonstrated through the use of in vitro tests).
21. TITANIUM AND
TITANIUM ALLOYS
In vitro evaluation of titanium biocompatibility,
percentage attachment efficiency, and
proliferation of human fetal fibroblasts and
human gingival fibroblasts reveals that a surface
layer of titanium oxide (Ti2O3) has the ability to
coexist with living tissues and organisms. Based
on these studies one can conclude that titanium is
relatively nontoxic, noninjurious, and not
physiologically reactive.
22. BASE METALAND NOBLE METALALLOYS
Base metal alloys are classified by
the ADA as those containing
less than 25% by weight of
noble metals (gold, platinum,
palladium, rhodium, ruthenium,
iridium, and osmium).
Some evidence suggests that metal
appliances can lead to gingivitis
or periodontitis.
The severity of these adverse effects
varies as a function of atomic or
molecular characteristics
(Schmalz and
Garhammer, 2002).
Noble alloys are classified as those
that contain between 25% and
60% of these noble metal
elements.
High noble metal alloys are
classified by the ADA as those
containing at least 40% gold and
60% of noble metal elements.
Allegations of adverse effects caused
by leaching of palladium have
raised concerns on the
biocompatibility of these alloys.
These analyses were based on use of
the subcutaneous implantation (histopathological) method.
Cast metal discs were implanted for 15, 30, or 60 days in rats.
23. NICKEL
Nickel is the most allergenic metal known, with an incidence of allergic reactions between
10% and 20%.
Nickel ions (Ni2+) are a documented mutagen in humans, but there is no evidence that
nickel ions cause any carcinogenic response intraorally.
Reactions to nickel-containing dental alloys are well documented, and quite severe in
sensitized individuals.
Some studies in guinea pigs have suggested that oral exposure
to nickel induces immunological tolerance.
There is a possible cross-reactivity between nickel and palladium allergy. Almost all patients
who are allergic to palladium will be allergic to nickel, whereas only about 33% of those
allergic to nickel will be allergic to palladium.
Base metal alloys containing both beryllium and nickel exhibit high beryllium release rates,
which may pose a health risk.
Interactions between metallic restorations and patient factors such as consumption frequency
of acidic foods and beverages and composition of saliva can significantly affect intraoral
corrosion.
Corrosion may also be accelerated by phagocytotic cells such as human neutrophils
(Yang et al., 1992).
Wear can also accelerate the corrosion processes in vivo because of the local
breakdown of the passivation layer (Khan et al., 1999).
24. BERYLLIUM
Beryllium is known to be highly toxic, it is used in some Ni-Cr alloys in
concentrations of 1% to 2% by weight (approximately 5.5% to 11% atomic
content) to increase the castability of these alloys and lower their melting range.
It also tends to form thin adherent oxides that are required to promote atomic bonding
of porcelain.
The use of beryllium in dental alloys is controversial because of its biological effects.
First, beryllium is a documented carcinogen in either the metallic (Be0) or ionic
(Be2+) state,
Although there are no studies showing that dental alloys containing beryllium cause
cancer in humans.
Acidic environments enhance beryllium release from Ni-Cr alloys.
Beryllium-containing particles that are inhaled and reach the alveoli of the lungs
may cause a chronic inflammatory condition called berylliosis (delayed type
of hypersensivity reaction).
25. DENTAL CERAMICS
Overall, the risk of surface degradation is low, and feldspathic
ceramics have been used as clinical veneers for many years
without significant biocompatibility issues.
Ceramic materials are known for their high levels of
biocompatibility.
These oxides and related compounds in dental ceramics exhibit
minimal dissolution in normal oral fluids and beverages.
However, highly acidic environments can increase the release
rates of certain metal and silicon ions.
For example, acidulated phosphate fluoride (APF) is crown to
corrode the surfaces of veneering porcelains as well as glaze
and stain ceramics. Thus contraindicated.
26. LATEX
In dentistry is the use of latex gloves and latex rubber dams,
which expose both patients and dental personnel to this
potential allergen.
In the early 1980s, when HIV infection became a major safety
issue, dental personnel began to routinely wear gloves to reduce
the risk of transmission.
Since that time, the incidence of latex hypersensitivity reactions
has increased enormously. In 1991, the FDA estimated that
about 6% to 7% of surgical personnel may be allergic to latex.
Ammonia and sulphur are allergen which are leached out during
soaking process in rubber manufacturing and comes to the
surface and unfortunately places the highest concentrations near
the skin of the wearer.
27. DENTURE BASE MATERIAL
Methacrylate with immune
hypersensitivity.
Visible light cure denture base
resin and denture base resin
sealants shows cytotoxicity to
epithelial cells.
28. REACTIONS TO RESORBABLE MATERIALS
In vivo
Suture material co polymer of poly
lactic acid and poly glycolic acid
are hydrolyzed to CO2 and H2O .
Resorbable fracture fixatation plate
and screws ,Guided tissue
membrane and controlled drug
released systems Degrades to
acidic by products and drop in pH
in surrounding tissue invoke
inflammatory responses.
29. ALLERGIC REACTIONS
Patch tests for potential allergies to dental materials also suggest that the most
likely allergens were components of cast dental alloys (Ditrichova et al., 2007).
In this study, patch tests were performed on 25 subjects with lichenoid lesions
located on the buccal mucosa, tongue and lips. Two sets of allergens, the
“European Standard "and “Dental Screening” (Chemo technique Diagnostics,
Sweden) were used, supplemented with pulverized amalgam, iridium, indium,
menthol, sorbet acid and platinum.
The greatest frequency of positives were associated with dental metals (27 positive
reactions). The order of tested metals according to frequency of positive
reactions was
Mercury (24%), amalgam (24%), nickel (16%), palladium (16%), cobalt
(12%), gold (8%), chromium (4%), and indium (4%).
relevant primarily for detecting dermal effects of hypersensitivity
(contact dermatitis).
30. Based on one study of 25 patients with lichenoid lesions, positive responses
to standard patch tests were found for amalgam (25%), nickel (16%),
palladium (16%), cobalt (1%), gold (8%), chromium (4%), and indium
(4%).
In another study of patients who exhibited patch test reactions to mercury
compounds, partial or complete replacement of amalgam fillings led to a
significant improvement in nearlyall patients (Laeijendecker et al.,
2004).
The results from one study (Khamaysi et al., 2006) indicate that the most
frequent oral manifestations were cheilitis and perioral dermatitis
(25.6%), burning mouth (15.7%), lichenoid lesions (14.0%), and
orofacial granulomatosis (10.7%). A total of 14.9% of the patients were
dental personnel, each of whom suffered from hand dermatitis.
31. Susceptibility to allergic reactions varies considerably from one
metal to another. Some estimates indicate that 15% of the
population is sensitized to nickel, whereas only 4.2%
(Valentine-Thon et al., 2006) of the population is sensitized to
titanium.
Memory lymphocyte immunostimulation assay (MELISAR) was
selected for investigating hypersensitivity to Ti. Muller and
Valentine-Thon (2006) demonstrated that titanium can induce
clinically relevant hypersensitivity in a subgroup of patients
chronically exposed via dental or endo-prosthetic implants.
Palladium-based alloys have been associated with stomatitis and
oral lichenoid reactions, and palladium allergy seems to occur
mainly in patients who have been sensitized to nickel.
32. REACTIONS TO TOXIC AGENTS
There are several adverse reactions that can be caused by exposure to
biomaterial substances and processes. These include reactions to the
following:
1. Systemic toxins such as chemical agents, which can act on target organs
or organ systems
2. Asphyxiants, which deprive the tissues of oxygen (anoxia)
3. Irritants, which cause inflammation of tissues by direct contact
4. Allergic sensitizers, which activate the production of antibodies—which,
in turn, react with the antigen to make it a latent complex (when the
body becomes exposed one or more times to the sensitized agent, the
concentration of antibodies increases until an antigen–antibody reaction,
or allergic reaction, results in one or more symptoms)
5. Carcinogens, which are substances known to cause cancer in an organism
6. Reproductive toxins, such as mutagens or teratogens.
33. GENOTOXICITY, MUTAGENICITY,
AND CARCINOGENICITY
Genotoxicity refers to any adverse effect on the DNA
of an organism.
The adverse effect is transferred to the next (heritable)
generation of cells, the effect is called mutagenicity.
Several metal ions from dental materials—such as
beryllium, copper, and nickel—are known mutagens,
and some components of other materials such as root
canal sealers have also been shown to be mutagenic.
Resin-based materials have also been identified as
having some mutagenic potential.
No dental material has ever been shown to be
carcinogenic in dental patients.
34. Genotoxic effects have been reported for beryllium and gallium salts
(Kuroda et al., 1991).
Occupational data indicate that beryllium may increase the risk of lung
cancer and other tumors in humans (Aller, 1990; Ashby et al., 1990;
Hayes, 1997).
No genotoxic effects were found for orthodontic appliances (wires,
brackets, extension screws) fabricated with base metal alloys and CP Ti
(Assad, et al., 1998; Tomakidi, 2000; Wever et al., 1997).
No genotoxic effects were found for several titanium-containing alloys, CP
Ti, and one Ni-Cr−based alloy (Wang and Li, 1998).
There is some evidence, which suggests that nickel, cobalt, chromium, and
beryllium tend to increase cancer risk in humans.
However, there is no validated evidence to prove that dental casting alloys
are genotoxic or carcinogenic.
35. BIOCOMPATIBILITY TESTS
Three types of tests are used to analyze the biocompatibility
of dental materials:
(1) an in vitro test,
(2) an animal test, and
(3) usage test performed clinically in animals or humans.
No single test can accurately estimate the biological response
to a material. In addition, there is no clear consensus on the
optimal combinations of tests that must be performed for
each type of material.
36. IN VITRO TESTS
THE CANDIDATE MATERIAL OR AN EXTRACT OF THE MATERIAL IS PLACED
IN DIRECT OR INDIRECT CONTACT WITH SOME BIOLOGICAL SYSTEM
OUTSIDE OF AN ORGANISM.
Direct contact exposes a
material or an extract of a
material directly to the
biological environment
Indirect contact involves a
barrier such as agar, a
membrane filter, or
dentin.
In vitro tests are relatively fast and inexpensive and they can be
standardized relatively easily. Also, in vitro tests can be controlled very
well to provide highly reliable data and
reproducible measurements.
Perhaps the greatest disadvantage of in vitro tests is their limited
relevance to clinical practice.
37. ANIMAL TEST
Animal tests involve the placement of a material in an
organism. Test animals include baboons, cats, dogs,
ferrets, guinea pigs, hamsters, mice, monkeys, pigs,
rats, and sheep.
In animal tests ,the materials are ground and fed to the
animals (e.g., rats) in so-called acute or chronic
toxicity tests; this process simulates the oral uptake of
the materials, although oral ingestion is not
realistic.(illegal)
In animal tests, those involving guinea pigs, the ability of
a substance from a material to sensitize and then elicit
an allergic reaction is evaluated. These test methods
have provided reliable data that can be extrapolated to
humans.
In contrast, tests are applied in the test animal as they are
in the patient, e.g., a restorative material in Class V
cavity preparations is placed in monkey teeth.
38. ANIMAL TESTS TO ACCESS
BIOCOMPATIBILITY
1. Mucous membrane irritation test.
2. Skin sensitization test: (intra-dermal
injections for the development of skin
hypersensitivity reaction followed by
secondary treatment with adhesive
patches containing the test substances).
3. Implantation test: (To test materials
that will contact subcutaneous tissue or
bone can be placed on connective tissue
, bone or muscle).
39. ADVANTAGE
The advantage of animal tests lies in their ability to
permit an intact biological system to respond to
or interact with a candidate material. The material
can thereby interact with many complex
biological systems to obtain a biological
response.
40. DISADVANTAGE
The disadvantages of animal tests are their high cost,
control difficulty, and the length of time that may be
required to obtain a measurable response.
These tests are criticized by animal rights activists and
other individuals because of concerns regarding the
ethical treatment of test animals.
Finally, the relevance of animal tests in simulating
human responses is often challenged.
In spite of these disadvantages, animal tests are
essential for evaluating new materials prior to their
clinical use.
41. USAGE TEST
Usage tests are the most clinically relevant tests.
They are performed either in animals or humans. Such
a test requires that the material be placed in a
clinically relevant environment similar to that to
which the material would be exposed in clinical
practice.
When a usage test is performed in humans, it is called a
clinical trial.
The ultimate relevance of a usage test depends on the
extent to which the test simulates the clinical use of
the product.
42. USAGE TEST
1. Dental pulp irritation test: dental materials on
class 5 cavity preparation in intact , non carious
teeth; the teeth are removed and sectioned for
microscopic examination with tissue necrotic and
inflammatory reaction . Classified according to
intensity of response for liners ,cements and
restorative agents.
2. Dental implant in bone: best predictors for
success of implants are careful patient selection and
ideal clinical conditions.
43. Dental implant in bone…
Following terms are used to define various degree of success
1. Early implant success {surviving 1-3 yrs.}
2. Intermediate implant success{surviving 3-7 yrs.}
3. Long term implant success {surviving more than 7 yrs.}.
Commonly used test for prediction :
1. Penetration of Pdl probe along the line of implant .
2. Morbidity of implant.
3. Radiographs indicating either osseointegration or
radiolucency around implants.
44. MUCOSA –GINGIVAL USAGE TEST:
Access by placement in cavity preparation with
subgingival extension.
Depending upon the no. of mononuclear inflammatory
cells (mainly lymphocytes and neutrophils ) in
epithelium and adjacent connective tissue
Response categorized as
Slight
Moderate
severe
45. DISADVANTAGE
Includes their design complexity, difficulty to control
experimentally, and interpretation challenges.
These tests are also extremely costly.
If humans are used in a clinical trial, approval for the
proposed usage tests must be obtained from an institutional
review board.
A test for the long-term performance of a material may take 5
years or more, which adds considerably to the typically
high cost of using human subjects.
Finally, human usage tests may involve legal and
confidentiality issues that do not occur for animal and in
vitro tests .
