Review

Biocompatibility of polymethylmethacrylate resins used in dentistry

Rupali Gautam,1 Raghuwar D. Singh,1 Vinod P. Sharma,2 Ramashanker Siddhartha,1

Pooran Chand,1 Rakesh Kumar2

1Department of Prosthodontics, Faculty of Dental Sciences, C.S.M. Medical University (upgraded K.G.M.C.),

Lucknow 226001, India2CSIR, Indian Institute of Toxicology and Research, Lucknow, India

Received 11 September 2011; revised 25 December 2011; accepted 2 January 2012

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jbm.b.32673

Abstract: Biocompatibility or tissue compatibility describes

the ability of a material to perform with an appropriate host

response when applied as intended. Poly-methylmethacrylate

(PMMA) based resins are most widely used resins in den-

tistry, especially in fabrication of dentures and orthodontic

appliances. They are considered cytotoxic on account of

leaching of various potential toxic substances, most common

being residual monomer. Various in vitro and in vivo experi-

ments and cell based studies conducted on acrylic based res-

ins or their leached components have shown them to have

cytotoxic effects. They can cause mucosal irritation and tis-

sue sensitization. These studies are not only important to

evaluate the long term clinical effect of these materials, but

also help in further development of alternate resins. This arti-

cle reviews information from scientific full articles, reviews,

or abstracts published in dental literature, associated with

biocompatibility of PMMA resins and it is leached out com-

ponents. Published materials were searched in dental litera-

ture using general and specialist databases, like the PubMED

database. VC 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B:

Appl Biomater 00B:000–000, 2012.

Key Words: biocompatible, cytotoxic, dentistry, leaching,

polymethylmethacrylate

How to cite this article: Gautam R, Singh RD, Sharma VP, Siddhartha R, Chand P, Kumar R. 2012. Biocompatibility ofpolymethylmethacrylate resins used in dentistry. J Biomed Mater Res Part B 2012:00B:000–000.

INTRODUCTION

The use of resin-based restorative materials in dentistry hasrisen exponentially. Barely a single clinical procedure isaccomplished without use of one or more of these products,which include sealants, dentin bonding agents, restorativecomposites, fiber-reinforced resin materials, cementing andlining agents, denture base materials, denture teeth, dentureliners, maxillofacial prosthetic products, core buildup mate-rials, orthodontic appliances, splinting materials, temporaryrestorative materials, and veneers.1–3 Most resin systemsused in dentistry are based on methacrylates, particularlymethylmethacrylates (MMA).4 Now-a-days dental poly-methyl methacrylates (PMMAs) are used primarily for den-tures and orthodontic devices. In addition, PMMAs are usedfor individual impression trays and temporary crowns.PMMAs are also used in daily life for nondental purposes:as bone cements and acrylic glass, as a base for variousstains, for artificial fingernails and nail varnish, and soforth.5 This fact is important to the dental professionbecause allergies to PMMA may be caused by acrylic materi-als used for nondental application as well.6,7 Literature

regarding the biocompatibility of PMMA resins mainly con-sists of in vitro studies. Although, intra-orally different fac-tors such as saliva characteristics, chewing, thermal, andchemical dietary changes may influence the biologicalbehavior of these materials. This article reviews the litera-ture associated with the biocompatibility of PMMA resins.

CHEMISTRY OF PMMAs

Methyl esters of methacrylic acid are the basic modules ofPMMA, but many other components are also contained inacrylics used for prosthetic dentistry. Heat-polymerizing den-ture acrylics are generally based on PMMA, whereas light-pol-ymerizing and microwave-polymerizing products are derivedpartly from PMMA and also from urethane dimethacrylates(UDMA).8 They can be classified as chemical, heat or lightactivated depending on the factor that initiates the reaction.Chemical or autopolymerized materials involve a chemical ac-tivator like N,N-dimethyl p-toluidine.9 For heat-polymerizingmaterials, heat can be generated by hot water bath or micro-wave energy, while the light polymerizing resins use visible

Correspondence to: R. D. Singh; e-mail: raghuwards@rediffmail.com

VC 2012 WILEY PERIODICALS, INC. 1

light as energy source. Most of these materials are composedof prepolymerized polymethylmethacrylate (PMMA) orpolyethylmethacrylate (PEMA) powder particles along with aperoxide initiator and a pigment, which are mixed with meth-acrylate monomers (MMA, hexamethylene-glycoldimethacry-late, hydroxyl-ethylmethacrylate, n-butylmethacrylate, and tet-rahydrofurfuryl-methacrylate) and crosslinking agents such asethylene-glycol-dimethacrylate (EGDMA), trimethylo-propanetrimethacrylate or 1,6-hexanediol dimethacrylate.9,10 Decompo-sition of the initiator (mainly dibenzoyl peroxide) into radicalsunder heat, initiates the setting of heat-polymerizing productswhile auto-polymerizing materials require an accelerator, suchas a tertiary amine, sulfinic acid, or substituted barbituric acid.The most important combination is an amine–peroxide redoxsystem. For light-cured, monomer-polymer conversion is deci-sively dependent on the duration of the light irradiation, equiv-alent to light-curable composite resins.11

LEACHING OF ADDITIVES AND DEGRADATIVE MOIETIES

Regarding leaching of elutes from PMMA resins, two aspectsare of particular importance: monomer–polymer conversionand residual monomer content. The rate of monomer–poly-mer conversion indicates the number of unsaturated doublebonds converting to saturated single bonds during polymer-ization. Residual monomer refers to those substances(monomers, additives, and reaction products) that are notfirmly incorporated in the polymer network and may there-fore leach. Subsequently, these components may cause localor systemic side effects. The concentration of residualmonomers and elutable additives is dependent on severalparameters and interrelated factors as mentioned below(Table I)

• Polymerization method• Polymerization cycle• Postpolymerization treatment

In general, heat-polymerized PMMA contains signifi-cantly fewer residual monomers than chemically curedacrylic resin. Thicker areas show smaller concentrations ofresidual monomers when compared with thin layers.12 Ked-jarune et al.13 observed a reduced amount of residualmonomer when the polymerization time was extended, thusresulting in less cytotoxic effects. To define an ideal poly-merization cycle for different acrylic resins, Harrison andHuggett14 conducted a study wherein 23 heat-polymerizeddenture base polymers were subjected to various polymer-ization cycles. The results of this investigation showed that7 h incubation in water at 70�C followed by 1 h at 100�Cwas ideal, because it provided maximum conversion ofmonomer to polymer. In contrast, a 7 h cycle at 60�C andthe cycle of immersing the flask in boiling water, followedby a 5 min immersion in water at 90�C, produced a highconcentration of released residual monomer.

To assess the effect of temperature, time and type of po-lymerization (heat and auto-polymerization) on the amountof residual MMA monomer, Vallittu et al.15 performed astudy with two autopolymerized resins in which the reac-tion was initiated by barbituric acid and two heat-polymer-ized resins activated by benzoyl peroxide. The resultsshowed that autopolymerized resins exhibited higher con-tents of residual MMA than the heat-polymerized resins.The findings of Tsuchiya et al.16,17 and Cimpam et al.18,19

revealed that autopolymerized resins eluted considerablymore substances than did the heat- and microwave-poly-merized resins. Yunus et al.20 studied the effect of

TABLE I. Concentration of Residual Monomer in Different Polymerization Steps

Polymerization Method Polymerization Cycle Postpolymerization Treatment

For residual monomerconcentration:

Time and temperature over which reactionproceeds are two important factors

Water immersion for a period of 24 h afterpolymerization is recommended for alltypes of resins because cytotoxic effect/residual monomer conc. of acrylic resinsis greater in the first 24 h after polymer-ization and decreased with time.

Self-cured resins>heat-curedresins>microwave curedresins

For heat curing resins, long curing cycles(7 h) are preferable than short cycles(1 h–90 min). Temperature near 100�Cresults in more complete curing becauseof increased mobility of monomer chainsthan at 70�C.

Residual monomer of an autopolymerizingresin decreased when specimens weresubmitted to microwave irradiation. Postpolymerization radiations are effectivemeans of reducing residual monomer.

Reason being more completeconversion of monomer topolymer duringpolymerization.

For, microwave polymerization a shorterpolymerization time and less residualmonomer are considered as two of theadvantages.

Visible light-polymerized den-ture base resins reported tobe nontoxic after polymeriza-tion, extent of their toxiceffect appears to be relatedto the specific formulation ofthe material and polymeriza-tion time

For light cured resins, increasing thepolymerization time may decreaseresin toxicity.

For autopolymerized acrylic resins, it seemsreasonable to suggest that they shouldbe heat-treated to decrease residualmonomer concentration.

2 GAUTAM ET AL. BIOCOMPATIBILITY OF PMMA RESINS USED IN DENTISTRY

microwave heating on the residual monomer level of anautopolymerized resin used in the repair of prostheses. Theresults demonstrated that the specimens submitted tomicrowave irradiation after 20 min of autopolymerizationshowed a reduced amount of residual monomer when com-pared with resins undergoing other polymerization meth-ods. A similar finding was observed by Blagojevic and Mur-phy21 who showed that the residual monomer of anautopolymerizing resin decreased by �4-fold when speci-mens were submitted to microwave irradiation. Therefore, itmay be assumed that the reduction in residual monomercontent by microwave irradiation could play an importantrole in decreasing the cytotoxic effects of autopolymerizingacrylic resins because of the heating that occurs. De Clerk22

also reported a lower amount of residual monomer aftermicrowave processing when this method was compared withthe conventional heat-polymerizing technique. Though, micro-wave curing is affected by the volume of the investing gyp-sum, the amount of water contained in the gypsum, the pow-der/liquid ratio of the resin, the thermal conductivity of theflask, and the microwave translucency of the flask material, ashorter polymerization time, and less residual monomer areconsidered as two of the advantages of microwavepolymerization.22

Numerous researchers have tried to identify the compo-nents that generally leach from polymerized resin. Mostauthors used high-performance liquid chromatography, gaschromatography, gas chromatography/mass spectroscopy,and occasionally infrared spectroscopy.23–25 Residual mono-mers or additives were extracted by means of aqueousmedia including distilled water, natural or artificial saliva,Ringer’s solution, and organic diluents (methanol, ethanol,tetrahydrofurane, acetone, etc.). In most studies either wateror ethanol or a mixtures of ethanol/water is used as theleaching media.

MMA in particular was identified in aqueous in vitroextracts.26–31 It was released over a period of several days.

These laboratory findings were confirmed by in vivo data.Baker et al.24 investigated the MMA level of saliva ofpatients with dentures and found that autopolymerizedresin releases MMA over a period of one week after inser-tion (up to 45 lg/mL saliva). MMA was not found in theurine or blood of the participants. The authors concludedthat the intraorally released MMA concentrations were farbelow the threshold doses.

In spite of the different experimental methodologies, themajority of published studies refer the elution of unboundcomponents mainly MMA monomer, phthalate esters,32–34

and additives like benzoyl peroxide35,36 as one of the mainconsequences of material biodegradation. Another importantingredient in aqueous elutes is formaldehyde. Tsuchiyaet al.,16 documented that this substance is released fromautopolymerized resin in relatively high amounts (40–50nmol/mL on the 1st day) in vitro and in vivo (saliva), butheat-polymerized and microwave-polymerized specimensdid not leach formaldehyde. Decomposition of the copoly-mer usually results in the formation of formaldehyde.17,35

Biphenyl and phenyl benzoate could be found in ethanolextracts.36–38 It may be speculated that these compoundsare reaction or decomposition products of the initiator(dibenzoyl peroxide) that are generated during the polymer-ization. Trace amounts of phenylsalicylate were documentedby Lygre et al.27 This substance could either be a contami-nant of PMMA, or it could also serve as an ultravioletabsorber (Table II).12,13,16,24,28–30

Most studies have focused on the cytotoxicity of leachedMMA monomer and its derivatives.39–42 Both permanent (L-929 fibroblast and osteoblast) and primary cells (gingivalfibroblast, epithelial cells, dental pulp, and periodontal liga-ment fibroblasts) have been used in the previous studies.43–47 Test systems vary considerably in the way cytotoxicity ismeasured but all indicate changes in basic cell structures,such as cell membrane integrity and cell functions likeenzyme activities or the synthesis of macromolecules.45,47

TABLE II. Name of the Substances Leaching from Polymethylmethacrylate Resins

Polymethylmethacrylate Resins Leaching Substances

Methylmethacrylate (MMA) MonomerMethacrylic acid Degradation product of methacrylate monomersEthylene glycol dimethacrylate Monomer, crosslinking agentDibenzoyl peroxide (DBP) InitiatorN,N-dimethyl-p-toluidine (tertiary amine) Activator of autopolymerizing resinsHydroquinone Stabilizer/inhibitorUrethane dimethacrylate (UDMA) Matrix monomer of light-polymerizing and

microwave-polymerizing resinsPoly(ethyl-methacrylate) Matrix monomer of light-curing resinsEthoxidized bisphenol A-dimethacrylate Matrix monomer of light-curing resinsCamphorquinone Photoinitiator of light-curing resinsInorganic fillers Fillers of light-curing resinsPigments, Organic stains (phenol derivatives) ColoringDibutyl-phthalate(DBP) PlasticizerPhenyl salicylate Eventually, UV absorberBisphenyl Reaction product of DBPBenzoic acid Reaction product of DBPPhenyl benzoate Reaction product of DBPFormaldehyde Oxidation product of MMA

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Taken together, studies addressing the residual mono-mer content and the leachable substances from heat-poly-merizing and autopolymerizing PMMA acrylics have shownthat fairly high amount of substances, specifically MMA, mayleach into the oral cavity during the initial days afterpolymerization. Clinical-experimental investigations havedocumented a correlation between residual monomer con-centration and irritation of the oral mucosa.

SYSTEMIC TOXICITY

It has been reported that the acute oral LD50 (median lethaldose) of MMA in rats is 8.4 g/kg body weight or 9 g/kgbody weight. This very high concentration indicates a verylow-acute systemic toxicity of MMA.48 A study on ratsreceiving MMA orally through a stomach tube is in accord-ance with this assessment. Five minutes after oral applica-tion, methacrylic acid, a degradation product of MMA gener-ated by a nonspecific carboxyl esterase, was identified inthe blood with a peak after 10–15 min. Alterations oforgans (liver, kidneys, heart, spleen, brain, lung, and guts)were not found. These data point to a low-acute toxicity oforally applied MMA, which is rapidly hydrolyzed byenzymes in blood serum and subsequently metabolized toless toxic substances, such as pyruvate, via the citric acidcycle.49 The half-life of MMA in human blood varies between20 and 40 min.50 Patients take up leaching substances fromPMMA resins through the oral cavity, but dental personneland lab technicians are also exposed to MMA-vapor. Meas-urements of the formaldehyde and MMA concentrations inthe air of a dental laboratory subsequent to the processingof dentures provided no indication of critical values. Themaximum allowable concentration values for MMA in Ger-many are 50 ppm or 210 mg/m3 compartment air. Legalregulations for dental laboratories are based on a directiveregarding hazardous substances and the technical rules forhazardous materials that is TRGS 900.51 It was reportedthat MMA vapor in dental practices caused vertigo.52,53

There is no evidence, however, that serious problems maybe caused by inhaling PMMA ingredients, although MMAmay irritate the eyes, skin, and respiratory system.

LOCAL TOXICITY AND TISSUE COMPATIBILITY

The cellular compatibility of solid specimens, aqueous resinextracts, formaldehyde, and MMA were investigated in per-manent cells and primary cultures as well.44–46 A study ofHensten-Pettersen and Wictorin53 revealed clear toxic reac-tions caused by solid specimens of two orthodontic acrylicresins (one autopolymerizing and another light-curable) inpermanent cultures of fibroblasts and keratinocytes. Thecytotoxic effect was greater in autopolymerized resins. Thecytotoxic effects of heat-activated, chemically-activated, andmicrowave-activated acrylic resins on gingival fibroblastswere also reported by Sheridan et al.47 They observed thatamong the tested materials, the greatest cytotoxic effect wasproduced by the chemically activated acrylic resins. Thelight-curing material was cytotoxic if the oxygen-inhibitedsurface layer was not removed. Both products were no lon-ger toxic 30 days after setting. Polymer samples made of

poly-ethylmethacrylate/tetrahydrofurfuryl methacrylate orPMMA were more toxic directly after polymerization, whencompared with aged specimens. Preincubation of the speci-mens in serum-containing medium decreased cytotoxicity inosteoblast cultures.54 Interestingly, the type of polymeriza-tion (heat-polymerizing or autopolymerizing) was of lessersignificance than the nature of the product.54

Besides MMA and formaldehyde, other substances thatleach from PMMA acrylics may also contribute to cytotoxiceffects. The relatively hydrophilic crosslinking agent EGDMAand the initiator dibenzoyl peroxide were comparably toxicin primary human fibroblasts derived from gingiva and peri-odontal ligament, but the accelerating substance N,N-di-methyl-p-toluidine and the photoinitiator camphorquinonewere only moderately cytotoxic. UDMA, an important basemonomer in light-polymerizing resins, elicited severe cyto-toxic effects.55 Furthermore, Stea et al.56 reported that N,N-dimethyl-p-toluidine may cause reversible cell damage asso-ciated with a retarded replication cycle.

MICROBIAL EFFECTS

Besides cytotoxicity, microbial effects such as promotion orinhibition of the proliferation of microorganisms may alsobe decisive for the biocompatibility of a compound or mate-rial. It has been well known since the beginning of the1970s from in vitro and in vivo observation that PMMA andparticularly permanent soft relining materials may promotethe growth of various fungi and bacteria such as Candidaalbicans and other Candida species, Escherichia coli andPseudomonas aeruginosa. The ‘‘microclefts’’ between perma-nent soft relining materials and the hard denture base maystimulate microbial growth, too.57,58 In addition, MMA,phthalates, and the crosslinking substance may stimulatemicrobial proliferation. This was corroborated by clinicalstudies on patients wearing dentures with a permanent softliner. It was found that up to 85% of these patients sufferedfrom oral fungi identifiable by culture techniques. Aninflamed mucosa was clearly correlated with these microor-ganisms.59 Colonization of permanent soft liner was signifi-cantly enhanced by the salivary denture pellicle or serumcomponents.60,61 In this context, it was also observed thatproliferation of fungi (Candida ssp.) was closely associatedwith poor denture hygiene.60 The tendency toward fungalcolonization could be reduced if the permanently soft relin-ing material were sealed with a varnish. It was also foundthat comparatively higher concentrations of MMA (>0.5%)are bactericidal, whereas larger quantities of the plasticizersbenzyl benzoate and benzyl salicylate are fungicidal.62 Inaddition, more recent experiments show that the crosslink-ing agent EGDMA may increase the proliferation of the twoimportant caries pathogens Streptococcus sobrinus and Lac-tobacillus acidophilus.63

REACTIONS OF THE GINGIVA AND ORAL MUCOSA

Irritation of the oral mucosa beneath or adjacent to resinrestorations is certainly the most severe local clinicaladverse effect. In an experimental clinical study, Austin andBasker23 documented a clear association between irritation

4 GAUTAM ET AL. BIOCOMPATIBILITY OF PMMA RESINS USED IN DENTISTRY

of the mucosa beneath dentures and the release of residualmonomers. In addition to released substances, mainly MMAand formaldehyde, microorganisms (e.g., Candida albicans)may significantly contribute to the development and sever-ity of a denture stomatitis.59 This was especially observedon dentures with a permanent soft liner.58,64 A clinical studyof 22 patients who suffered from burning mouth syndromerevealed an allergy to MMA in five cases, as well as a highresidual monomer concentration in their dentures. Three ofthese five patients were free of symptoms after theyreceived new dentures with low-residual monomer content.This was corroborated by findings on four other patients inthis investigation who suffered from an irritation (not anallergy) of the mucosa caused by residual monomers. Theirsymptoms disappeared after ‘‘postpolymerization’’ of thedentures. The complaints of the remaining 11 patients weregenerated by the following causes: a poor dental prosthesis,diseases such as iron deficiency anemia, Addison’s anemia,and burning mouth without discernible or diagnosablecause (idiopathic burning mouth).65

ALLERGIC SYMPTOMS AND IMPLICATIONS

Skin contact with MMA and PMMA may result in allergicreactions. MMA has been classified as an important contactallergen.64,66,67 Mild to moderate dermatitis on the hands orfingers is the most frequent consequence of allergic reac-tions in dental personnel and dental technicians. A recentSwedish publication reported that 3% of the dental person-nel in one rural district suffer from contact dermatitiscaused by acrylates.68 Tschernitschek et al.69 documentedthat between 1982 and 1997, only 13% of 311 supposedlyallergic patients revealed an allergy, which was the cause oftheir complaints. MMAs, in particular autopolymerizingmaterials, triggered the allergy in eight cases. An extensiveurticaria without intraoral symptoms, because of an allergyto MMA released from a denture, was also observed.70

Besides MMA, almost all other components of PMMA cancause an allergy.69–71 The initiator dibenzoyl peroxide elicitsallergic reactions relatively often, especially in dental assis-tants and dental technicians. Other important allergens inlab technicians are EGDMA and hydroquinone.70–72 Takentogether, the frequency of allergies to components of PMMAresins, particularly MMA and dibenzoyl peroxide, hasincreased in the past decades in patients, dental personnel,and lab technicians. Data from the literature indicate a dis-proportionately high increase in occupationally exposeddental personnel, since more and more resin-based materi-als are used in dentistry.72,73 However, allergies of patientsto dental resins and their components are still very rare.Repeated and comprehensive patch tests to verify an allergyto acrylates should be avoided because an active sensitiza-tion may, in fact, be caused by the test.74–76

MUTAGENICITY AND CARCINOGENICITY

Older studies reported generation of fibrous sarcomas andcarcinomas after subcutaneous implantation of PMMA.These data were not confirmed by subsequent publica-tions.77–79 Long-term studies on industrial workers who had

been exposed to MMA for a long period of time indicatedno carcinogenic effect. In general, it may be inferred thatthe rapid degradation and excretion of MMA should preventan accumulative toxic effect or severe systemic adversereactions.80,81

AREAS FOR FUTURE RESEARCH

Biodegradation of acrylic based resins in the oral environ-ment has been so far incompletely studied. Further well-controlled clinical studies are necessary to improve theknowledge about materials’ biocompatibility in intraoralconditions including their potential to cause chronic localadverse effects or/and systemic side effects over time. Agap in the published literature exists regarding in vitro stud-ies that allow a good knowledge of the biodegradationmechanisms and its consequences. Improvements in the ex-perimental design should be done in order to better simu-late the intraoral conditions. The incorporation of productslike antioxidant molecules intending to enhance the biocom-patibility of the materials has been recently explored withpromising results.82–84 More in vivo studies are required toincrease our knowledge regarding biocompatibility of theseresins and hence, to diversify their applications not only indentistry but otherwise also.

CONCLUSION

PMMA resins are intensively used in dentistry especially asdenture base materials and liners. Increasing concern arisesregarding the safe clinical application of these materialsbecause of the release of potential toxic compounds fromthe polymer network and changes in materials’ physical andmechanical properties in oral condition. There is a sizeableliterature on in vitro release studies concerning the elutionof residual monomers, mainly MMA, but few in vivo studieshave been reported. The studies using human saliva arecomparatively rare and need exhaustive, coordinated, andrapid investigation. Further research is required regardingbiodegradation and biocompatibility of these resins. Theinformation acquired from such studies can also provideinvestigators with alternative polymeric chemistries that canbe used in a new generation of materials to induce favor-able reactions in the living tissues.

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JOURNAL OF BIOMEDICAL MATERIALS RESEARCH B: APPLIED BIOMATERIALS | MONTH 2012 VOL 9999B, ISSUE 00 7