Hydrophobically Modified Isosorbide Dimethacrylates As a Bisphenol-A (BPA)-Free Dental Filling Material

materials

Article Hydrophobically Modiﬁed Isosorbide Dimethacrylates as a Bisphenol-A (BPA)-Free Dental Filling Material

Bilal Marie 1,2, Raymond Clark 2, Tim Gillece 2, Seher Ozkan 2, Michael Jaffe 1 and Nuggehalli M. Ravindra 1,*

1 Interdisciplinary Program in Materials Science and Engineering, New Jersey Institute of Technology, Newark, NJ 07012, USA; [email protected] (B.M.); [email protected] (M.J.) 2 Ashland Specialty Ingredients, Bridgewater, NJ 08807, USA; [email protected] (R.C.); [email protected] (T.G.); [email protected] (S.O.) * Correspondence: [email protected]

Abstract: A series of bio-based hydrophobically modiﬁed isosorbide dimethacrylates, with para-, meta-, and ortho- benzoate aromatic spacers (ISBGBMA), are synthesized, characterized, and evaluated as potential dental restorative resins. The new monomers, isosorbide 2,5-bis(4-glyceryloxybenzoate) dimethacrylate (ISB4GBMA), isosorbide 2,5-bis(3-glyceryloxybenzoate) dimethacrylate (ISB3GBMA), and isosorbide 2,5-bis(2-glyceryloxybenzoate) dimethacrylate (ISB2GBMA), are mixed with triethylene glycol dimethacrylate (TEGDMA) and photopolymerized. The resulting polymers are evaluated for the degree of monomeric conversion, polymerization shrinkage, water sorption, glass transition temperature, and ﬂexural strength. Isosorbide glycerolate dimethacrylate (ISDGMA) is synthesized, and Bisphenol A glycerolate dimethacrylate (BisGMA) is prepared, and both are evaluated as a reference. Poly(ISBGBMA/TEGDMA) series shows lower water sorption (39–44 µg/mm3) over 3 3 Poly(ISDGMA/TEGDMA) (73 µg/mm ) but higher than Poly(BisGMA/TEGDMA) (26 µg/mm ). Flexural strength is higher for Poly(ISBGBMA/TEGDMA) series (37–45 MPa) over Poly(ISDGMA/

Citation: Marie, B.; Clark, R.; Gillece, TEGDMA) (10 MPa) and less than Poly(BisGMA/TEGDMA) (53 MPa) after immersion in phosphate- T.; Ozkan, S.; Jaffe, M.; Ravindra, N.M. buffered saline (DPBS) for 24 h. Poly(ISB2GBMA/TEGDMA) has the highest glass transition tem- ◦ Hydrophobically Modiﬁed Isosorbide perature at 85 C, and its monomeric mixture has the lowest viscosity at 0.62 Pa·s, among the Dimethacrylates as a Bisphenol-A (ISBGBMA/TEGDMA) polymers and monomer mixtures. Collectively, this data suggests that the (BPA)-Free Dental Filling Material. ortho ISBGBMA monomer is a potential bio-based, BPA-free replacement for BisGMA, and could be Materials 2021, 14, 2139. https:// the focus for future study. doi.org/10.3390/ma14092139 Keywords: isosorbide dimethacrylates; dental ﬁlling material; hydrophobic; bio-based; bisphenol-A Academic Editor: Javier Gil (BPA)

Received: 21 March 2021 Accepted: 19 April 2021 Published: 22 April 2021 1. Introduction

Publisher’s Note: MDPI stays neutral Dental amalgam and resin-based composites are commonly used dental filling materi- with regard to jurisdictional claims in als. The recent US-FDA epidemiological review of exposure to dental amalgam mercury published maps and institutional affil- did not find sufficient evidence correlating adverse health outcomes with exposure to den- iations. tal amalgam mercury [1]. However, the negative perception of amalgam, lower aesthetic appeal [2], and the Minamata convention to minimize mercury production and impact [3], are leading reasons that resin-based composites are preferred. Dental resin composites consist of a polymeric resin, filler particles, and a coupling agent. The polymeric resin is largely made up of hydrophobic dimethacrylates that Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. crosslink into a three-dimensional network. These polymeric networks should have a This article is an open access article high degree of monomeric conversion, low water uptake, low polymerization shrinkage, distributed under the terms and and good mechanical properties [4,5]. conditions of the Creative Commons The most common dental restorative dimethacrylate monomer is 2,2-bis [4-(2-hydroxy- Attribution (CC BY) license (https:// 3-methacryloyloxypropoxy)phenyl] propane (BisGMA). Its structure imparts a high poly- creativecommons.org/licenses/by/ meric modulus, low shrinkage, and strong adhesion to the tooth enamel [6–8]. It is highly 4.0/). viscous and is typically mixed with the dental diluent, triethylene glycol dimethacrylate

Materials 2021, 14, 2139. https://doi.org/10.3390/ma14092139 https://www.mdpi.com/journal/materials Materials 2021, 14, x FOR PEER REVIEW 2 of 18

Materials 2021, 14, 2139 It is highly viscous and is typically mixed with the dental diluent, triethylene glycol2 of di- 17 methacrylate (TEGDMA). However, TEGDMA is reported to increase water sorption and polymerization shrinkage [9,10]. In contrast, 1,6-bis(2-methacryloxy-2-ethoxycarbonyla- (TEGDMA).mino)-2,4,4-trimethylhexane However, TEGDMA (UDMA) is reported is a urethane to increase dimethacrylate water sorption with and lower polymeriza- viscosity tionin comparison shrinkage to [9 ,BisGMA,10]. In contrast, and exhibits 1,6-bis(2-methacryloxy-2-ethoxycarbonylamino)-2,4,4- good durability and adhesion to the tooth enamel trimethylhexane[11,12]. (UDMA) is a urethane dimethacrylate with lower viscosity in comparison to BisGMA,Dimethacrylates and exhibits exhibit good excellent durability properties and adhesion in resin to the dental tooth restoration. enamel [11, 12However,]. dentalDimethacrylates dimethacrylate exhibit monomers, excellent and properties the resulting in resin degradation dental restoration. products, However, were demon- den- talstrated dimethacrylate to exhibit a monomers,cytotoxic and and genotoxic the resulting effect degradation [13,14]. Further, products, prior were investigations demonstrated sug- togest exhibit that aTEGDMA cytotoxic and genotoxicUDMA can effect induce [13,14 apoptosis]. Further, in prior dental investigations pulp [15,16]. suggest Trace thatamounts TEGDMA of Bisphenol and UDMA A (BPA), can induce a suspected apoptosis estrogen in dental mimic, pulp can [15 be,16 ].present Trace amountsin BisGMA of Bisphenoland elute into A (BPA), the oral a suspected environment estrogen [17,18]. mimic, Increased can be levels present of inBPA BisGMA exposure and have elute been into thelinked oral to environment various prenatal, [17,18 ].childhood, Increased and levels adult of BPA adverse exposure health have outcomes. been linked These to include, various prenatal,but are not childhood, limited andto, reduced adult adverse fertility, health altered outcomes. childhood These behavior include, and but areneurodevelop- not limited to,ment, reduced type-2-diabetes, fertility, altered cardiovascular childhood behaviordisorders, and inflammation, neurodevelopment, and altered type-2-diabetes, gene expres- cardiovascularsion [19]. Hence, disorders, there has inflammation, been a growing and inte alteredrest in gene developing expression safer [19 ].alternative Hence, there materi- has beenals. a growing interest in developing safer alternative materials. IsosorbideIsosorbide isis aa sugar-basedsugar-based molecule derived from starch and is classifiedclassified as “gener- allyally recognizedrecognized asas safe”.safe”. It isis mademade upup ofof twotwo ciscis-fused-fused tetrahydrofurantetrahydrofuran rings,rings, whichwhich areare nearlynearly planar,planar, and and contains contains two two hydroxyls hydroxyls at positions at positions 2 and 2 5,and as shown5, as shown in Figure in 1Figure[20,21 ].1 Isosorbide[20,21]. Isosorbide has found has potentialfound potential applications applications in the in biomedical the biomedical field, field, including including aspirin as- prodrugspirin prodrugs [22,23 ],[22,23], substrates substrates for human for human butyrylcholinesterase butyrylcholinesterase [24], tissue [24], engineering tissue engineer- scaf- foldsing scaffolds [25,26], and[25,26], dental and restorative dental restorative materials materials [27–30]. [27–30].

FigureFigure 1.1. Chemical structure ofof isosorbide.isosorbide.

SomeSome of the the studies studies on on isosorbide isosorbide for for dent dentalal materials materials include include the synthesis the synthesis and eval- and evaluationuation of the of BisGMA the BisGMA analogue, analogue, 1,4:3,6-dianhydro- 1,4:3,6-dianhydro-D-sorbitolD-sorbitol 2,5-bis( 2,5-bis(2-hydroxy-3-2-hydroxy-3-meth- methacylolxypropoxy)acylolxypropoxy) (ISDGMA) (ISDGMA) as reported as reported by Ł byukaszczyk Łukaszczyk et al., et al.,and and Shin Shin and and coworkers coworkers[27,28]. [27,28 Duarte]. Duarte et al., et al.,have have studied studied the thesynthesis synthesis of an of isosorbide an isosorbide urethane urethane dimethacrylate dimethacrylate(IS-UDMA) (IS-UDMA) [29]. [ 29Vasifihasel]. Vasiﬁhasel et al. et and al. andŁukaszczyk Łukaszczyk and andco-workers co-workers developed developed ethoxylated ethoxy- latedisosorbide isosorbide dimethacrylates dimethacrylates (ISETDMA) (ISETDMA) as a de asntal a dental diluent diluent [30,31]. [30 ,Jun31]. et Jun al. et developed al. devel- opedisosorbide isosorbide dimethacrylates dimethacrylates based based on isocyano on isocyanoethylethyl methacrylates methacrylates and evaluated and evaluated their their per- performanceformance as dental as dental sealants sealants [32]. [32 Kim]. Kim et al. et al.reported reported on onisosorbide isosorbide 2,5-bis(propoxy) 2,5-bis(propoxy) di- dimethacrylatemethacrylate (ISOPMA) (ISOPMA) and and evaluated evaluated it itas as a a dental dental resin resin composite in comparisoncomparison toto ISDGMAISDGMA [[33].33]. TheThe aim aim of of this this study study is to is synthesize to synthesize and investigate and investigate the development the development of new of hydro- new hydrophobically-modifiedphobically-modified isosorbide isosorbide dimethacrylate dimethacrylate monomers, monomers, using using parapara, meta, meta, and, and orthoor-- thosubstituted-substituted hydroxy hydroxy benzoates benzoates as ashydrophobic hydrophobic spacers. spacers. The The new new monomers monomers are are 1,4:3,6- dianhydro-D-sorbitol 2,5-bis [4-(2-hydroxy-3-methacryloyloxypropoxy)benzoate](ISB4GBMA), dianhydro-D-sorbitol 2,5-bis [4 -(2-hydroxy-3-methacryloyloxypropoxy)benzoate] 1,4:3,6-dianhydro-D-sorbitol 2,5-bis [3-(2-hydroxy-3-methacryloyloxypropoxy)benzoate] (ISB3 (ISB4GBMA), 1,4:3,6-dianhydro-D-sorbitol 2,5-bis [3 -(2-hydroxy-3-methacryloyloxypro- GBMA), and 1,4:3,6-dianhydro-D-sorbitol 2,5-bis[2-(2-hydroxy-3-methacryloyloxypropoxy) poxy)benzoate] (ISB3GBMA), and 1,4:3,6-dianhydro-D-sorbitol 2,5-bis[2-(2-hydroxy-3- benzoate] (ISB2GBMA). Their chemical structures are shown in Figure2. The biobased methacryloyloxypropoxy)benzoate] (ISB2GBMA). Their chemical structures are shown in carbon content of these monomers is about 18%. Figure 2. The biobased carbon content of these monomers is about 18%. This new series of isosorbide dimethacrylates is evaluated as copolymers with TEGDMA, and the performance attributes as dental restorative resins are compared to copolymers of ISDGMA/TEGDMA and BisGMA/TEGDMA. The chemical structures of ISDGMA, BisGMA, and TEGDMA are depicted in Figure3.

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Figure 2. Hydrophobically modified isosorbide dimethacrylates with a para, meta, and ortho aromatic spacer. Materials 2021, 14, 2139 3 of 17 Materials 2021, 14, x FOR PEER REVIEW 3 of 18 This new series of isosorbide dimethacrylates is evaluated as copolymers with TEGDMA, and the performance attributes as dental restorative resins are compared to copolymers of ISDGMA/TEGDMA and BisGMA/TEGDMA. The chemical structures of ISDGMA, BisGMA, and TEGDMA are depicted in Figure 3. This investigation was performed under the hypothesis that hydrophobic ISBGBMA (bio-based hydrophobically modified isosorbide dimethacrylates) monomers, in contrast to hydrophilic ISDGMA, will result in lower water uptake and improved mechanical properties, when co-polymerized with TEGDMA for dental applications. This concept was previously addressed by the Jaffe group [34]. In that study, the water uptake of an isosorbide thermoset was reduced, and its mechanical properties were enhanced when a hydrophobic moiety was incorporated into the backbone of the polymer. We also theorize the ISBGBMA monomers to have properties similar to BisGMA. FigureTheFigure findings 2. HydrophobicallyHydrophobically of this investigation modified modiﬁed willisosorbide isosorbide provide dimeth dimethacrylates valueacrylates for further with with aisosorbide para, a para, meta, meta,dimethacrylate and ortho and ortho aro- aromaticdevelopment.matic spacer. spacer.

This new series of isosorbide dimethacrylates is evaluated as copolymers with TEGDMA, and the performance attributes as dental restorative resins are compared to copolymers of ISDGMA/TEGDMA and BisGMA/TEGDMA. The chemical structures of ISDGMA, BisGMA, and TEGDMA are depicted in Figure 3. This investigation was performed under the hypothesis that hydrophobic ISBGBMA (bio-based hydrophobically modified isosorbide dimethacrylates) monomers, in contrast

to hydrophilic ISDGMA, will result in lower water uptake and improved mechanical FigureFigureproperties, 3.3. ISDGMAISDGMA when (1,4:3,6-dianhydro-(1,4:3,6-dianhydro-co-polymerized withD-sorbitol-sorbitol TEGDMA 2,5-bis(2-hydroxy-3-methacylolxypropoxy)), 2,5-bis(2-hydroxy-3-methacylolxypropoxy)), for dental applications. Bis- Bis- GMA (2,2-bis [4-(2-hydroxy-3-methacryloyloxypropoxy)phenyl] propane), and TEGDMA (triethy- GMAThis (2,2-bis concept [4-(2-hydroxy-3-methacryloyloxypropoxy)phenyl] was previously addressed by the Jaffe group propane), [34]. andIn that TEGDMA study, (triethy-the wa- lene glycol dimethacrylate). leneter uptake glycol dimethacrylate). of an isosorbide thermoset was reduced, and its mechanical properties were enhanced when a hydrophobic moiety was incorporated into the backbone of the poly- 2. MaterialsThis investigation and Methods was performed under the hypothesis that hydrophobic ISBGBMA mer. We also theorize the ISBGBMA monomers to have properties similar to BisGMA. (bio-basedIsosorbide hydrophobically (98%), methyl modified 4-hydroxybenzoate isosorbide dimethacrylates) (≥99%), methyl monomers, 3-hydroxybenzoate in contrast The findings of this investigation will provide value for further isosorbide dimethacrylate to(99%), hydrophilic methyl ISDGMA,2-hydroxybenzoate will result (≥ in99%), lower methacrylic water uptake acid and(MAA, improved 99%), bisphenol mechanical A development. properties,glycerolate whendimethacrylate co-polymerized (BisGMA, with TEGDMA >98%), for triethylene dental applications. glycol dimethacrylate (TEGDMA,This concept 95%), was camphorquino previously addressedne (CQ, by97%), the Jaffe2-(dimethyla group [34mino)ethyl]. In that study, methacrylate the water uptake(DMAEMA, of an isosorbide98%), and thermosettriphenylphosphine was reduced, (TPP, and 99%) its mechanicalwere acquired properties from Sigma-Al- were en- hanceddrich (St. when Louis, a hydrophobic MO, USA) and moiety used was without incorporated further intopurification. the backbone Allyl of bromide the polymer. (99%), We 3- alsochloroperbenzoic theorize the ISBGBMA acid (mCPBA, monomers 75%), to ethylcarbodiimide have properties similar hydrochloride to BisGMA. (EDC, The findings99%), 4- of(dimethylamino)pyridine this investigation will provide (DMAP, value 98%), for further 4-methoxyphenol isosorbide dimethacrylate (MeHQ), phenothiazine development. (98%), N,N-dimethylformamide (DMF, 99%), methanol (MeOH, 99%), methylene chloride 2. Materials and Methods (DCM, 99%), anhydrous potassium carbonate (K2CO3, 99%), and sodium hydroxide Isosorbide (98%), methyl 4-hydroxybenzoate (≥99%), methyl 3-hydroxybenzoate (NaOH,Figure 3. ISDGMA98%) were (1,4:3,6-dianhydro- obtained from DOakwood-sorbitol 2,5-bis(2-hydroxy-3-methacylolxypropoxy)), Chemical (Estill, SC, USA) and used as Bis- re- ≥ (99%),ceived.GMA (2,2-bis methyl Gibco [4-(2-hydroxy-3-methacryloyloxypro DPBS 2-hydroxybenzoate (1X) pH 7.1 was ( 99%),obtained methacrylicpoxy)phenyl] from Thermo acid propane), (MAA,Fisher and Scientific 99%), TEGDMA bisphenol (Waltham, (triethy- A glycerolate dimethacrylate (BisGMA, >98%), triethylene glycol dimethacrylate (TEGDMA, MA,lene glycol USA) dimethacrylate). and used as supplied. 95%), camphorquinone (CQ, 97%), 2-(dimethylamino)ethyl methacrylate (DMAEMA, 98%), and2. Materials triphenylphosphine and Methods (TPP, 99%) were acquired from Sigma-Aldrich (St. Louis, MO, USA)Isosorbide and usedwithout (98%), furthermethyl purification.4-hydroxybenzoate Allyl bromide (≥99%), (99%), methyl 3-chloroperbenzoic 3-hydroxybenzoate acid (mCPBA,(99%), methyl 75%), 2-hydroxybenzoate ethylcarbodiimide hydrochloride (≥99%), methacrylic (EDC, 99%), acid 4-(dimethylamino)pyridine(MAA, 99%), bisphenol A (DMAP, 98%), 4-methoxyphenol (MeHQ), phenothiazine (98%), N,N-dimethylformamide glycerolate dimethacrylate (BisGMA, >98%), triethylene glycol dimethacrylate (DMF, 99%), methanol (MeOH, 99%), methylene chloride (DCM, 99%), anhydrous potas- (TEGDMA, 95%), camphorquinone (CQ, 97%), 2-(dimethylamino)ethyl methacrylate sium carbonate (K CO , 99%), and sodium hydroxide (NaOH, 98%) were obtained from (DMAEMA, 98%),2 and3 triphenylphosphine (TPP, 99%) were acquired from Sigma-Al- Oakwood Chemical (Estill, SC, USA) and used as received. Gibco DPBS (1X) pH 7.1 was drich (St. Louis, MO, USA) and used without further purification. Allyl bromide (99%), 3- obtained from Thermo Fisher Scientific (Waltham, MA, USA) and used as supplied. chloroperbenzoic acid (mCPBA, 75%), ethylcarbodiimide hydrochloride (EDC, 99%), 4- Fourier Transform Nuclear Magnetic Resonance spectroscopy data were obtained (dimethylamino)pyridine (DMAP, 98%), 4-methoxyphenol (MeHQ), phenothiazine using an Agilent 400 MHz FT-NMR spectrometer (Santa Clara, CA, USA). Attenuated (98%), N,N-dimethylformamide (DMF, 99%), methanol (MeOH, 99%), methylene chloride Total Reflectance Fourier-Transform infrared (ATR-FTIR) spectroscopy was performed on a (DCM, 99%), anhydrous potassium carbonate (K2CO3, 99%), and sodium hydroxide Thermo Fisher Nicolet iS10 instrument (Waltham, MA, USA). Contact angle measurements (NaOH, 98%) were obtained from Oakwood Chemical (Estill, SC, USA) and used as re- with water were carried out using a Kruss—DSA30S drop shape analyzer (Hamburg, Germany).ceived. Gibco Viscosity DPBS measurements(1X) pH 7.1 was were obtained performed from usingThermo a Brookfield Fisher Scientific AMETEK (Waltham, DV2D LVMA, viscometer USA) and atused 200 as RPM supplied. (Middleborough, MA, USA). Glass transition temperatures (Tg) were measured with a TA Instruments Q800 DMA (New Castle, DE, USA). Flexural

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Fourier Transform Nuclear Magnetic Resonance spectroscopy data were obtained using an Agilent 400 MHz FT-NMR spectrometer (Santa Clara, CA, USA). Attenuated To- tal Reflectance Fourier-Transform infrared (ATR-FTIR) spectroscopy was performed on a Thermo Fisher Nicolet iS10 instrument (Waltham, MA, USA). Contact angle measure- Materials 2021, 14, 2139 4 of 17 ments with water were carried out using a Kruss—DSA30S drop shape analyzer (Ham- burg, Germany). Viscosity measurements were performed using a Brookfield AMETEK DV2D LV viscometer at 200 RPM (Middleborough, MA, USA). Glass transition tempera- strengthtures (Tg) was were measured measured with with a a TA.XT TA Instrument Plus textures Q800 analyzer DMA (New (Hamilton, Castle, MA, DE, USA). Flex- The logarithmural strength of thewas 1-octanol/water measured with partitiona TA.XT coefﬁcientPlus texture was analyzer estimated (Hamilton, using ChemDraw MA, USA). PrimeThe logarithm 17.1 (Cambridge of the 1-octanol/water Software from partitio Perkinn coefficient Elmer). One-way was estimated ANOVA using with ChemDraw a Tukey post-hocPrime 17.1 test (Cambridge was used for Software statistical from analysis, Perkin withElmer). a signiﬁcance One-way ANOVA level of p with< 0.05 a Tukey using IBMpost-hoc SPSS test Statistics was used software, for statistical version 27.analysis, with a significance level of p < 0.05 using IBM SPSS Statistics software, version 27. 2.1. Synthesis 2.1. SynthesisSince the synthesis of the para-, ortho-, and meta-substituted isosorbide 2,5- bis(glyceryloxybenzoate)Since the synthesis of dimethacrylates the para-, ortho-, is and similar, meta-substitut the para-substituteded isosorbide isosorbide 2,5-bis(glyc- 2,5- bis(4-glyceryloxybenzoate)eryloxybenzoate) dimethacrylates dimethacrylate is similar, reaction the para-substituted scheme is given isosorbide as an example 2,5-bis(4- in Figureglyceryloxybenzoate)4. dimethacrylate reaction scheme is given as an example in Figure 4.

HO O O Br O O NaOH, H2O OH MeOH O DMF, K2CO3 O O Methyl 4-hydroxybenzoate Methyl 4-allyl benzoate Allyl 4-benzoic acid H O EDC HO OH DMAP H H O O DCM O O Isosorbide O O O O O MCPBA O H H O O O DCM Isosorbide 2,5-bis(4-glycidyloxybenzoate) O O O O O H O O TPP OH Isosorbide 2,5-bis(4-allyloxybenzoate)

O H O O OH O O O O O O OH O H O O Isosorbide 2,5-bis(4-glyceryloxybenzoate) dimethacrylate (ISB4GBMA)

FigureFigure 4.4. ReactionReaction scheme scheme for for ISB4GBMA ISB4GBMA (1,4:3,6-dianhydro- (1,4:3,6-dianhydro-D-sorbitolD-sorbitol 2,5-bis 2,5-bis [4 -(2-hydroxy-3- [4-(2-hydroxy-3- methacryloyloxypropoxy)benzoate]).methacryloyloxypropoxy)benzoate]).

StartingStarting withwith methylmethyl 4-hydroxybenzoate,4-hydroxybenzoate, allylallyl bromidebromide isis addedadded inin thethe presencepresence ofof anhydrousanhydrous potassiumpotassium carbonatecarbonate andand DMF.DMF. TheThe resultingresulting productproduct isis distilleddistilled toto produceproduce methylmethyl 4-allyloxybenzoate.4-allyloxybenzoate. After saponificationsaponification with sodiumsodium hydroxidehydroxide inin methanol,methanol, 4-4- allyloxybenzoicallyloxybenzoic acidacid isis esterifiedesterified withwith isosorbideisosorbide inin thethe presencepresence ofof EDCEDC andand DMAPDMAP inin DCMDCM toto makemake isosorbideisosorbide 2,5-bis(4-allyloxybenzoate).2,5-bis(4-allyloxybenzoate). IsosorbideIsosorbide 2,5-bis(4-allyloxy 2,5-bis(4-allyloxybenzoate)benzoate) is is further further reacted reacted with with MCPBA MCPBA to generate to generate iso- ◦ isosorbidesorbide 2,5-bis(4-glycidyloxybenzoate) 2,5-bis(4-glycidyloxybenzoate) (60% (60% yield, yield, >98% >98% pure, pure, mp 112–113112–113 °C).C). 1 1HH NMRNMR (CDCl(CDCl33--δ𝛿,, ppm):ppm): 2.782.78 (2H,(2H, -CH-CH oxirane),oxirane), 2.932.93 (2H,(2H, -CH-CH oxirane),oxirane), 3.373.37 (2H,(2H, -CH-CH oxirane),oxirane), 3.9–4.13.9–4.1 (6H,(6H, 4H4H -CH-CH22 isosorbide,isosorbide, 2H-CH2H-CH22 glycidyloxy),glycidyloxy), 4.29–4.314.29–4.31 (2H,(2H, -CH-CH22 glycidyloxy),glycidyloxy), 4.674.67 (1H,(1H, -CH -CH isosorbide), isosorbide), 5.03 5.03 (1H, (1H, -CH -CH isosorbide), isosorbide), 5.39 5.39 (1H,-CH (1H,-CH isosorbide), isosorbide), 5.46 5.46 (1H-CH (1H- isosorbide),CH isosorbide), 6.94 (4H,6.94 -CH(4H, aromatic),-CH aromatic), 7.9 (2H, 7.9 -CH (2H, aromatic), -CH aromatic), and 8.0 and (2H, 8.0 -CH (2H, aromatic). -CH aromatic).The final dimethacrylate monomer (ISB4GBMA) is attained upon reacting 20 g (40 mmol) of isosorbideThe final 2,5-bis(4-glycidyloxybenzoate) dimethacrylate monomer (ISB4GBMA) with 100 mLis attained (1.14 mol) upon methacrylic reacting 20 acid g (40 in themmol) presence of isosorbide of 0.3 g (1.142,5-bis(4-glycidyloxybenzoate) mmol) of triphenyl phosphine with as100 the mL catalyst. (1.14 mol) MEHQ methacrylic (10 mg, 0.81acid mmol)in the presence and Phenothiazine of 0.3 g (1.14 (10 mmol) mg, 50 ofµ triphenylmol) were phosphine added as inhibitorsas the catalyst. and stabilizers.MEHQ (10 ◦ Themg, reaction0.81 mmol) was and run atPhenothiazine 76 C for up to(10 24 mg, h. Excess50 µmol) methacrylic were added acid as is inhibitors first removed and under stabi- vacuumlizers. The and reaction then the was crude run at is 76 mixed °C for with up to DCM 24 h. Excess and washed methacrylic with aacid saturated is first removed sodium carbonate solution. The final product is purified through column chromatography (ethyl acetate/hexanes-70:30 w/w) and stabilized with 500 ppm of MeHQ. The synthesis and characterization of intermediate compounds are provided in the supplementary materials. 1 ISB4GBMA (69% yield, >98% pure), H NMR (CDCl3-δ, ppm): 1.9 (6H, 2x-CH3 methacrylate), 3.9–4.4 (14H, 4H-CH2 isosorbide, 8H-CH2, 2H-CH glyceryloxy), 5.03 (1H, -CH isosorbide), 4.6 (1H, -CH isosorbide), 5.39 (1H, -CH isosorbide), 5.45 (1H, -CH isosorbide), 5.6 (2H, =CH2 methacrylate), 6.15 (2H, =CH2 methacrylate), 6.9 (4H, -CH aromatic), 7.9 (2H, -CH aromatic), 8.04 (2H, -CH aromatic). Materials 2021, 14, x FOR PEER REVIEW 5 of 18

under vacuum and then the crude is mixed with DCM and washed with a saturated sodium carbonate solution. The final product is purified through column chromatography (ethyl acetate/hexanes-70:30 w/w) and stabilized with 500 ppm of MeHQ. The synthesis and characterization of intermediate compounds are provided in the supplementary materials. ISB4GBMA (69% yield, >98% pure), 1H NMR (CDCl3-𝛿, ppm): 1.9 (6H, 2x-CH3 methacrylate), 3.9–4.4 (14H, 4H-CH2 isosorbide, 8H-CH2, 2H-CH glyceryloxy), 5.03 (1H, -CH Materials 2021, 14, 2139 isosorbide), 4.6 (1H, -CH isosorbide), 5.39 (1H, -CH isosorbide), 5.45 (1H, -CH isosorbide),5 of 17 5.6 (2H, =CH2 methacrylate), 6.15 (2H, =CH2 methacrylate), 6.9 (4H, -CH aromatic), 7.9 (2H, -CH aromatic), 8.04 (2H, -CH aromatic). 1 ISB3GBMA (76% yield, >98% pure), 1H NMR (CDCl3-𝛿, ppm): 1.9(6H, 2x-CH3 meth- ISB3GBMA (76% yield, >98% pure), H NMR (CDCl3-δ, ppm): 1.9(6H, 2x-CH3 methacry- acrylate), 3.9–4.4 (14H, 4H-CH2 isosorbide, 8H-CH2, 2H-CH glyceryloxy), 5.03 (1H, -CH late), 3.9–4.4 (14H, 4H-CH isosorbide, 8H-CH , 2H-CH glyceryloxy), 5.03 (1H, -CH isosor- isosorbide), 4.6 (1H, -CH isosor2 bide), 5.39 (1H, -CH2 isosorbide), 5.45 (1H, -CH isosorbide), bide), 4.6 (1H, -CH isosorbide), 5.39 (1H, -CH isosorbide), 5.45 (1H, -CH isosorbide), 5.6 5.6 (2H, =CH2 methacrylate), 6.15 (2H, =CH2 methacrylate), 7.1 (2H, -CH aromatic), 7.3– (2H, =CH methacrylate), 6.15 (2H, =CH methacrylate), 7.1 (2H, -CH aromatic), 7.3–7.4 7.4 (2H, -CH2 aromatic), 7.5 (1H, -CH aromatic),2 7.6 (2H, -CH aromatic), 7.7 (1H, -CH aro- (2H, -CH aromatic), 7.5 (1H, -CH aromatic), 7.6 (2H, -CH aromatic), 7.7 (1H, -CH aromatic). matic). 1 ISB2GBMA (79% yield, >96% pure), H NMR (CDCl3-δ, ppm): 1.9(6H, 2x-CH3 ISB2GBMA (79% yield, >96% pure), 1H NMR (CDCl3-𝛿, ppm): 1.9(6H, 2x-CH3 meth- methacrylate), 3.9–4.4 (14H, 2H-CH isosorbide, 2H-CH isosorbide, 8H-CH , 2H-CH acrylate), 3.9–4.4 (14H, 2H-CH isosorbide, 2H-CH2 isosorbide,2 8H-CH2, 2H-CH glycer-2 glyceryloxy),yloxy), 5.03 (1H, 5.03 -CH (1H, isosorbide -CH isosorbide),), 4.6 (1H, 4.6 -CH (1H, isosorbide), -CH isosorbide), 5.39 (1H, 5.39 -CH (1H, isosorbide), -CH isosorbide), 5.45 5.45 (1H, -CH isosorbide), 5.6 (2H, =CH methacrylate), 6.15 (2H, =CH methacrylate), (1H, -CH isosorbide), 5.6 (2H, =CH2 methacrylate),2 6.15 (2H, =CH2 methacrylate),2 6.9–7.0 6.9–7.0(4H, -CH (4H, aromatic), -CH aromatic), 7.45–7.52 7.45–7.52 (2H, -CH (2H, aromatic), -CH aromatic), 7.8–7.9 (2H, 7.8–7.9 -CH aromatic). (2H, -CH aromatic). ISDGMAISDGMA was synthesized synthesized according according to to the the reaction reaction scheme scheme in inFigure Figure 5. 5.

FigureFigure 5.5. Reaction scheme for for ISDGMA. ISDGMA.

IsosorbideIsosorbide was was etherified etherified in inthe the presence presence of allyl of allylbromide, bromide, potassium potassium hydroxide, hydroxide, and andwater. water. The subsequent The subsequent reaction reaction step with step MC withPBA MCPBA provided provided isosorbide isosorbide diglycidyl diglycidyl ether. ether.ISDGMA ISDGMA was synthesized was synthesized via the addition via the additionof 75 mL of(0.85 75 mLmol) (0.85 methacrylic mol) methacrylic acid to 20 g acid to(77 20 mmol) g (77 mmol)of isosorbide of isosorbide diglycidyl diglycidyl ether in etherthe presence in the presence of 0.15 ofg (0.57 0.15 gmmol) (0.57 mmol)tri- triphenylphosphine.phenylphosphine. MEHQ MEHQ (12.5 (12.5 mg, 0.1 mg, mmol) 0.1 mmol) and Phenothiazine and Phenothiazine (12.5 mg, (12.5 63 µmol) mg, 63wereµmol) wereadded added as inhibitors as inhibitors and stabilizers. and stabilizers. The reaction The reactionwas run at was 76 run°C for at up 76 ◦toC 24 for h. up Excess to 24 h. Excessmethacrylic methacrylic acid was acid first was removed first removed under va undercuum vacuumand then and the thencrude the was crude mixed was with mixed withDCM DCM and washed and washed with a with saturated a saturated sodium sodium carbonate carbonate solution. solution. The final The product final product was pu- was purifiedrified through through column column chromatograp chromatographyhy (ethyl (ethyl acetate/hexanes-95:5 acetate/hexanes-95:5 w/ww)/ andw) and stabilized stabilized with 500 ppm MeHQ. The synthesis and characterization of intermediate compounds are with 500 ppm MeHQ. The synthesis and characterization of intermediate compounds are provided in the supplementary materials. provided in the supplementary materials. ISDGMA (82% yield, >85% disubstituted with up to 15 mole% branching), 1H NMR ISDGMA (82% yield, >85% disubstituted with up to 15 mole% branching), 1H NMR (CDCl3-𝛿, ppm): 1.9 (6–7.5H, 2-CH3 methacrylate), 3.5–4.2 (16–20H, 4H-CH2 isosorbide, (CDCl3-δ, ppm): 1.9 (6–7.5H, 2-CH3 methacrylate), 3.5–4.2 (16–20H, 4H-CH2 isosorbide, 2H-CH isosorbide, 8H-CH2, 2H-CH glyceryloxy), 4.5 (1H, -CH isosorbide), 4.65 (1H, -CH 2H-CH isosorbide, 8H-CH2, 2H-CH glyceryloxy), 4.5 (1H, -CH isosorbide), 4.65 (1H, -CH isosorbide), 5.6 (2–2.5H, =CH2 methacrylate), 6.15 (2–2.5H, =CH2 methacrylate). The vary- isosorbide), 5.6 (2–2.5H, =CH methacrylate), 6.15 (2–2.5H, =CH methacrylate). The ing proton area integration observed2 in various regions of the NMR spectrum2 will be ad- varyingdressed protonin the discussion area integration section. observed in various regions of the NMR spectrum will be addressed in the discussion section.

2.2. Resin Preparation and Evaluation Resins were prepared by mixing each isosorbide monomer, or the reference BisGMA

material, with TEGDMA in a 60:40 weight ratio, and by adding the photoinitiator, camphorquinone, and the co-initiator, dimethyl aminoethyl methacrylate (0.4% and 1.0%, respectively, by weight) [27]. The ﬁnal mixture was poured into a stainless-steel mold and bounded by two microscope slides. The mixture was then cured using an AZDENT 1900 mW/cm2 LED curing light with an 8 mm diameter light guide tip, operating in the wavelength range of 400–500 nm, and placed 50 mm above the mold. This polymerization technique was adopted as a general method to compare the different resins. Resin mixtures for water sorption testing had the dimensions of (1 mm thick × 15 mm diameter) and were cured for 40 s on the top and bottom sides. ISDGMA/TEGDMA samples were cured for 80 s on both sides for reasons to be addressed in the discussion section. Materials 2021, 14, 2139 6 of 17

The evaluation for the remaining tests (degree of conversion, polymerization shrinkage, glass transition temperature, flexural strength and modulus) was done on resin mixture samples with 2 mm × 6 mm × 38 mm dimensions, in which the top and bottom sides were cured for 40 s twice in an alternating manner. The resulting samples were evaluated as is. For the degree of conversion and polymerization shrinkage, five samples were evaluated, while the evaluation of flexural strength and glass transition temperatures was done on three samples. Water sorption: Five disc-shaped samples were prepared to measure the water sorption according to ISO4049 [35]. Upon curing, the samples were placed in a 37 ◦C oven to obtain a constant mass. Then, they were placed upright in the center of a 14 mL vial using a holder, and 10 mL of DPBS were added. The samples were kept at 37 ◦C for 7 days. Samples were then removed and pat dried with Kim wipes before mass measurement. Water sorption was measured according to Equation (1), where m7 is the weight after 7 days of immersion, m0 is the initial weight prior to immersion, and V0 is the initial volume of the specimen. m − m Water sorption (WS, µg/mm3) = 7 0 (1) V0 Degree of monomer conversion: ATR-FTIR was used to measure the degree of conversion of the methacrylate double bonds according to Equation (2) in polymers derived from BisGMA and ISBGBMA monomers [36]. The degree of conversion was calculated using the polymer to monomer ratio of the absorbance height of the methacrylate vinyl C=C stretching at a frequency ν = 1636 cm−1. The spectra of the absorbance bands were normalized using the C=C aromatic stretching band at ν = 1610 cm−1 as an internal standard. The degree of conversion is reported as the average between the top and bottom layers of the test specimen. On the other hand, ISDGMA does not contain an aromatic group to be used as an internal standard, and as such, its degree of conversion was not calculated in this study.

A(c = c) methacrylate (polymer) Degree of conversion = [1 − ] × 100% (2) A(c = c) methacrylate (monomer)

Polymerization shrinkage: A 25 mL pycnometer (Wilmad lab glass, Vineland, NJ, USA), and an analytical balance (OHAUS explorer, Parsippany, NJ, USA), were used to determine the mass, volume, and the corresponding densities of the cured specimens. Polymerization shrinkage, [PS(%)], as a result of volumetric shrinkage, was calculated according to Equation (3), where dp is the density of the polymer and dm is the density of the monomer mixture [37].

dp − dm PS (%) = × 100% (3) dp

Glass transition temperature: Glass transition temperature (Tg) was determined using a three-point bending test in the temperature range of −40 ◦C to 200 ◦C, at a rate of ◦ 10 C/min and a frequency of 1 Hz. Tg was evaluated at the maximum tan delta peak [38]. Flexural strength and modulus: Flexural strength was calculated based on a modiﬁed ISO 4049 method [35]. TA-XT Plus texture analyzer equipped with a 50 Kg load cell and a strain rate of 1.2 mm/min was used. Resin sample sets were divided into two groups. One group was measured after immersion in a DPBS buffer solution for 24 h at 37 ◦C, while the other group was measured after being placed in an oven at 37 ◦C for 24 h. Flexural strength (σ, MPa) was calculated using Equation (4), where F is the maximum load exerted on the specimen at the point of fracture (N), l is the distance between the supports (mm), b is the width of the specimen (mm), and h is the thickness of the specimen (mm). Flexural modulus was obtained from the slope in the linear region between 0.05–0.25% strain, similar to ISO 178 [39]. 3Fl σ = (4) 2bh2 Materials 2021, 14, x FOR PEER REVIEW 7 of 18

Flexural strength and modulus: Flexural strength was calculated based on a modified ISO 4049 method [35]. TA-XT Plus texture analyzer equipped with a 50 Kg load cell and a strain rate of 1.2mm/min was used. Resin sample sets were divided into two groups. One group was measured after immersion in a DPBS buffer solution for 24 h at 37 °C, while the other group was measured after being placed in an oven at 37 °C for 24 h. Flexural strength (σ, MPa) was calculated using Equation (4), where 𝐹 is the maximum load exerted on the specimen at the point of fracture (N), 𝑙 is the distance between the supports (mm), 𝑏 is the width of the specimen (mm), and ℎ is the thickness of the specimen (mm). Flexural modulus was obtained from the slope in the linear region between 0.05–0.25% strain, similar to ISO 178 [39]. Materials 2021, 14, 2139 7 of 17 3𝐹𝑙 𝜎 (4) 2𝑏ℎ

3. Results and Discussion 3. Results and Discussion Isosorbide with its two-ring structure and hydroxyl functionality can resemble Bisphe- Isosorbide with its two-ring structure and hydroxyl functionality can resemble Bi- nol A, and as such, it is typically viewed as a potential BPA replacement [40]. In the sphenol A, and as such, it is typically viewed as a potential BPA replacement [40]. In the work of Łukaszczyk et al., and Shin and coworkers, ISDGMA was proposed as a BisGMA work of Łukaszczyk et al., and Shin and coworkers, ISDGMA was proposed as a BisGMA replacement [27,28]. However, because of its hydrophilic nature, ISDGMA is reported replacement [27,28]. However, because of its hydrophilic nature, ISDGMA is reported to to have higher water sorption relative to BisGMA. To overcome this, three isosorbide have higher water sorption relative to BisGMA. To overcome this, three isosorbide di- dimethacrylate monomers with hydrophobic benzoate aromatic spacers were synthesized methacrylate monomers with hydrophobic benzoate aromatic spacers were synthesized and evaluated. They differ amongst each other based on the position of the dimethacrylate and evaluated. They differ amongst each other based on the position of the dimethacrylate substituent on the aromatic ring (para-, meta-, or ortho-). substituent on the aromatic ring (para-, meta-, or ortho-). Inspection of the 1H NMR spectra reveals that, during the ﬁnal step of the synthesis of Inspection of the 1H NMR spectra reveals that, during the final step of the synthesis of ISB4GBMA, the epoxide protons of the glycidyloxybenzoate intermediate at 3.37, 2.93, and ISB4GBMA, the epoxide protons of the glycidyloxybenzoate intermediate at 3.37, 2.93, and 2.78 ppm disappear and give rise to methacrylate protons at 5.6 and 6.15 ppm, as shown in 2.78 ppm disappear and give rise to methacrylate protons at 5.6 and 6.15 ppm, as shown in Figures6 and7. Similarly, the related proton NMR spectra of the meta and ortho benzoate Figures 6 and 7. Similarly, the related proton NMR spectra of the meta and ortho benzoate substituted isosorbides are provided in Figures S1–S4 (Supplementary Materials). substituted isosorbides are provided in Figures S1–S4 (Supplementary Materials).

Materials 2021, 14, x FOR PEER REVIEW 8 of 18

FigureFigure 6. 6.1 H1H NMR NMR IsosorbideIsosorbide 2,5-bis(4-glycidyloxybenzoate).2,5-bis(4-glycidyloxybenzoate).

1 FigureFigure 7. 7.1 HH NMRNMR IsosorbideIsosorbide 2,5-bis(4-glycerloxybenzoate)2,5-bis(4-glycerloxybenzoate) dimethacrylate. dimethacrylate.

FigureFigure8 8displays displays thethe NMR spectrum spectrum of of ISDGMA. ISDGMA. Branching Branching in inthe the form form of bis-meth- of bis- methacrylation,acrylation, up to up 15 to mole 15 mole %, at %,the at glyceryl the glyceryloxyoxy hydroxyl hydroxyl functionality functionality is suspected is suspected as evidenced by the excess area integration of the isosorbide cycle protons H3/H4 to the methacrylate protons at 5.6/6.1 ppm, and to the methyl protons at 1.9 ppm. The new ISBGBMA monomers were found to be less susceptible to such branching. The NMR spectrum of isosorbide diglycidyl ether is provided in Figure S5 (Supplementary Materials).

Figure 8. 1H Isosorbide 2,5-bis(glyceryloxy) dimethacrylate.

The benzoate functionality in ISBGBMA monomers was added to increase the hydrophobicity over ISDGMA. Contact angle measurements and cLogP estimations of ISBGBMA monomers, ISDGMA, and BisGMA are reported in Table 1. The mean contact angle (θ) of ISBGBMA monomers at (~62.9°) is higher than 13.41° for ISDGMA. This indi- cates that the new monomers are more hydrophobic [41]. However, they are less hydrophobic than BisGMA at 77°. The cLogP estimations indicate the ISBGBMA monomers to be more hydrophobic than ISDGMA, but less hydrophobic than BisGMA as well [42].

Materials 2021, 14, x FOR PEER REVIEW 8 of 18

Materials 2021, 14, 2139 Figure 7. 1H NMR Isosorbide 2,5-bis(4-glycerloxybenzoate) dimethacrylate. 8 of 17

Figure 8 displays the NMR spectrum of ISDGMA. Branching in the form of bis-methacrylation, up to 15 mole %, at the glyceryloxy hydroxyl functionality is suspected as evi- asdenced evidenced by the by excess the excess area integration area integration of the ofisosorbide the isosorbide cycle protons cycle protons H3/H4 to H3/H4 the meth- to theacrylate methacrylate protons at protons 5.6/6.1 atppm, 5.6/6.1 and ppm,to the methyl and to theprotons methyl at 1.9 protons ppm. The at 1.9 new ppm. ISBGBMA The newmonomers ISBGBMA were monomers found to were be less found susceptible to be less to susceptible such branching. to such The branching. NMR spectrum The NMR of spectrum of isosorbide diglycidyl ether is provided in Figure S5 (Supplementary Materials). isosorbide diglycidyl ether is provided in Figure S5 (Supplementary Materials).

1 FigureFigure 8. 8.1 HH Isosorbide Isosorbide 2,5-bis(glyceryloxy) 2,5-bis(glyceryloxy) dimethacrylate. dimethacrylate.

TheThe benzoate benzoate functionality functionality in in ISBGBMA ISBGBMA monomers monomers was was added added to to increase increase the the hy- hy- drophobicitydrophobicity over over ISDGMA. ISDGMA. Contact Contact angle angle measurements measurements and and cLogP cLogP estimations estimations of IS- of BGBMAISBGBMA monomers, monomers, ISDGMA, ISDGMA, and and BisGMA BisGMA are are reported reported in in Table Table1. The1. The mean mean contact contact angleangle ( θ(θ)) of of ISBGBMAISBGBMA monomers at at (~62.9°) (~62.9◦ )is is higher higher than than 13.41° 13.41 for◦ forISDGMA. ISDGMA. This This indi- indicatescates that that the the new new monomers monomers are are more more hydrop hydrophobichobic [41]. [41 However,]. However, they they are are less less hydro- hy- drophobicphobic than than BisGMA BisGMA at at77°. 77 ◦The. The cLogP cLogP esti estimationsmations indicate indicate the the ISBGBMA ISBGBMA monomers monomers to tobe be more more hydrophobic hydrophobic than than ISDGMA, ISDGMA, but but less less hydrophobic hydrophobic than than BisGMA BisGMA as as well well [42]. [42].

Table 1. Contact Angle Measurements and cLogP Estimations of BisGMA, ISB4GBMA, ISB3GBMA, ISB2GBMA, and ISDGMA.

Sample Contact Angle (Degrees ◦) cLogP BisGMA a 76.97 (2.84) [b,c,d,e] 5.09 ISB4GBMA b 63.21 (4.08) [a,e] 2.75

ISB3GBMA c 62.65 (1.33) [a,e] 2.75 ISB2GBMA d 62.82 (1.74) [a,e] 2.75 ISDGMA e 13.41 (1.76) [a,b,c,d] −0.53 Letters indicate statistically signiﬁcant difference (p < 0.05) based on group. Standard deviation in parenthesis.

The viscosity of the monomer mixture is an important parameter that affects the degree of polymerization conversion and the amount of ﬁller that can be incorporated into a composite. Therefore, it is typically preferred to have resin mixtures with lower viscosities as long as polymerization shrinkage and water sorption are kept to a minimum [43,44]. Viscosity increased for the ISBGBMA/TEGDMA monomer mixtures in the order of ortho < meta < para, as shown in Table2. ISB4GBMA/TEGDMA had the highest viscosity at 2.49 Pa·s, while the ortho mixture ISB2GBMA/TEGDMA had the lowest at 0.63 Pa·s. The viscosity of the ortho mixture was near to that of the BisGMA/TEGDMA reference at 0.48 Pa·s and was noticeably higher than the viscosity of ISDGMA/TEGDMA at 0.06 Pa·s. In the work of Kim et al., the viscosity of ISDGMA/TEGDMA at 70:30 wt% was similar to that of BisGMA/TEGDMA at 60:40 wt% [28]. Materials 2021, 14, 2139 9 of 17

Table 2. Brookﬁeld Viscosity of BisGMA/TEGDMA, ISB4GBMA/TEGDMA, ISB3GBMA/TEGDMA, ISB2GBMA/TEGDMA, and ISDGMA/TEGDMA at 60:40 wt% and 25 ◦C.

Sample Viscosity at 25 ◦C (Pa·s) BisGMA/TEGDMA 0.48 ISB4GBMA/TEGDMA 2.48 ISB3GBMA/TEGDMA 1.26 ISB2GBMA/TEGDMA 0.63 ISDGMA/TEGDMA 0.06

The size and shape of the molecule, its molecular weight, and ability for inter and in- tramolecular interactions have an impact on its viscosity [7]. The ISBGBMA monomers are larger at (~671 g/mol) in comparison to ISDGMA (~431 g/mol) and BisGMA (~513 g/mol), and can therefore cause more friction and increase the viscosity of the mixture. On the other hand, since all the ISBGBMA monomers have the same molecular weight, we propose that the difference in viscosity is likely related to the conformation of the isosorbide monomer. ISB4GBMA is relatively planar while ISB2GBMA is sterically hindered; planar aromatic molecules are known to closely align in parallel, in what is called π-stacking [45]. The steric hindrance and lower potential of ISB2GBMA for packing is believed to result in lower friction and lower viscosity for ISB2GBMA/TEGDMA. The degree of conversion, polymerization shrinkage, and glass transition temperatures are presented in Table3. Conversion of p(ISB2GBMA/TEGDMA) at 52% was signiﬁcantly different from the conversion of p(ISB4GBMA/TEGDMA) at 47%, but statistically similar to the conversion of p(BisGMA/TEGDMA) at 54%. As stated earlier, ISDGMA does not contain an aromatic ring and its degree of conversion was not calculated in this study. On the other hand, Łukaszczyk et al., reported the degree of conversion of p(ISDGMA/TEGDMA) at 60:40 wt% to be slightly higher than that of P(BisGMA/TEGDMA) by means of photo- DSC in their studies [27].

Table 3. Degree of Conversion, Polymerization Shrinkage, and Glass transition Temperature of p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB3GBMA/TEGDMA), p(ISB2GBMA/TEGDMA), and p(ISDGMA/TEGDMA) at 60:40 wt%.

Glass Transition Sample Degree of Conversion (%) Polymerization Shrinkage (%) Temperature (◦C) p(BisGMA/TEGDMA) a 54 (3) [b] 6.54 (1) [b] 95.73 (3.73) [b,c,e] p(ISB4GBMA/TEGDMA) b 47 (4) [a,d] 4.25 (1) [a,d,e] 80.57 (0.46) [a] p(ISB3GBMA/TEGDMA) c 51 (3) 5.41 (1) [d,e] 77.38 (3.86) [a] p(ISB2GBMA/TEGDMA) d 52 (5) [b] 6.7 (1) [b,c] 86.52 (1.18) p(ISDGMA/TEGDMA) e N/A 7.28 (1) [b,c] 85.56 (7.30) [a] Letters indicate statistically signiﬁcant difference (p < 0.05) based on group. Standard deviation in parenthesis.

Unreacted double bonds can indicate the presence of free monomers or pendant groups. A degree of conversion of less than 50% suggests the presence of unreacted residual dimethacrylates. Free monomers can leach and irritate the soft tissue, while pendant groups lower chemical crosslink density and reduce mechanical integrity [6,46]. The efﬁciency of the photopolymerization system and the stiffness and elasticity of the monomers can affect the degree of conversion [47]. The addition of a diluent helps increase the degree of conversion through a reduction in the overall viscosity and an increase in reaction diffusion [48]. In the work of Pfeifer et al., the degree of conversion of p(BisGMA) was improved with increasing TEGDMA content and lowering the viscosity of the mixture [49]. Therefore, the higher degree of monomer conversion of p(ISB2GBMA/TEGDMA), in comparison to the other ISBGBMA isomers, is attributed to its lower viscosity. The polymerization shrinkage was highest around 7% for p(ISB2GBMA/TEGDMA), p(BisGMA/TEGDMA), and p(ISDGMA/TEGDMA) and was statistically different from the Materials 2021, 14, 2139 10 of 17

polymerization shrinkage of p(ISB4GBMA/TEGDMA) at 4.25%. Polymer systems shrink as the covalently bonded monomers occupy less space [37]. This depends on the degree of conversion, functionality, and molecular weight [50]. Polymerization shrinkage causes stresses within the matrix and within the matrix and tooth interface. It is associated with microleakage, gap formation, enamel crack propagation, and post-operative sensitivity [51]. The lower degree of conversion for the para- and its bulky structure is believed to result in lower polymerization shrinkage. According to Pfeifer et al. [49], higher degrees of conversion resulted in higher polymerization shrinkage in p(BisGMA/TEGDMA). Simi- larly, the polymerization shrinkage of p(ISDGMA/TEGDMA) was slightly higher than that of p(BisGMA/TEGDMA) in the work of Łukaszczyk et al., and was attributed to higher degrees of monomeric conversion [27]. Materials 2021, 14, x FOR PEER REVIEW 11 of 18 Glass transition temperatures were determined from the maxima of tan delta curves, as shown in Figure9.

0.5 0.45 p(BisGMA/TEGDMA) 0.4 [95.73°C (3.72)] 0.35 0.3 p(ISB4GBMA/TEGDMA) 0.25 [80.57°C (0.45)] tan δ tan 0.2 p(ISB3GBMA/TEGDMA) 0.15 [77.38°C (3.86)] 0.1 p(ISB2GBMA/TEGDMA) 0.05 [86.52°C (1.17)] 0 p(ISDGMA/TEGDMA) -1 12 25 38 51 64 77 90 -40 -27 -14

103 116 129 142 155 168 [84.56°C (7.29)] Temperature, °C

Figure 9. Tan delta of p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB3GBMA/TEGDMA), Figurep(ISB2GBMA/TEGDMA), 9. Tan delta of p(BisGMA/TEGDMA), and p(ISDGMA/TEGDMA) p(ISB4GBMA/TEGDMA), at 60:40 wt%. p(ISB3GBMA/TEGDMA), Maximum tan delta value in p(ISB2GBMA/TEGDMA),brackets and standard deviationand p(ISDGMA/TEGDMA) in parenthesis. at 60:40 wt%. Maximum tan delta value in brackets and standard deviation in parenthesis. The glass transition temperature must exceed cure temperature and temperature rangesThe glass encountered transition in thetemperature oral environment, must ex forceed the cure material temperature to be clinically and temperature viable [7]. The rangeslower encountered Tg of the polymers in the oral derived environment, from ISBGBMA, for the material relative to to that be clinically of p(BisGMA/TEGDMA), viable [7]. The lowerare attributedTg of the to theirpolymers relative derived lower degrees from ofISBGBMA, monomeric conversion.relative to Stansburythat of etp(Bis- al. and GMA/TEGDMA),Sideridou and co-workersare attributed demonstrated to their relative higher lower glass degrees transition of monomeric temperatures conversion. that were Stansburyobtained et with al. and higher Sideridou degrees and of co-workers conversion [demonstrated6,7]. The polymer higher derived glass transition from ISB2GBMA tem- peratureshad a slightly that were higher obtained glass transitionwith higher temperature degrees of (86 conversion◦C) than the[6,7]. polymer The polymer derived de- from rivedISB4GBMA from ISB2GBMA (80 ◦C) orhad ISB3GBMA a slightly higher (77 ◦C). glass Steric transition hindrance, temperature increased (86 rigidity, °C) than and the im- polymerproved derived degree offrom conversion ISB4GBMA are likely(80 °C) to beor theISB3GBMA cause for (77 this °C). behavior. Steric hindrance, in- creasedIn rigidity, contrast, and statistical improved analysis degree did of not conv showersion a signiﬁcant are likely difference to be the between cause for the this glass behavior.transition temperatures of p(BisGMA/TEGDMA) at 95 ◦C and p(ISB2GBMA/TEGDMA) atIn 86 contrast,◦C, suggesting statistical the analysis corresponding did not crosslinked show a significant networks difference to be structurally between similar.the glass The transitionglass transition temperatures temperature of p(BisGMA/TEG of p(ISDGMA/TEGDMA)DMA) at 95 °C and at 85 p(ISB2GBMA/TEGDMA)◦C was statistically differ- at ent86 °C, only suggesting from the Ttheg of corresponding p(BisGMA/TEGDMA). crosslinked On networks the other to hand,be structurally the glass similar. transition Thetemperature glass transition of p(BisGMA/TEGDMA) temperature of p(ISDGMA and p(ISDGMA/TEGDMA)/TEGDMA) at 85 °C was were statistically reported dif- to be ferentcomparable only from in the the T workg of p(BisGMA/TEGDMA). of Łukaszczyk et al., andOn the were other attributed hand, the to similarglass transition degrees of temperatureconversion of between p(BisGMA/TEGDMA) the two polymers. and Different p(ISDGMA/TEGDMA) curing and Tg characterization were reported methodsto be comparablewere used in in the that work study of [ 27Łukaszczyk]. et al., and were attributed to similar degrees of conversionThe between corresponding the two storage polymers. modulus Differ isent shown curing in Figure and Tg 10 characterization. It is highest for p(BisGMA/methods wereTEGDMA) used in that and study p(ISB2GBMA/TEGDMA) [27]. where the degree of conversion is higher. The lowThe modulus corresponding obtained storage for p(ISDGMA/TEGDMA) modulus is shown in mightFigure be 10. attributed It is highest to its for structural p(Bis- GMA/TEGDMA)ﬂexibility. and p(ISB2GBMA/TEGDMA) where the degree of conversion is higher. The low modulus obtained for p(ISDGMA/TEGDMA) might be attributed to its structural flexibility.

Materials 2021, 14, x FOR PEER REVIEW 12 of 18 Materials Materials 20212021, 14, 14, x, FOR 2139 PEER REVIEW 12 11of of18 17

5000 5000 4500 p(BisGMA/TEGDMA) 4500 p(BisGMA/TEGDMA) 4000 p(ISB4GBMA/TEGDMA) 4000 p(ISB4GBMA/TEGDMA)p(ISB3GBMA/TEGDMA) 3500 p(ISB3GBMA/TEGDMA)p(ISB2GBMA/TEGDMA) 3500 p(ISB2GBMA/TEGDMA)p(ISDGMA/TEGDMA) 3000 p(ISDGMA/TEGDMA) 3000 2500 2500

E' (MPa) 2000 E' (MPa) 2000 1500 1500 1000 1000 500 500 0 0 -50 -25 0 25 50 75 100 125 150 175 200 -50 -25 0 25 50 75 100 125 150 175 200 Temperature , °C Temperature , °C

Figure 10. Storage modulus of p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), FigureFigure 10. 10. StorageStorage modulus modulus of p(BisGMA/TEGDMA), of p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB3GBMA/ p(ISB3GBMA/TEGDMA), p(ISB2GBMA/TEGDMA), and p(ISDGMA/TEGDMA) at 60:40 wt%. p(ISB3GBMA/TEGDMA),TEGDMA), p(ISB2GBMA/TEGDMA), p(ISB2GBMA/TEGDMA), and p(ISDGMA/TEGDMA) and p(ISDGMA/TEGDMA) at 60:40 wt%. at 60:40 wt%. TheThe lower lower water sorption of p(ISB2GBMA/TEGDMA) at 39 µµg/mmg/mm33 waswas statistically statistically The lower water sorption of p(ISB2GBMA/TEGDMA) at 39 µg/mm3 was statistically differentdifferent from from the the water water sorption sorption of of p(ISB4GBMA/TEGDMA) p(ISB4GBMA/TEGDMA) at 44 at 44g/mm g/mm3. However,3. However, the different from the water sorption of p(ISB4GBMA/TEGDMA) at 44 g/mm3. However, the polymerthe polymer derived derived from from BisGMA BisGMA had hadthe lowest the lowest water water sorption sorption at 26 at µg/mm 26 µg/mm3, and3, the and pol- the polymer derived from BisGMA had the lowest water sorption at 26 µg/mm3, and the pol- ymerpolymer derived derived from from ISDGMA ISDGMA had had the thehighest highest at 73 at µg/mm 73 µg/mm3, as 3shown, as shown in Figure in Figure 11. 11. ymer derived from ISDGMA had the highest at 73 µg/mm3, as shown in Figure 11.

90.00 [a,b,c,d] 90.00 80.00 [a,b,c,d] 80.00

) 70.00 3 ) 70.00

3 60.00 60.00 [a,d,e] [a,e] 50.00 [a,d,e] [a,e] [a,b,e] 50.00g/mm [a,b,e]

µ 40.00 [b,c,d,e] g/mm

µ 40.00 30.00 [b,c,d,e] 30.00 WS ( 20.00 WS ( 20.00 10.00 10.00 abcde 0.00 abcde 0.00

FigureFigure 11.11.Water Water sorption sorption of p(BisGMA/TEGDMA), of p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB3GBMA/TEGDMA), p(ISB3GBMA/TEGDMA), p(ISB2GBMA/ Figure 11. Water sorption of p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB3GBMA/TEGDMA), p(ISB2GBMA/TEGDMA),TEGDMA), and p(ISDGMA/TEGDMA) and p(ISDGMA/TEGDMA) at 60:40 wt%. Lettersat 60:40 indicate wt%. Letters statistically indicate signiﬁcant statistically difference significant (p < 0.05) based differ- on p(ISB2GBMA/TEGDMA), and p(ISDGMA/TEGDMA) at 60:40 wt%. Letters indicate statistically significant differ- encegroup. (p Individual< 0.05) based groups on aregroup. represented Individual by (a–e). groups are represented by (a–e). ence (p < 0.05) based on group. Individual groups are represented by (a–e). The improved hydrophobicity of the ISBGBMA series over ISDGMA helped lower the The improved hydrophobicity of the ISBGBMA series over ISDGMA helped lower waterThe sorption improved by abouthydrophobicity 40%. However, of the it ISBGBMA was not enough series to over result ISDGMA in lower helped water sorptionlower the water sorption by about 40%. However, it was not enough to result in lower water thethan water p(BisGMA/TEGDMA). sorption by about 40%. The isosorbideHowever, coreit was is hygroscopicnot enough withto result hydrophilicity in lower water similar sorption than p(BisGMA/TEGDMA). The isosorbide core is hygroscopic with hydrophilic- sorptionto diethylene than p(BisGMA/TEGDMA). glycol [20,52]. Therefore, The improvingisosorbide thecore hydrophobicity is hygroscopic with further hydrophilic- is expected ity similar to diethylene glycol [20,52]. Therefore, improving the hydrophobicity further ityto similar reduce to the diethylene water sorption glycol further. [20,52]. Therefore, improving the hydrophobicity further is expected to reduce the water sorption further. is expectedHygroscopic to reduce expansion the water duesorption to water further. can weaken mechanical properties, increase Hygroscopic expansion due to water can weaken mechanical properties, increase wearHygroscopic rate, and reduce expansion dimensional due to water stability can [ 53weaken–55]. Polymer mechanical samples properties, derived increase from the wear rate, and reduce dimensional stability [53–55]. Polymer samples derived from the wearhydrophilic rate, and ISDGMA reduce dimensional deteriorated andstability cracked [53–55]. as a resultPolymer of water samples uptake derived after immersionfrom the hydrophilic ISDGMA deteriorated and cracked as a result of water uptake after immer- hydrophilicin buffer solution,ISDGMA as deteriorated shown in Figureand cracked 12a. Thisas a wasresult also of water noted uptake by Kim after et al., immer- where sion in buffer solution, as shown in Figure 12a. This was also noted by Kim et al., where sionp(ISDGMA) in buffer solution, resins and as resin-basedshown in Figure composites 12a. This showed was also surface noted cracks by Kim after et al., buffer where stor-

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Materials 2021, 14, 2139 12 of 17

p(ISDGMA) resins and resin-based composites showed surface cracks after buffer storage age[33]. [33 On]. the On other the other hand, hand, polymer polymer samples samples derived derived from fromthe ISBGBMA the ISBGBMA monomers monomers exhib- exhibitedited greater greater stability stability due to due improved to improved hydrop hydrophobicityhobicity and reduced and reduced water sorption, water sorption, similar similarto the BisGMA to the BisGMA reference. reference. This is Thisillustrated is illustrated in Figure in Figure12b,c. 12b,c.

FigureFigure 12.12. SEMSEM images images at at 150× 150 and× and 2.5 kV 2.5 of kV (a of) p(ISDGMA/TEGDMA), (a) p(ISDGMA/TEGDMA), (b) (b) p(ISB2GBMA/ p(ISB2GBMA/TEGDMA), and (c) p(BisGMA/TEGDMA) after buffer immersion for 7 days at 37 °C. TEGDMA), and (c) p(BisGMA/TEGDMA) after buffer immersion for 7 days at 37 ◦C.

WhenWhen ISDGMA/TEGDMA ISDGMA/TEGDMA samplessamples werewere initiallyinitially curedcured similarlysimilarly toto otherother resinresin sam-sam- plesples for for water water sorption, sorption, the the results results obtained obtained were were inconsistent. inconsistent. Lower Lower degree degree of conversion, of conver- samplesion, sample deterioration, deterioration, and dissolution and dissolution are probable are probable causes. To causes. optimize To theoptimize curing conditionthe curing further,condition the further, samples the were samples cured were longer. cured As along result,er. As the a water result, sorption the water was sorption consistent, was andcon- thissistent, is shown and this in Figure is shown S6 (Supplementaryin Figure S6 (Supplementary Materials). Materials). InIn addition, addition, thethe choicechoice toto store store the the samples samples in in DPBS DPBS instead instead of of DI DI water water for for water water sorptionsorption was was to to compare compare this this data data to to ISDGMA ISDGMA values values reported reported in in the the literature literature [ 27[27,28].,28]. To To determinedetermine anyany interferenceinterference thatthat thethe bufferbuffer solution solutionmay mayhave have to to the the water water sorption sorption data, data, SEM-EDSSEM-EDS was was used used to determineto determine the extentthe extent of phosphorus of phosphorus deposition deposition on all sample on all groups.sample Thegroups. results The revealed results norevealed detectable no detectable deposition deposition levels and levels therefore, and anytherefore, interference any interfer- to the waterence to sorption the water from sorption the storage from medium the storage would medium be negligible. would be negligible. DentalDental restorative restorative materials materials should should have have sufﬁcient sufficient mechanical mechanical integrity integrity to to function function properly.properly. While While ISO ISO 4049 4049 reports reports on on the the minimum minimum requirements requirements for resin-basedfor resin-based composites, compo- itsites, is generally it is generally recognized recognized that the that higher the thehigher mechanical the mechanical strength strength is, the better is, the is better the perfor- is the manceperformance [56]. In [56]. our studies,In our studies, ﬂexural flexural strength stre analysisngth analysis showed showed a decrease a decrease in strength in strength for all samples once immersed in DPBS for 24 h as shown in Figure 13. The decrease in strength Materials 2021, 14, x FOR PEER REVIEWfor all samples once immersed in DPBS for 24 h as shown in Figure 13. The decrease14 of 18 in wasstrength greatest was (80%) greatest for p(ISDGMA/TEGDMA),(80%) for p(ISDGMA/TEGDMA), where signs where of network signs of degradationnetwork degrada- were observed.tion were Allobserved. other samples All other had samples a comparable had a comparable 50% loss. 50% loss. Although one can note differences in flexural strength across various groups as indi- 120 cated in the graph, statistical analysis did not confirm such variations, which might be due to the limited number of sample sets per group. The flexural strength of p(Bis- 100 GMA/TEGDMA)[e] was statistically significant only from p(ISDGMA/TEGDMA) in both 80 dried and immersed states. On the other hand, p(ISDGMA/TEGDMA) was statistically significant[e’] from all samples in the immersed sample set. 60 [a] [e’] [e’] [e’] 40

20 [a’,b’,c’,d’] Flexural Strength (MPa) Strength Flexural a a’ b b' c c' d d' e 0 e'

Samples dried at 37C for 24 hours Samples immersed in PBS at 37C for 24 hours

Figure 13. Flexural strength of p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB3GBMA/TEGDMA), p(ISB2GBMA/ Figure 13. Flexural strength of p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB3GBMA/TEGDMA), TEGDMA), and p(ISDGMA/TEGDMA) at 60:40 wt% at RT. Letters indicate statistically signiﬁcant difference (p < 0.05) p(ISB2GBMA/TEGDMA), and p(ISDGMA/TEGDMA) at 60:40 wt% at RT. Letters indicate statistically significant dif- based on group. ference (p < 0.05) based on group.

In the work of Yiu et al., the tensile strength of unfilled dental resins was lower for hydrophilic materials upon water storage, where water sorption was highest and water acted as a plasticizer [57]. As such, we believe the improved hydrophobicity and increased rigidity of the ISBGBMA monomers over ISDGMA, through the presence of the aromatic groups, to improve flexural strength by reducing the water uptake of the samples. Table 4 shows the percent water uptake with respect to mass after 24 h of sample storage. The hydrophilic material p(ISDGMA/TEGDMA) had the highest water uptake and the lowest flexural strength. Since the storage time was short (24 h), it is unclear if saturation was obtained, and thus, caused such significant decreases in flexural strength. Longer storage times are needed to verify this concept further. Similarly, Kim et al. reported a decrease in flexural strength in resins and resin-based composites of p(BisGMA/TEGDMA) and p(ISDGMA) after PBS buffer storage for 7 days at 37 °C [33].

Table 4. Water uptake after 24 h and at 37 °C in DPBS for p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB3GBMA/TEGDMA), p(ISB2GBMA/TEGDMA) and p(ISDGMA/TEGDMA).

p(BisGMA p(ISB4GBMA p(ISB3GBMA p(ISB2GBMA p(ISDGMA Test /TEGDMA) /TEGDMA) /TEGDMA) /TEGDMA) /TEGDMA) WU% 0.91% (0.05) 1.48% (0.09) 1.35% (0.13) 1.19% (0.06) 4.20% (0.17) WU%: water uptake percentage. Standard deviation in parenthesis.

The lower flexural strength of the ISBGBMA polymers, in comparison to p(Bis- GMA/TEGDMA), is due to the lower degree of monomeric conversion and corresponding cross link density, where the concentration of methacrylate double bonds is 5.13 mol/Kg for BisGMA/TEGDMA, and 4.58 mol/Kg for ISBGBMA/TEGDMA. Gajewski et al. have shown that flexural strength improves with higher degree of conversion and cross link density [58]. The flexural modulus is given in Figure 14; it is highest for p(BisGMA/TEGDMA) and p(ISB4GBMA/TEDMA) in the samples dried at 37 °C. However, no statistical significance in the modulus was noted between all samples dried at 37 °C. As expected, the

Materials 2021, 14, 2139 13 of 17

Although one can note differences in flexural strength across various groups as indi- cated in the graph, statistical analysis did not confirm such variations, which might be due to the limited number of sample sets per group. The flexural strength of p(BisGMA/TEGDMA) was statistically significant only from p(ISDGMA/TEGDMA) in both dried and immersed states. On the other hand, p(ISDGMA/TEGDMA) was statistically significant from all samples in the immersed sample set. In the work of Yiu et al., the tensile strength of unfilled dental resins was lower for hydrophilic materials upon water storage, where water sorption was highest and water acted as a plasticizer [57]. As such, we believe the improved hydrophobicity and increased rigidity of the ISBGBMA monomers over ISDGMA, through the presence of the aromatic groups, to improve flexural strength by reducing the water uptake of the samples. Table4 shows the percent water uptake with respect to mass after 24 h of sample storage. The hydrophilic material p(ISDGMA/TEGDMA) had the highest water uptake and the lowest flexural strength. Since the storage time was short (24 h), it is unclear if saturation was obtained, and thus, caused such significant decreases in flexural strength. Longer storage times are needed to verify this concept further. Similarly, Kim et al. reported a decrease in flexural strength in resins and resin-based composites of p(BisGMA/TEGDMA) and p(ISDGMA) after PBS buffer storage for 7 days at 37 ◦C[33]. The lower flexural strength of the ISBGBMA polymers, in comparison to p(BisGMA/ TEGDMA), is due to the lower degree of monomeric conversion and corresponding cross link density, where the concentration of methacrylate double bonds is 5.13 mol/Kg for BisGMA/TEGDMA, and 4.58 mol/Kg for ISBGBMA/TEGDMA. Gajewski et al. have shown that flexural strength improves with higher degree of conversion and cross link Materials 2021, 14, x FOR PEER REVIEW density [58]. 15 of 18 The flexural modulus is given in Figure 14; it is highest for p(BisGMA/TEGDMA) and p(ISB4GBMA/TEDMA) in the samples dried at 37 ◦C. However, no statistical significance in the modulus was noted between all samples dried at 37 ◦C. As expected, the flexural flexural modulus of the immersed samples is lower. In the work of Ito et al., the modulus modulus of the immersed samples is lower. In the work of Ito et al., the modulus of of elasticity was lower in resins with higher water sorption. The more hydrophilic the elasticity was lower in resins with higher water sorption. The more hydrophilic the resin . resin is, the higheris, the is the higher water is thesorption, water an sorption,d the lower and is the the lower modu islus the of modulus elasticity of [59] elasticity [59]. The The flexural modulusflexural of modulusp(ISDGMA/TEGDMA) of p(ISDGMA/TEGDMA) was statistically was significant statistically from significant all sam- from all samples ples in the immersedin the state. immersed Similar state. to flexural Similar strength, to flexural the strength, limited number the limited of sample number sets of sample sets per per group may contributegroup may to contribute the findings to the of statistical findings of analysis. statistical analysis.

1,800 1,600 1,400 1,200 [e’] 1,000 [e’] [e’] 800 [e’] 600 400 [a’,b’,c’,d’]

Flexural Modulus (MPa) Modulus Flexural 200 a a’ b b' c c' d d' e 0 e'

Samples dried at 37C for 24 hrs Samples immersed in PBS at 37C for 24 hrs

Figure 14. Flexural modulus of p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB3GBMA/TEGDMA), p(ISB2GBMA/ Figure 14. Flexural modulus of p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), TEGDMA), and p(ISDGMA/TEGDMA) at 60:40 wt% at RT. Letters indicate statistically signiﬁcant difference (p < 0.05) p(ISB3GBMA/TEGDMA), p(ISB2GBMA/TEGDMA), and p(ISDGMA/TEGDMA) at 60:40 wt% at based on group. RT. Letters indicate statistically significant difference (p < 0.05) based on group.

Additionally, the reported modulus of p(BisGMA/TEGDMA) in this study might be lower than what is described in the literature [60,61]. We attribute these differences to the polymerization technique in this work, which as stated earlier, is adopted as a general approach to compare the different resins. Thus, the modulus and the corresponding properties of all polymers reported herein, are dependent on the polymerization condition, where light intensity at the sample surface and various depths might play a role.

4. Conclusions The focus of this study was to identify bio-based, BPA-free, dental resin methacrylates with similar key characteristics to BisGMA. In this regard, three hydrophobically- modified isosorbide dimethacrylate isomers (ISBGBMA) were synthesized, characterized, and evaluated in the form of copolymers with TEGDMA as potential dental filling resins. ISBGBMA monomers were more hydrophobic than ISDGMA based on contact angle measurements and cLogP estimations, but less hydrophobic than BisGMA. The para, meta, and ortho substitution of the benzoate functionality in the ISBGBMA monomers resulted in different properties. In this series, the monomer mixture of TEGDMA and the ortho ISBGBMA monomer had the least viscosity. The corresponding copolymer had the lowest water sorption and the highest degree of monomeric conversion, polymerization shrinkage, glass transition temperature, and storage modulus. How- ever, flexural strength was comparable, while the flexural modulus was highest for the copolymer of TEGDMA and the para-substituted ISBGBMA monomer in the dry sample set. The hydrophobic ISBGBMA monomers showed greater improvement over the hydrophilic ISDGMA monomer. The corresponding copolymers with TEGDMA had lower

Materials 2021, 14, 2139 14 of 17

Table 4. Water uptake after 24 h and at 37 ◦C in DPBS for p(BisGMA/TEGDMA), p(ISB4GBMA/TEGDMA), p(ISB3GBMA/TEGDMA), p(ISB2GBMA/TEGDMA) and p(ISDGMA/TEGDMA).

Test p(BisGMA/TEGDMA) p(ISB4GBMA/TEGDMA) p(ISB3GBMA/TEGDMA) p(ISB2GBMA/TEGDMA) p(ISDGMA/TEGDMA) WU% 0.91% (0.05) 1.48% (0.09) 1.35% (0.13) 1.19% (0.06) 4.20% (0.17) WU%: water uptake percentage. Standard deviation in parenthesis.

Additionally, the reported modulus of p(BisGMA/TEGDMA) in this study might be lower than what is described in the literature [60,61]. We attribute these differences to the polymerization technique in this work, which as stated earlier, is adopted as a general approach to compare the different resins. Thus, the modulus and the corresponding properties of all polymers reported herein, are dependent on the polymerization condition, where light intensity at the sample surface and various depths might play a role.

4. Conclusions The focus of this study was to identify bio-based, BPA-free, dental resin methacrylates with similar key characteristics to BisGMA. In this regard, three hydrophobically-modified isosorbide dimethacrylate isomers (ISBGBMA) were synthesized, characterized, and evaluated in the form of copolymers with TEGDMA as potential dental filling resins. ISBGBMA monomers were more hydrophobic than ISDGMA based on contact angle measurements and cLogP estimations, but less hydrophobic than BisGMA. The para, meta, and ortho substitution of the benzoate functionality in the ISBGBMA monomers resulted in different properties. In this series, the monomer mixture of TEGDMA and the ortho ISBGBMA monomer had the least viscosity. The corresponding copolymer had the lowest water sorption and the highest degree of monomeric conversion, polymerization shrinkage, glass transition temperature, and storage modulus. However, flexural strength was comparable, while the flexural modulus was highest for the copolymer of TEGDMA and the para-substituted ISBGBMA monomer in the dry sample set. The hydrophobic ISBGBMA monomers showed greater improvement over the hydrophilic ISDGMA monomer. The corresponding copolymers with TEGDMA had lower water sorption and improved mechanical strength, modulus, and buffer stability. On the other hand, the viscosity of their monomeric mixtures with TEGDMA was much higher. The performance of the ortho ISBGBMA monomer was comparable to that of BisGMA among the ISBGBMA series. The viscosity of the monomer mixture with TEGDMA was similar. The degree of conversion of the corresponding copolymer, polymerization shrinkage, glass transition temperature, storage modulus, flexural strength, and modulus resembled those of p(BisGMA/TEGDMA). However, the water sorption was significantly higher. Taken together, these data suggest that the ortho ISBGBMA monomer is a potential bio-based, BPA-free replacement for BisGMA, and should be the focus for future studies.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/ma14092139/s1, Figure S1: 1H NMR spectrum of Isosorbide 2,5-bis(3-glycidyloxybenzoate), Figure S2: 1H NMR spectrum of Isosorbide 2,5-bis(3-glyceryloxybenzoate) dimethacrylate, Figure S3: 1H NMR spectrum of Isosorbide 2,5-bis(2-glycidyloxybenzoae), Figure S4: 1H NMR spectrum of Isosorbide 2,5-bis(2-glyceryloxybenzoate) dimethacrylate, Figure S5: 1H NMR spectrum of Isosorbide 2,5-bis(glycidylether), Figure S6: Water sorption of p(ISDGMA/TEGDMA) when cured at different time lengths. Author Contributions: Conceptualization, B.M. and M.J.; Data curation, B.M.; Formal analysis, B.M., R.C., T.G., and S.O.; Investigation, B.M.; Project administration, N.M.R.; Resources, N.M.R.; Supervision, M.J.; Writing—original draft, B.M.; Writing—review & editing, N.M.R. All authors have read and agreed to the published version of the manuscript. Funding: This study was not supported by external funding. Materials 2021, 14, 2139 15 of 17

Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: All data presented in this study is available in Marie, B; Clark, R; Gillece, T; Ozkan, S; Jaffe, M; Ravindra, N.M. Hydrophobically Modified Isosorbide Dimethacrylates as Bisphenol-A (BPA)-Free Dental Filling Materials. Conflicts of Interest: All the authors declare that they have no conflict of interest.

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