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22/03/2014 1 BIOCOMPATIBILITY OF POLYMETHYLMETHACRYLATE RESINS Presented by: Dr. Hashmat Gul Demonstrator, Dental Materials. AMC, NUST. 1. INTRODUCTION

Biocompatibility of Polymethylmethacrylate resins

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PDF, Polymethylmethacrylate Uses, Classification, Composition, Basic Material properties, Release of substances & degradation, Toxicity , Tissue Compatability, Allergies, Mutagenecity & Carcinogenicity.

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Page 1: Biocompatibility of Polymethylmethacrylate resins

22/03/2014

1

BIOCOMPATIBILITY OF POLYMETHYLMETHACRYLATE RESINS

Presented by:

Dr. Hashmat Gul

Demonstrator,

Dental Materials.

AMC, NUST.

1. INTRODUCTION

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USESIN DENTISTRY DAILY LIFE

� Construction of � Dentures � Orthodontic Devices.� Individual Impression Trays� Temporary crowns.

� Veneering

� As Bone Cements� Acrylic Glass

� A Base For Various Stains for Artificial Fingernails, Nail Varnish etc

Classification Of Denture Base Polymers

Type Class Description

1

1

2

2

3

4

5

1

2

1

1

-

-

-

� Heat-processing polymers, P/L� Heat-processed (plastic cake)� Autopolymerised polymers, P/L� Autopolymerised polymers (P/L pour type resins)� Thermoplastic blank or powder� Light-activated materials� Microwave-cured material

According To The Setting Reaction

� Heat Polymerizing � Light Curing� Chemically (Auto)curing.

According To ISO 1567

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COMPOSITION OF PMMA RESINS

POWDER LIQUID

� Polymer� Polymethylmethacrylate beads

� Initiator� A peroxide such as benzoyl peroxide

(0.5%)� Pigments

� Salts of cadmium or iron or organic dyes

� Monomer� Methyl methacrylate

� Cross-linking agent� Ethylene-glycol-dimethacrylate (10%)

� Inhibitor� Hydroquinone (trace)

� Activator*� N N′-dimethyl-p-toluidine (1%)

* Only in Self Curing Material

2. BASIC MATERIAL PROPERTIES

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HEAT CURE LIGHT CURE�Composition: Generally based on PMMA.

�Setting: Initiated by heat decomposition of the initiator (mainly dibenzoyl peroxide) into radicals.

�Composition: Derived partly from PMMA and also from urethane-dimethacrylates.

�Setting: �Initiated by light exposure, at room or oral temperature.

�Triggered by a redox system. e.g. amine–peroxide redox system.

� Accelerator, such as a tertiary amine, sulfinic acid, or substituted barbituric acid.

SETTING Of PMMA RESINS

RELEASE OF SUBSTANCES & DEGRADATION

�Methods Used To Identify Substances Released From MMA

�High-performance Liquid Chromatography,

�Gas Chromatography,

�Gas Chromatography/Mass Spectroscopy,

�Infrared Spectroscopy.

� Factors Effecting The Concentration Of Residual Monomers & Elutable Additives:

�Polymerization type

� Polymerization time

� Polymerization temperature

� Surface finish and structure

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RELEASE OF SUBSTANCES & DEGRADATION

�Residual Monomer

� The unreacted monomer that is not firmly incorporated in the polymer network and may

therefore leach.

�Concentration Of Residual Monomers In Denture Base Polymer Resins

HEAT CURE LIGHT CURE�AFTER CURING little i.e. 0.1–1.5 wt.%

� Thickness: Thicker regions < Thin layers.� Curing Time: When the Curing Time was

extended from 15 min to 12 h at a temperature of 100°C, RM conc. dropped from 1 wt% to less than 0.1 wt%

� AFTER CURING more i.e. 3–5 wt.%� Curing Temp.: An increase in temperature

during curing, from 30°C to 60°C, causes a significant decrease in the amount of residual monomers.

RELEASE OF SUBSTANCES & DEGRADATION�Residual Monomers/Additives Were Extracted By Means Of

�Aqueous media including distilled water, natural or artificial saliva, Ringer’s solution.

�Organic diluents (methanol, ethanol, tetrahydrofurane, acetone)

HEAT CURE LIGHT CURE

� In-vivo study:� After insertion did not leach MMA.

� In-vitro studies:� Revealed that heat-polymerized acrylic

also releases MMA over several days but in significantly smaller quantities than autopolymerized products.

� In-vivo study:� Releases MMA over a period of 1 week

after insertion (up to 45 μg/ml saliva). � MMA was not found in the urine or blood

of the participants. � The intra-orally released MMA

concentrations were far below the threshold doses.

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RELEASE OF SUBSTANCES & DEGRADATION

� Clinical Correlation Between Residual Monomer

Concentration & Irritation Of The Oral Mucosa.

� The eluable share of residual monomers & additives should be as low as possible.

� To minimize the concentration of residual monomers , it is recommended that dentures and orthodontic devices be stored for up to 24 h in warm water (37–50°C) before insertion.

RELEASE OF SUBSTANCES & DEGRADATION

�FORMALDEHYDE

HEAT CURE LIGHT CURE� Released in much smaller quantities � Released in high amounts (40–50 nmol/ml on

the1st day) in vitro and in vivo (saliva).

�Mechanisms of formaldehyde formation � First, a primary oxidation of unsaturated methacrylate groups is possible.

� Secondly, oxygen can copolymerize with methacrylate groups during the initial phase of the polymerization.

� Decomposition of this copolymer will then result in the formation of formaldehyde.

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RELEASE OF SUBSTANCES & DEGRADATIONMONOMERS INITIATORS STABALIZERS ACCELERATOR

IN LC-BDP

REACTION

PRODUCT OF DBP

� Methyl-

methacrylate

(MMA)

� Meth-acrylic acid

� Ethylene-glycol di-

methacrylate

� Di-benzoyl

peroxide (DBP)

� Hydroquinone

� Resorcinol

� Pyro-gallol

� N,N-dimethyl-p-

toluidine (tertiary

amine)

� Phenyl benzoate

� Benzoic acid

� Biphenyl

3. SYSTEMIC TOXICITY

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SYSTEMIC TOXICITYIn-vivo study in Irritants Released Oral LD50 Acute Systemic Toxicity

� Rats, Oral administration

to calculate LD50 value

� dibenzoyl peroxide

� MMA

� 950 mg/kg body weight

� 8.4-9 g/kg body weight

� Very low

� Very low

Rats receiving MMA “orally” through a stomach tube

Degradation of MMA by a nonspecific carboxyl esterase

Methacrylic acid, identified in blood after 5min.

peak after 10–15 min with no Organ damage

subsequently metabolized to pyruvate, via the citric acid cycle

SYSTEMIC TOXICITY

�The half-life of MMA

� In human blood varies between 20 min and 40 min.

Studies on dogs

MMA released from the bone cement of hip implants

also excreted via the lungs

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SYSTEMIC TOXICITY

Effects of MMA

�Cardiovascular effects e.g. a relaxing effect, on the non-striated muscles of blood vessels.

�GIT : Inhibited peristalsis of the ileum due to inhaled MMA vapor in rat experiments.

�MMA vapor in dental practices caused vertigo.

�No serious problems may be caused by inhaling PMMA ingredients.

�PMMA May irritate the eyes, skin, and respiratory system.

SYSTEMIC TOXICITY

In-Vivo study, Rats

The embryo-fetal toxicity of MMA

MMA, when injected intra-peritoneally at LD50 conc.

malformations and other injury to embryos or fetuses.

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SYSTEMIC TOXICITY

�Route Of Administration of MMA, Humans

�Patients leaching substances from PMMA resins through the oral cavity,

�Dental personnel and lab technicians MMA-vapor.

�The Maximum Allowable Concentration Values For MMA

�In Germany, 50 ppm or 210 mg/m3 compartment air.

�Legal regulations for dental laboratories are based on A DIRECTIVE regarding hazardous substances and the technical rules for hazardous materials e.g. TRGS 900.

4. LOCAL TOXICITY & TISSUE COMPATIBILITY

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CYTOTOXICITY & TISSUE COMPATABILIY

� The cellular compatibility of solid specimens, aqueous resin extracts, formaldehyde, and

MMA was investigated in permanent cells and primary cultures as well.

STUDY 1: By Nakamura & Kawahara

2-week-old aqueous extracts of 2 Heat-cure acrylics and 3 Auto-cure acrylics.

Conclusion: MMA and formaldehyde, are volatile.

The test solutions did not contain the original conc. of these 2 substances due to the extended extraction time

CYTOTOXICITY & TISSUE COMPATABILIY

STUDY 2: Toxic reactions caused by solid specimen of two orthodontic acrylic resins in permanent cultures of fibroblasts & keratinocytes.

Both products were no longer toxic 30 days after setting

1 light-cure

Cytotoxic if the oxygen-inhibited surface layer was not removed

1 Self-cure

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CYTOTOXICITY & TISSUE COMPATABILIY

KB cells: human oral keratinocytes ,

BF cells: human mucosal fibroblasts.

� STUDY 3:� The auto-cure product

showed the highest

cytotoxicity.

� The light-cure material

was the least cytotoxic.

� Cytotoxicity of all

products decreased

after several

extractions using

aqueous cell culture

medium.

CYTOTOXICITY & TISSUE COMPATABILIY

CONCLUSION:

�The initial high toxicity immediately after polymerization was due to various released radicals.

�Compatibility, depends on

� The general composition (e.g., type of base resin)

� Material aspects or the formulation of the individual product.

�No toxic effects in primary human gingival fibroblast cultures and osteoblast-like cells were

caused by aqueous 24-h and 7-day extracts of another PMMA-type bone cement.

�In solid specimens: Only a slight or moderate cytotoxicity exhibited.

�Auto-polymerizing acrylics are significantly more toxic than heat-polymerizing products.

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CYTOTOXICITY & TISSUE COMPATABILIY

Clinical Practice Advice

�To lower Cytotoxicity , it is recommended to store dentures for 1 day in water to

significantly reduce the amount of residual monomers.

�Heat-polymerizing products should be preferred over auto-polymerizing materials if

possible.

�Patients should be advised not to wear dentures at night at first because this might

contribute to irritation of the mucosa due to an accumulation of residual monomers in the

tissue.

TC50 (median toxic concentration) values of several resin compounds

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MICROBIAL EFFECTS

�PMMA acrylics and permanent soft relining

materials may promote the growth of

� Fungi such as Candida

� Bacteria like Escherichia coli, and

Pseudomonas aeruginosa.

�Substances promoting Microbial proliferation

�MMA

� Phthalate

� The cross-linking substance.

“microclefts” between permanent soft relining materials and the “hard” denture base + Poor Oral Hygiene

stimulate microbial growth

An inflamed mucosa

(Candidiasis)

MICROBIAL EFFECTSSUBSTANCE CONCENTERATION EFFECTS

� MMA

� Plasticizers�benzyl benzoate �benzyl salicylate

� N,N-dimethyl-p-toluidine

� The cross-linking agent EGDMA

� High Conc. (>0.5%)� Low Conc.

� High Conc.

� High Conc.� Low Conc.

� Bactericidal� Promote Bacterial growth

� Fungicidal

� Inhibit Bacterial growth� Promote Bacterial growth

� increase the proliferation ofStreptococcus sobrinus and Lactobacillus acidophilus

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MICROBIAL AFFECTS

�Candida albicans & “denture stomatitis”

� The pellicle of dentures of stomatitis patients contained an

increased conc. of cell particles derived from

�Candida albicans.

�Salivary compounds that promoted adhesion of Candida

�Adherence Of Candida promoted by

� A rough surface structure of PMMA-based dentures.

� Permanent soft, porous relining materials promoted adhesion in some cases.

MICROBIAL AFFECTS

�Dentures may transfer certain pathogenic & highly virulent microbes

from the oral cavity to

� The Distal Gastrointestinal Tract

� Respiratory system.

�Matsuura et al. reported that

� Staphylococcus aureus colonized dentures and tongues of “resected” patients with

extended oral tissue defects at much higher concentration than in edentulous

“nonresected” patients

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IMPLANTATION STUDIES�Local reactions are primarily dependent on the amount of substances leached and their

toxicity. Thus, heat-polymerized products should cause fewer effects than auto-

polymerizing materials.

In vivo implantation study on rats and rabbits

Specimens of various acrylic resin were implanted

1st Day: a mild to severe tissue irritation depending on the product

16th Day:Tissue irritation decreased

a reduced release of residual monomers over time.

IMPLANTATION STUDIES

�PMMA implants were also very well tolerated after insertion into the alveolar bone of

dogs or the limb bones of baboons. No signs of inflammatory reactions in adjacent tissues

were found

Residual Monomer Release

In vivo study

Two PMMA bone cements on rabbits implanted into the

femoral bone marrow

a reduced release of residual monomers over time.

In vitro studies

immersion of the mixed specimens into an aqueous environment

50% of the unbound MMA was released within 15 min

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PULP REACTIONS

�Auto-polymerizing PMMA resins caused pulp irritations when used for temporary

restorations.

�CAUSES

� Release of residual monomers, particularly during the first days after polymerization.

� High temperatures during setting (80–120°C)

�Temperatures higher than 42°C is considered The Critical Temperature regarding

irreversible pulpitis.

�Polymerization of PMMA temporaries should be completed outside the oral cavity.

REACTIONS OF THE GINGIVA & ORAL MUCOSA

�Irritation of the oral mucosa beneath or adjacent to resin restorations is the most severe local

clinical adverse effect. Denture stomatitis is characterized by three degrees of severity:

PUNCTUAL ERYTHEMA SHEET-LIKE ERYTHEMAS PAPILLARY HYPERPLASIA

� Small reddish areas that are not elevated above the level of the mucosa; These areas are covered by the denture.

� Associated with partial or complete dentures.

� Extensive erythemas that are also located beneath dentures and have a high tendency to bleed.

� Nodule-like hyperplasia with a diameter of 2–3 mm and a size of 3–4 mm that develop particularly on the palate.

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REACTIONS OF THE GINGIVA & ORAL MUCOSA

Factors Contributing To The Development And Severity Of Denture Stomatitis

� Released substances, mainly MMA and formaldehyde.

� Microorganisms (e.g., Candida albicans).

� Dentures with a permanent soft relinings.

Experimental clinical study by Austin and Basker

Three cases of denture stomatitis were examined

The residual monomer conc. exceeded the normal levels by 6–11-fold.

It was reported in 1962 that dentures with a residual monomer concentration of 0.6–3% a year after insertion did not cause mucosal irritations.

BURNING MOUTH SYNDROME

�Possible Causes Of Burning Mouth Syndrome

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BURNING MOUTH SYNDROME

Clinical study of 22 patients with BMS

5 cases: allergy to MMA + high residual monomer conc.

in their dentures

Symptoms relieved in 3 pts. On receiving new dentures with a low residual monomer content

11 patients: Causes of BMS

a poor dental prosthesis, diseases such as iron deficiency

anemia, Addison’s anemia, idiopathic burning mouth.

BURNING MOUTH SYNDROME

�Correlation between BMS & colonization of the oral cavity with H-pylori was investigated.

� 16% subjects with BMS revealed H-pylori in the tongue mucosa.

�CONCLUSION

� Gastritis + BMS Colonization of Tongue with H-Pylori.

� The oral cavity and oral diseases are important factors for the health/disease of the

entire GIT.

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5. ALLERGIES

ALLERGIES

�MMA

a. CONTACT DERMATITIS MMA classified as an important contact allergen

b. An Extensive URTICARIA without intraoral symptoms was also observed.

c. CROSS-ALLERGY:

� After sensitization with MMA, cross-allergies to other acrylates may develop .

� The in vitro leukocyte migration inhibition assay revealed that MMA, a specific antigen, causes cellular immunity.

� Nail varnish or acrylic substances used for artificial fingernails caused allergic reactions (type IV)

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ALLERGIES

�Almost all other components of PMMA acrylates can cause an allergy

�The initiator , dibenzoyl peroxide

�ethylene glycol dimethacrylates

�Hydroquinone

Allergic Contact Reaction in a 58-year-old woman with tingling sensations at the palate & at the tongue; patch test was positive for hydroquinone and the base resin.

6. MUTAGENICITY & CARCINOGENICITY

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MUTAGENICITY AND CARCINOGENICITY

�Older studies reported generation of fibrous sarcomas and carcinomas after

subcutaneous implantation of PMMA. These data were not confirmed by subsequent

publications.

�Long-term studies on industrial workers, exposed to MMA for a long period of time

indicated no carcinogenic effect.

�In General, it may be concluded that the rapid degradation and excretion of MMA

should prevent an accumulative toxic effect or severe systemic adverse reactions