WO2024254677A1

WO2024254677A1 - Synthesis of functional and clinically practical ester-free vinyl monomers for applications in dentistry

Info

Publication number: WO2024254677A1
Application number: PCT/CA2024/050748
Authority: WO
Inventors: Zachary Alexander GOUVEIA; Paul Santerre; Yoav FINER
Original assignee: University of Toronto
Current assignee: University of Toronto
Priority date: 2023-06-12
Filing date: 2024-06-04
Publication date: 2024-12-19
Anticipated expiration: 2025-12-12
Also published as: GB202308789D0; EP4724420A1

Abstract

The present disclosure provides biostable dental resin acrylate-based monomers useful in resin-based restorative materials which exhibit enhanced resistance to breakdown catalyzed by salivary enzymes. These hydrolytically stable monomers possess crosslinkable moieties susceptible to free radical polymerization.

Description

SYNTHESIS OF FUNCTIONAL AND CLINICALLY PRACTICAL ESTER-FREE VINYL MONOMERS FOR APPLICATIONS IN DENTISTRY

FIELD OF THE DISCLOSURE

This disclosure relates to the synthesis of functional and clinically practical ester-free vinyl monomers for applications in dentistry.

BACKGROUND

The prevalence of dental caries has continued to increase with an extended aging population and its subsequent tooth retention^{1 2}. Specifically, caries have been reported to occur in as much as 19% of adults over the age of 45³, and show particular recurrence among groups of socioeconomic disadvantage and those with pre-existing risk factors such as periodontal disease. The restoration of dental caries is most commonly achieved using dental resin composite (composed of monomers and filler) that are bonded to the tooth using adhesive materials (mainly monomers), which account for over 160 million restoration procedures annually in the United States at an approximate $20B cost^4-6. The dental polymer resins used in these restorations and adhesives, particularly in North America, have replaced traditionally used amalgam restorations due to improved aesthetics, minimized invasiveness, and minimized toxicity concerns. Dental sealants, used to seal deep anatomical fissures to prevent the development of occlusal caries are based on similar concepts and compositions⁷.

Despite being the preferred material for restorations (composite restorative materials, adhesives and sealants) in the clinic, current dental resins experience enzymatic degradation in the oral cavity and lack the durability of amalgam fillings in terms of both inherent mechanical and chemical stability⁶⁷. This instability thereby limits their lifetime in vivo, and, requires their frequent replacement due to the ability of secondary caries to form in the breakdown of their margins, or their total restoration failure. Some resin restorations, such as cervical restorations, have failure rates of 30% within 5 years for individuals 50 years and older, with some individuals having a restoration lifespan of only 2 years^8-10.

Most commercially available dental resin systems, which are used to formulate composites, adhesives and sealants, rely on ester-containing methacrylate derivatives to achieve rapid photo-polymerization; where the latter design feature is important in maintaining patient comfort and saliva-free sealing, enabled by the short polymerization periods. However, the ester component of these methacrylate derivatives, introduce hydrolytically susceptible linkages within the crosslinking elements of these materials. Specifically, the esters have been shown to experience enzymatic degradation, enabled in the oral cavity by salivary-, bacterial-, and neutrophil-derived enzymes, leading to resin instability (Figure -|)4,11,12

The challenge of hydrolysis has been the rationale for research on dental restoratives that has focused on the development of new chemistries. Santerre- Finer developed novel monomers that incorporated bulky fluoro-moieties in an attempt to shield methacrylate derivatives from esterolytic hydrolysis⁴. These efforts were only able to achieve minimal reduction (< 5%) in monomer mass loss relative to curing commercial methacrylate monomers BisGMA and TEGDMA.

Several other groups have focused on the development of crosslinkable dental resin monomers without the use of ester-dependent methacrylates. Such crosslinkable moieties have included styrene, thiol-ene, methacrylamide (MAA) and acrylamides (AA). For example, Gonzalez-Bonet et al. developed an ester-free styrene-based monomer that was completely resistant to enzymatic hydrolysis¹³. However, this monomer possessed poor UV curing kinetics, with further iterative blends all requiring the re-introduction of some amount of the original ester- methacrylate-based monomers to provide suitable setting¹⁴. Unfortunately, the latter mitigation brings the field back to where it started with the issue of ester- containing monomers still being an issue.

Currently, work with MAA- and AA-based monomers have shown the greatest promise in directly replacing methacrylate-based monomers in dental restoratives. Moszner et al. have pioneered monomer development in this area with one of their AA-based monomers currently being used in a universal adhesive (Surefil one™)^15-17.

More recent developments have been made by Pfiefer et al., through the development of new MAA and AA monomers. However, a more thorough analysis of their curing behavior, mechanical properties, and susceptibility to impurities has revealed some challenges^18-21. To date, most of the developments by research groups have focused on the use of these monomers for dental adhesive systems. While the curing kinetics and handling properties of MAA and AA based resins have been optimized to perform similarly to that of methacrylate-based resins, their bulk properties have not achieved that standard. Similarly, to the example is the styrene-based monomer discussed above, suitable mechanical properties for bulk restorations with MAA and AA monomers have only been achieved through the re- introduction of methacrylate functionalities due to the slow curing of styrenehomopolymerization²². The challenge with this continual dependence on ester- containing methacrylates to mitigate the shortcomings of the de-novo resins based on other hydrolytically-stable chemistry was highlighted in a resent review article but the authors²³.

SUMMARY The present disclosure provides a monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

R1 and R2 may be different alkyl.

R1 and R2 may be the same alkyl.

R1 and R2 may be independently C1 , C2, C3 or C4 alkyl.

R1 and R2 may be C1 and X1 may be (A), so that the compound is:

R1 and R2 may be C2 and X1 may be (A), so that the compound is:

R1 and R2 may be C1 and X1 may be (B), so that the compound is:

R1 and R2 may be C2 and X1 may be (B), so that the compound is:

R1 and R2 are C3 and X1 may be (A), so that the compound is:

R1 and R2 may be linear C4 and X1 may be (A), so that the compound is:

R1 and R2 may be branched C4 and X1 may be (A), so that the compound is:

R1 and R2 may be C3 and X1 may be (B), so that the compound is:

R1 and R2 may be linear C4 and X1 may (B), so that the compound is:

R1 and R2 may be branched C4 and X1 may be (B), so that the compound

The present disclosure provides a monomeric compound of formula (II):

wherein O is oxygen, N is nitrogen, R1 and R2 are alky, and n is in a range from 1 to about 5.

R1 and R2 may be independently C2, C3, C4 alkyl.

R1 and R2 may be different alkyl.

R1 and R2 may be the same alkyl.

R1 and R2 may be C2 alkyl and n is 2, so that the compound is:

R1 and R2 may be C1 alkyl and n may be 1 , so that the compound is:

R1 and R2 may be C1 alkyl and n may be 2, so that the compound is:

R1 and R2 may be C1 alkyl and n may be 3, so that the compound is:

R1 and R2 may be C1 alkyl and n may be 4, so that the compound is:

R1 and R2 may be C1 alkyl and n may be 5, so that the compound is:

R1 and R2 may be C2 alkyl and n may be 1 , so that the compound is:

R1 and R2 may be C2 alkyl and n may 2, so that the compound is:

and R2 may be C2 alkyl and n may be 3, so that the compound is:

R1 and R2 may be C2 alkyl and n may be 4, so that the compound is:

R1 and R2 may be C2 alkyl and n may be 5, so that the compound is:

R1 and R2 may be C3 alkyl and n may be 1 , so that the compound is:

R1 and R2 may be C3 alkyl and n may be 2, so that the compound is:

R1 and R2 may be C3 alkyl and n may be 3, so that the compound is:

R1 and R2 may be C3 alkyl and n may be 4, so that the compound is:

R1 and R2 may be C3 alkyl and n may be 5, so that the compound is:

R1 and R2 may be linear C4 alkyl and n may be 1 , so that the compound is:

R1 and R2 may be linear C4 alkyl and n may be 2, so that the compound is:

and R2 may be linear C4 alkyl and n may be 3, so that the compound is:

and R2 may be linear C4 alkyl and n may be 4, so that the compound is:

and R2 may be linear C4 alkyl and n may be 5, so that the compound is:

R1 and R2 may be branched C4 alkyl and n may be 1 , so that the compound is:

R1 and R2 may be branched C4 alkyl and n may be 2, so that the compound is:

R1 and R2 may be branched C4 alkyl and n may be 3, so that the compound is:

R1 and R2 may be branched C4 alkyl and n may be 4, so that the compound is:

R1 and R2 may be branched C4 alkyl and n may be 5, so that the compound is:

The present disclosure provides a dental resin that comprises at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

a monomeric compound of formula (II):

The dental resin may comprise at least on monomeric compound of of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

a monomeric compound of formula (II):

The dental resin may comprise at least one monomeric compound selected within the group consisting of

the compound

The dental resin wherein the at least one monomeric compound may be 3BM alone, 3BE alone, 3BLDI alone, combination of 3BM and 3BE, combination of 3BM and 3BLDI, combination of 3BE and 3BLDI or combination of 3BM, 3BE and 3BLDI.

The dental resin wherein the at least one monomeric compound may be 3BE, 3TE or a combination thereof.

The dental resin composition may further comprise one or more polymerization initiators.

The dental resin composition may further comprise at least one polymerization inhibitor and/or stabilizer.

The dental resin composition wherein the one or more polymerization initiators may be selected from the group of camphorquinone (CQ); trimethylbenzoyl-diphenyl-phosphine oxide (TPO); Ethyl-4-dimethylamino benzoate (EDMAB); 2,2-Dimethoxy-2-phenylacetophenone (DMPA); Bisacylphosphine oxide (BAPO); 1-Phenyl-1 ,2-propanedione (PPD); phosphine oxide compounds, including naphthacene (APO), 9-anthracene (APO), and bisacylphosphine oxide (BAPO); 1- phenyl-1 ,2-propanedione (PPD); thioxanthone (TX) and its derivatives; a dibenzoyl germanium derivative, benzoyltrimethylgermane (BTG), dibenzoyldiethylgermane; hexaarylbiimidazole derivatives; a silane based derivative; (diethylgermanediyl)bis((4-methoxyphenyl)methanone); benzenesulfinic acid sodium salt (BS); a diaryliodonium salt, diphenyliodonium chloride or iodonium salt [diphenyliodonium hexafluorophosphate (DPIHP or DPI-PF6))], bromide, iodide, or hexafluorophosphate; and benzoyl peroxide (BPO).

The dental resin composition wherein the one or more polymerization initiators may be a combination of polymerization initiators selected from the group consisting of of camphorquinone/ethyl-4-(dimethylamino)benzoate (EDMAB), camphorquinone/2-(dimethylamino)ethyl methacrylate (DMAEMA)), DMPA/DPI- PF6, CQ/PPD, CQ/DMAEMA, CQ/EDMAB, CQ/DMAEMA/PDIHP, CQ/EDMAB/DPIHP or initiators containing ,bis-(4-methoxybenzoyl)diethyl germane, or phenylbis(2,4,6-trimethylbenzoyl) phosphine oxide (BAPO ).

The dental resin composition wherein the one or more polymerization inhibitors may be selected from the group consisting 4-tert-butylcatechol (TBC), 4- methoxyphenol (MEHQ), butylated hydroxytoluene (BHT) and hydroquinone (HQ), inhibitors of the class of phenols, aryl amines, phenylenediamines, N,N- dialkylhydroxylamines, m-nitro-p-cresol, 2,6-dinitro-p-cresol, and nitroxides, 2,2,6,6-tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1- yl)oxidanyl),2,4-dinitrophenol (DNP) and 2,4-dinitro-6-sec-butyl phenol (DNBP), and wherein the one or more stabilizers may be selected from the group consisting of 2,6-di-tert-butyl-p-cresol, hydroquinone, 4-methoxyphenol, 4-tert- butylpyrocatechol,tert-butylhydroquinone,n2-tert-butyl-1 ,4-benzoquinone, copper(ii) dibutyldithiocarbamate, 2,6-di-tert-butylphenol, 2-[1-(2-hydroxy-3,5-di-tert- pentylphenyl)ethyl]-4,6-di-tert-pentylphenyl acrylate, phenothiazine, 1 , 1 -diphenyl-2- picrylhydrazyl free radical, 1 ,4-benzoquinone, 6-tert-butyl-2,4-xylenol. The dental resin composition may further comprise dental based plurifuntionalized methacrylate monomers and/or methacrylate oligomers.

The dental resin composition wherein the dental based plurifuntionalized methacrylate monomers may be any one or combination of bisphenol A-glycidyl methacrylate (BisGMA), ethoxylated bisphenol A glycol dimethacrylate (BisEMA), urethane dimethacrylate (UDMA), triethylene glycol dimethacrylate (TEGDMA), 2- hydroxyethyl methacrylate (HEMA).

The present disclosure provides a dental adhesive composition comprising a dental resin composition and a solvent.

The dental adhesive composition wherein the solvent may be any one or combination of water, ethanol, acetone, DMSO.

The dental filler composite may comprise a dental resin composition and filler materials.

The dental filler composite wherein the filler materials may be inorganic filler materials, organic filler materials or a combination thereof.

The present disclosure provides a dental adhesive composition that comprises at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

(A), or

one or more polymerization initiators; at least one polymerization inhibitor and/or stabilizer; dental based pluri-functionalized methacrylate monomers and/or methacrylate oligomers; and/or solvent.

The dental adhesive composition further may comprise a monomeric compound of formula (II):

wherein O is oxygen, N is nitrogen, R1 and R2 are alkyl; and n is in a range from 1 to about 5.

The present disclosure provides a dental filler composite that comprises at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

one or more polymerization initiators; at least one polymerization inhibitor and/or stabilizer; dental based pluri-functionalized methacrylate monomers and/or methacrylate oligomers; and inorganic and/or organic filler materials.

The dental filler composite may further comprise a monomeric compound of formula (II):

The present disclosure provides a dental sealant composition that comprises a dental resin composition and a solvent.

The dental sealant composition may further comprise up to about 60 wt% or less of inorganic and/or organic filler materials.

The dental sealant composition wherein the amount of filler may be 50% or less, 40% or less, 30% or less, 20 % or less, 10% or less, or 5% or less.

The present disclosure provides a dental adhesive composition that comprises a dental sealant composite comprising at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

one or more polymerization initiators; at least one polymerization inhibitor and/or stabilizer; dental based plurifuntionalized methacrylate monomers and/or methacrylate oligomers; and a solvent.

The dental sealant may further comprise a monomeric compound of formula

(II):

The dental sealant composition may further comprise up to 60 wt% or less of inorganic and/or organic filler materials.

The dental sealant composition wherein the amount of filler may be 50% or less, 40% or less, 30% or less, 20 % or less, 10% or less, or 5% or less. A further understanding of the functional and advantageous aspects of the disclosure can be realized by reference to the following detailed description and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure will be more fully understood from the following detailed description thereof taken in connection with the accompanying drawings, which form part of this application, and in which:

Figure 1 illustrates the esterase degradation of methacrylate monomers, where here MA = methacrylic acid, BisHPPP = 2,2-Bis[4(2,3- hydroxypropoxy)phenyl]propane and TEG = triethylene glycol.

Figure 2 shows the formulas for the experimental acrylamide-based monomers generated in this study. Monomers 2TE and DEPBAM were previously synthesized by others, and were used as relative control examples of earlier acrylamides²⁴.

Figure 3A shows the degree of double bond conversion (DC) measured by ATR-FTIR of developed resin blends. ** represents significant differences (p < 0.05) in DC.

Figure 3B shows the degree of double bond conversion (DC) measured by ATR-FTIR of select single monomer resins. ** represents significant differences (p < 0.05) in DC.

Figure 4A shows the quantified water contact angle (WCA) of developed resin blends. ** represents significant differences (p < 0.05) in WCA. Figure 4B shows water uptake (Swell %) of selected cured resin specimens. * represents significant differences in swelling compared to control material composed of Bis/TEGDMA.

Figure 5 shows the measured surface hardness of cured resin specimens. ** represents significant differences (p < 0.05) in Knoop hardness number (KHV).

Figure 6A shows residual monomer versus time. Monomer degradation was conducted over 3 days in simulated human salivary esterase (SHSE) and PBS.

Figure 6B shows resin surface hardness degradation, following immersion in SHSE or PBS for 0 and 14 days. ** represents significant differences (p < 0.05) in surface hardness from day 0.

Figure 7 shows the cytotoxicity of evaluated resin monomers against human gingival fibroblasts (HGFs) as measured using WST-1 assay. ** represents significant differences (p < 0.05) in MN compared to the negative control culture.

Figure 8A shows the cytostasis observed for each monomer test concentration.

Figure 8B shows he percentage of micronuclei (MN) observed in human gingival fibroblasts (HGFs) following exposure to experimental monomer test concentrations. ** represents significant differences (p < 0.05) in MN compared to the negative control culture.

Figure 9A shows the flexural strength of cured resin composite bar specimens as measured by three-point bending test. In-house methacrylate (MA) composite was formulated using BisGMA and TEGDMA (60:40 wt%) with identical filler loading and type (microfill, 60 wt%) to that of the experimental composite formulated with 60 and 40wt% of 3BE and 3TE, respectively. Commercial control used was 3M Filtek™ Z250 flowable composite.

Figure 9B shows the flexural modulus of cured resin composite bar specimens as measured by three-point bending test. In-house methacrylate (MA) composite was formulated using BisGMA and TEGDMA (60:40 wt%) with identical filler loading and type (microfill, 60 wt%) to that of the experimental composite formulated with 60 and 40wt% of 3BE and 3TE, respectively. Commercial control used was 3M Filtek™ Z250 flowable composite.

Figure 10A shows the microtensile bond strength (pTBS) of composite/dentin bar specimens bonded using both experimental adhesive made with the novel monomers, and compared to a commercial 3-step adhesive systems. Commercial 3-step used was 3M™ Adper™ Scotchbond™.

Figure 10B shows the interfacial fracture toughness (Kic) of composite/dentin miniature short-rod specimens bonded using both the experimental adhesives system, and compared to a commercial 3-step adhesive system both before and following enzymatic aging in simulated human salivary esterase for up to 6 months. Commercial 3-step used was 3M™ Adper™ Scotchbond™.

DETAILED DESCRIPTION

The synthesis of novel functional ester-free vinyl monomers for applications in dentistry are disclosed herein. Although embodiments of the present invention are disclosed herein, the disclosed embodiments are merely exemplary and it should be understood that the invention relates to many alternative forms, including different shapes and sizes. Furthermore, the Figures are not drawn to scale and some features may be exaggerated or minimized to show details of particular features while related elements may have been eliminated to prevent obscuring novel aspects. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting but merely as a basis for the claims and as a representative basis for enabling someone skilled in the art to employ the present invention in a variety of manners.

As used herein, the terms “comprises”, “comprising”, “includes” and “including” are to be construed as being inclusive and open ended, and not exclusive. Specifically, when used in this specification including claims, the terms “comprises”, “comprising”, “includes” and “including” and variations thereof mean the specified features, steps or components are included. These terms are not to be interpreted to exclude the presence of other features, steps or components.

As used herein, the terms “about” and “approximately”, when used in conjunction with ranges of dimensions, compositions of mixtures or other physical properties or characteristics, is meant to cover slight variations that may exist in the upper and lower limits of the ranges of dimensions so as to not exclude embodiments where on average most of the dimensions are satisfied but where statistically dimensions may exist outside this region. It is not the intention to exclude embodiments such as these from the present invention.

As used herein, the coordinating conjunction “and/or” is meant to be a selection between a logical disjunction and a logical conjunction of the adjacent words, phrases, or clauses. Specifically, the phrase “X and/or Y” is meant to be interpreted as “one or both of X and Y” wherein X and Y are any word, phrase, or clause.

The current work aimed to address the challenges of hydrolysis with new biostable monomers that retain or improve upon the physical properties, vinyl group conversion, and polymerization kinetics of commercial monomers currently used in bulk restorative such as BisGMA and TEGDMA, while maintaining compatibility with current clinical workflows. Their development focused on a performance triage which focused on designing around the limitations of previous non-ester based monomers throughout the monomer design stages (Figure 2), as described in recent published work²³.

In the present disclosure the inventors provide novel monomers that are functional, scalable, and clinical practical on multiple facets that have been today ignored in the literature.

Further in the disclosure we provide examples of cured co-polymer systems, filler/monomer composite systems, and diluted resin adhesives systems.

Materials and Methods

The following reagents were purchased from Sigma-Aldrich Canada unless otherwise indicated: Acryloyl chloride (distilled prior to use; A24109), Triethylamine (TEA; T0886), 2,6-di-tert-butyl-4-methylphenol (BHT; B1378), dibutyltin dilaurate (DBTDL; 291234), magnesium sulfate (M7506), camphorquinone (CQ; 124893), 2- (dimethylamino)ethyl methacrylate (DMAEM; 234907), potassium carbonate (K2CO3; P5833), sodium hydroxide (NaOH; 221465), cholesterol esterase (CE, COE-313, Toyobo Co., Ltd., Osaka, Japan), butyrylcholinesterase from equine serum also known as pseudocholinesterases (PCE; C7512-6KU), and 4- nitrophenyl butyrate (p-NPB; N9876). 2,2'-(Ethylenedioxy)bis(ethylamine) (N-TEG; 385506), ethylamine (471208), N,N'-Diethyl-1 ,3-propanediamine (138428), 1 ,2- Bis(2-chloroethoxy)ethane (241628), 1 ,4-Bis(2-hydroxyisopropyl)benzene (BHIB, 255149), 2-(methamino)ethanol (471445), 2-(ethylamino)ethanol (471461), lysine diisocyanate (LDI, Kyowa Yuka, Yokkaichi, Japan), 1 ,3-Bis(1-isocyanato-1- methylethyl)benzene (TMXDI; 409502), Hoechst 33258 (94403) and Acridine orange (AO, A9231).

Acetone, Acetonitrile (MeCN; MS), chloroform (CHCh; dichloromethane (DCM; MS), methanol (MeOH), were purchase from Fisher Scientific and were dried with molecular sieves (MS) as indicated. N-(2-hydroxyethyl)-N-methyl acrylamide (HEMAM)¹⁶, N,N-Dimethyl-1 ,3-bis(acrylamido)propane (DEPBAM) and 1 ,8-Bis(acrylamido)-3,6-dioxaoctane(2TE)²⁴ were synthesized according to the literature.

NMR spectra were recorded on a B-400 spectrometer (Bruker Avance III, 1 H: 400 MHz, 13 C: 101 MHz) using CDCI3, Acetone-d6 (Sigma Aldrich), and DMSO-d6 (Sigma Aldrich) all containing tetramethylsilane (TMS) as an internal standard. Partition coefficients (log P) were calculated for each molecule using ChemDraw (ChemBioDraw Ultra, v14, Perkin Elmer, Waltham, MA, USA).

Synthesis

N-(2-hydroxyethyl)-N-ethyl acrylamide (3EH) precursor:

The synthesis of 3EH was carried out using a method adapted from

Moszner et al. 2007¹⁶. First, a solution of acryloyl chloride (110 mmol) and BHT (30 mg) in dry acetonitrile was cooled to -15°C. Next, a chilled solution of N- methylethanolamine (100 mmol) and triethylamine (105 mmol) in dry acetonitrile was added to the mixture dropwise using an addition funnel and allowed to proceed for 2 hours at -15°C and 1 hour at room temperature. Following the reaction, the white amine hydrochloride salt was filtered off using a Buchner funnel, and the remaining filtrate was collected, evaporated, and stored at 4°C overnight. The resulting residue was then filtered over a glass-fritted funnel and washed thrice (3 x 30 mL) with acetone. The collected filtrate was evaporated and the product was collected as a pale-yellow liquid at - 68% yield. Log P - 0.02.

¹H-NMR (CDCI₃-d6, 400 MHz) 5 6.51-6.73 (1 H, m), 6.24-6.43 (1 H, m), 5.6-5.78 (1 H, m), 4.35 (1 H, s), 3.66-3.79 (2H, m), 3.43-3.6 (4H, m), 1.22 (3H, t)

¹³C-NMR (CDCI₃-d6, 101 MHz) 5 167.28 (C=O), 128.17 (=CH), 127.42 (=CH2), 61.07 (OCH2), 49.30 (NCH2 low), 43.99 (NCH2), 12.62 (CH2CH3)

1,2 Bis(2-ethylamino-ethoxy)ethane (p3TE) precursor:

First, 1 , 2-bis(2-chloroethoxy)ethane (304 mmol) was added slowly to a stirred solution of aqueous ethylamine (70%, 6 mol) and NaCO₃ (450 mmol). The mixture was then stirred and refluxed at 50°C for 24 hours before being evaporated to dryness. The residue was resuspended in MeOH (200 mL) and filtered using a Buchner funnel. The remaining filtrate was collected and evaporated under reduced pressure. The crude product was distilled to purify the product as a yellow liquid at a yield of -60%.

¹H-NMR (DMSO-d6, 400 MHz) 5 3.60-3.49 (8H, m), 2.96-2.87 (4H, m), 2.76-2.86 (4H, m), 1.19 (6H, m)

¹³C-NMR (DMSO-d6, 101 MHz) 5 69.53, 47.42, 42.90, 13.49

3TE:

3TE was synthesized under two-phase Shotten-Baumann conditions. First, p3TE (33 mmol) was added to a chilled round bottom flask in a mixture (2:1) of CHCI₃ and water. Next, acryloyl chloride (94 mmol) dissolved in CHCI₃, and K2CO₃ (13g) dissolved in water were added simultaneously to the stirred reaction vessel at 0°C over 30 minutes. Following an hour under cooling, the reaction was stirred for an additional 2 hours at room temperature. After 2 hours, the organic layer was separated, washed thrice with water (30 mL) and dried with MgSC Following a concentration step under reduced pressure, the crude oil was chromatographed over silica gel to produce the final product at a yield of -74%. Log P: 0.52.

¹H-NMR (CDCI₃-d6, 400 MHz) 5 6.48-6.66 (2H, m), 6.25-6.40 (2H, m), 5.62-5.72 (2H, m), 3.5 (16H, m), 1.19 (6H, m)

¹³C NMR (CDCI₃-d6, 101 MHz) 5 166.02, 127.63, 127.38, 70.80, 69.57, 47.19, 43.99, 12.80.

3T_P, 3TJP, and 3T_B:

The total synthesis and purification of select variants of 3TE with increased degrees of N-alkylation were conducted analogously to 3TE with the exception of chosen alkylating amine using propylamine, isopropylamine, and butylamine for p3T_P, p3T_iP and p3T_B, respectively.

3B-LDI:

First, LDI (21 .86 mmol) and 27.61 mg of DBDL was dissolved in 25 mL of DMAc in a round bottom flask under an inert environment (N2). Next, a solution of BHIB (10.40 mmol) in 25 mL of DMAc was added dropwise and allowed to react for 2 hours at 50°C. Following the diol addition, a solution of N-(2-hydroxyethyl)-N- acrylamide (21 .86 mmol) in 20 mL DMAc was added dropwise to the reaction and the reaction was allowed to progress for an additional 20 hours. The product was isolated through precipitation in cold diethyl ether (2 x 1000 mL) followed by removal of residual solvent under reduced pressure. The product was isolated as a pale-yellow solid at a yield of -39%.

¹H-NMR (DMSO-d6, 400 MHz) 5 7.23-7.44 (4H, m), 5.73-6.39 (6H, m), 4.07-4.12 (4H, m), 3.58-3.61 (8H, m), 3.33-3.36 (6H, s), 2.91-2.97 (6H, m), 1.60-1.70 (10H, br), 1.17-2.36 (14H, br), 1.37-1.17(14H, br), 1 .71-1 .55 (10H, m), 3.00-2.81 (6H, m), 3.36-3.29 (6H, s), 3.67-3.54(8H, m), 4.17-4.02 (6H, m), 6.72-6.69(6H, m), 7.46-7.21 (4H, m)

¹³C-NMR (DMSO-d6, 101 MHz) 5 173.52, 157.55, 154.92, 144.59, 124.17, 123.80, 123.48, 79.13, 70.42, 64.90f, 52.39, 51.65, 40.13, 38.88, 31.87, 31.61 , 29.68, 22.55.

3BM:

The synthesis of 3BM was carried out using methods adapted from the literature¹⁷²⁵ Briefly, TMXDI (28.65 mmol), HEMAM (65.90 mmol), DBDTL (0.11 mmol) and BHT (50 mg) were added to a round bottom flask under a controlled atmosphere glovebox under dry nitrogen gas at 35°C. After 30 hours, the viscous mass was diluted with DCM (250 mL), washed with 0.1 N NaOH and DI Water (3 x 100 mL), and dried with MgSC Following concentration under reduced pressure, the viscous liquid was stored at -20°C until use. Product was isolated at a yield of -64%. Log P: 2.14.

¹H-NMR (CDCI₃-d6, 400 MHz) 5 7.45 (1 H, s), 7.26 (3H, br), 6.50-6.65 (2H, m), 6.24-6.38 (2H, m), 5.62-5.73 (2H, m), 4.12 (4H, s), 3.6 (4H, b), 3.06 (6H, m), 1 .64 (12H, s), 1.16 (6H, s) ¹³C NMR (CDCI₃-d6, 101 MHz) 6 156.13, 147.59, 146.19, 128.65, 128.14, 123.33, 120.51 , 60.91 , 54.97, 47.35, 33.09, 30.34.

3BE:

The synthesis of 3BE follows the methods described for 3BM but replaces the addition of HEMAM with 3EH in the same molar ratio. The resultant product was similarly viscous to 3BM and stored at -20°C until use. Product was isolated at a yield of -71 %. Log P: 2.82.

¹H-NMR (CDCI₃-d6, 400 MHz) 5 7.45 (1 H, s), 7.25 (3H, b), 6.48-6.66 (2H, m), 6.24- 6.40 (2H, m), 5.61-5.73 (2H, m), 4.12 (4H, s), 3.57 (4H, m), 3.44 (4H, m), 1.64 (12H, s)

¹³C NMR (CDCI₃-d6, 101 MHz) 5 166.25, 163.15, 147.07, 131.13, 128.18, 127.53, 123.12, 62.39, 61.77, 53.49, 45.38, 30.88, 12.78.

Resin Preparation and Curing

Single and multi-component resins were prepared in this study. Monomers that are defined as structural included: 3-LDI, 3BM, 3BE, and BisGMA (relative commercial control). Monomers used as diluents included 2TE, DEPBAM, 3TE and TEGDMA (relative commercial control). The multi-component resins evaluated included combinations of 3BE and DEPBAM, 3BE and 3TE, and BisGMA and TEGDMA (Bis/TEGDMA) in a 60:40 structurakdiluent (wt%) ratio. Prior to curing, samples for each resin mixture (500 mg) were combined with photo-initiator components with (0.4 wt % camphorquinone (CQ) and 0.8 wt % of ethyl 4-N,N- dimethyl-aminobenzoate) and stored away from light. For curing, resin mixtures were poured into Teflon™ molds, that were placed between two Mylar™ strips and secured with glass slides. Samples were then cured using a Sapphire Plus (DenMat, Santa Maria CA, USA) curing lamp for 1 minute per side at an irradiance of 2500-2750 mW/cm². Samples were cured as thin discs (diameter 10 mm, height 2 mm) unless otherwise indicated.

Degree of conversion

The degree of conversion (n = 5) was determined using an attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). A Perkin Elmer Spectrum One (Perkin Elmer, Shelton, CT, USA) equipped with a ZnSe/Diamond Crystal Universal ATR accessory (Perkin Elmer) was used at the Analest Facility (Dept, of Chemistry, University of Toronto, Toronto, Canada). Transmission spectra of the unreacted solutions and cured films were acquired by scanning the samples 16 times over a range of 4000-550 cm^-1.

Peak fitting and peak height measurements were performed using GRAMS/AI spectroscopy software (Thermo Scientific, Tewksbury, MA, USA). The vinyl stretches of 1644 cm'¹ and 1638 cm'¹ were used to calculate conversions for acrylamide and methacrylate monomers, respectively. The aromatic C=C stretches at 1608 cm'¹ or amide stretches at 1537 cm'¹ were used as the internal standards depending on the resin system. DC was calculated by evaluating the peak height ratios between unreacted (Ru) and cured resins (Rc). Degree of conversion was then calculated using the following equation: DC (%) = [1 - (Rc/Ru)] x 100.

Water Contact Angle and Water Uptake

Thin discs of sample resin materials were prepared using the same components and methods as described above. The water advancing and receding contact angles were measured on the surface of cured specimens using a contact angle goniometer (NRL Model 100-00, Rame-Hart, Inc., Mountain Lakes, NJ, USA). All measurements were conducted using MilliQ water, deposited using a micro-syringe. The contact angle was measured from both sides of the droplet, with the average of the two constituting a single measurement. For each material, 3 specimens were used with at least 5 drops per specimen. Samples were also characterized for their water uptake. This was assessed using an analytical balance with accuracy of ± 0.0001 g (Mettler AT 201 , Fisher Scientific, USA). Samples (n=5) were immersed in MilliQ water for 48 hours at 37°C. Following immersion, and the degree of water uptake (measured through mass percent swelling) was calculated by weighing cured samples before (w1) and after immersion (w2). Water uptake (S) was calculated using the following equation: S (%) = (w2 - w1) / w1.

Knoop Hardness Testing

The microhardness of resin specimens was carried out using a microhardness tester with a Knoop indenter (Tukon 300, Acco Industries Inc., Wilson instruments division, Bridgeport CT, USA) with an indentation load of 10 g and dwell time of 30 seconds. Indentation sizes were determined using a 10 X objective and measured along the long axis of indentation. Knoop Hardness Numbers (KHN) were calculated by the instrument using the known quantities and calibrations provided by the operator. Reported KHN were representative of five repetitive measurements. The known uncertainty with the testing apparatus is 5%, and reports values to be compared within this study but not across studies (due to the inherent uncertainty across different testing devices from one lab to another). Biodegradation

Media preparation

Simulated human salivary esterase (SHSE) was prepared as a representative oral enzymatic solution by mixing CE and PCE in PBS to obtain a solution possessing 20 units(U)/mL CE and 0.01 U/mL PCE activity, respectively. Prior to biodegradation testing, a study determining the enzymatic stability was conducted to determine replenishment schedules. Based on the stability study, to maintain SHSE activity, media was replaced daily over the first 5 days of incubation and thereafter the media was replenished through the addition of a small volume (1 :10) of concentrated SHSE (56U/ml CE and 0.0175U/ml PCE) every 5th day for the remainder of the incubation period.

Biodegradation - Monomers

Monomers were prepared in MeOH to a concentration of 1 x 10'⁴ M. Monomer solutions were then added to PBS or to SHSE at 2 vol% MeOH. This MeOH content was previously shown not to affect enzyme activity. Protein containing solutions were sterile filtered using a 0.22 pm syringe filter (Millipore SLGP033RS) prior their addition to monomer solutions. At specific time points (0, 1 , 2, and 3 days), 500 pL samples of the incubating solution was collected, replaced, and added to an equal volume of MeOH to denature the enzyme and cease hydrolysis. Samples were filtered using a 0.22 pm syringe filter and the supernatant was then collected and stored at -20°C until UPLC analysis.

Biodegradation - Cured Resins and Composites

Cured resins and composite formulations were prepared in the form of discs as described above. All cured specimens were vacuum dried at 60°C for 24 hours prior to biodegradation analysis. Prior to incubation in either PBS or SHSE, cured samples were pre-incubated in a diluted (1 :10 with DPBS) penicillin-streptomycin solution (Gibco 15140-122) for 48 hours at 37°C to decontaminate samples and minimize subsequent bacterial contamination. This step also readily removes unreacted monomer. Following preincubation, the antibiotic solution was removed and replaced with either 1 mL of PBS or filtered SHSE and incubated at 37°C. At specific time points (1-5, 10, and 14 days) the incubation solution was collected and replaced with 1 mL of fresh DPBS or SHSE depending on the condition. An equal volume of MeOH was added to the withdrawn samples and filtered through a using a 0.22 pm syringe filter. The sample’s supernatant was then stored at -20°C until UPLC analysis. In addition to UPLC analysis, cured specimens were evaluated for biodegradation through post-immersion Knoop hardness. Surface hardness was measured as previously described.

Biodegradation - UPLC Analysis

The degradation products from monomer and cured specimen incubations were analyzed using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), Acquity H-class with C18 column, coupled to a Xevo G2-XS Q-ToF MS with electro-spray ionization source, and quantified with QuanLynx analysis software, all from Waters, Mississauga, ON. The polar mobile phase was prepared from HPLC-grade water (18 MQ resistivity) and HPLC grade solvents which included HPLC grade methanol (Caledon Laboratories LTD, Georgetown, ON, Canada) and 2 mM ammonium acetate 99.999% buffered solution (Aldrich, Milwaukee, Wl, USA). A gradient method used in this study in which A: methanol and B: 10 mM ammonium acetate buffer adjusted to a pH of 3.2 with hydrochloric acid run in isocratic flow of 75% A 25% B for 15 minutes.

To identify resin monomers and degradation chromatograph peaks, a library of standards curves, and UV spectrum profiles were established using pure compounds associated with the resins and their degradation products. BisGMA, MA, 3BE, 3TE and their degradation products were analyzed in this study.

Cytotoxicity and Genotoxicity

Human gingival fibroblasts (HGFs)

HGFs were chosen as a representative cell type for cytotoxicity assessment given their abundant prevalence in gingival tissues. HGFs were cultured at 37°C and 5% CO2 in Dulbecco’s Modified Eagle’s Medium (DMEM; GibcoBRL) supplemented with 10% fetal bovine serum, and 100 U/mL penicillin/streptomycin. The media was changed every 2-3 days with cells being trypsinized at 80-90% confluency.

Sample preparation and setup

For monomeric cyto- and genotoxicity evaluations monomers BisGMA, TEGDMA, 3BE and 3TE were dissolved and prediluted in dimethyl sulfoxide (DMSO). Stock solutions were further diluted with culture media (DMEM) and tested at concentrations of 0.15, 3, 12, and 25 pM with a final concentration of DMSO in culture not exceeding 0.3%.

In addition to monomeric evaluations, the cytotoxicity of cured resin discs (1 mm H x 3 mm D) of both experimental (3BE+3TE) and control (BisTEG) resins was assessed. Prior to cell culture, discs were treated with 70% ethanol at room temperature for 24 h in a 48 well polystyrene plate. Following removal of ethanol after 24 h, the samples were left to air dry for 1 h under a laminar flowhood under sterile conditions. All sample discs were then conditioned with 250 pL of DMEM for 24 h.

Cytokinesis-block Micronucleus (MN) Assay

Measurement of the potential genotoxic effects of control and experimental resin monomers on HGFs was evaluated as follows. HGFs (1 x 10⁵) were pre- attached in a 24 well polystyrene plate for 24 h. Following attachment, cells were subjected to test concentrations of resin monomers diluted with media containing cytokinesis-block reagent cytochalasin-B (3 pg/mL) and incubated for 24 hrs. Following the exposure period, the test media was aspirated, rinsed twice with PBS, and further incubated in growth media supplemented with cytochalasin-B for an additional 24 h. To maintain the fibroblastic cell morphology, cells were fixed directly on the 24 well plates using 5% formalin solution in PBS.

Fixed cells were subjected to dual staining with Hoechst 33258 and Acridine orange (AO) which was found to enable easier differentiation of the boundaries of binucleated cells that improved counting efficiency and accuracy. The frequency of MN were compared to inter-plate media + DMSO controls, where monomer concentrations with statistically greater (p < 0.05) MN to that of the control well were deemed as potentially genotoxic. Cytostasis was also evaluated in parallel based on cytokinesis-block proliferation index (CBPI). Concentrations of monomers that provided cytostasis and cytotoxicity >70% were not included for genotoxic evaluation. Positive controls included a known genotoxic aneugen (colchicine, 0.05 pM), and negative controls were those containing the same volume of DMSO (0.05 vol%) in growth media.

Cell Viability Assays

The viability of HGFs exposed to control and experimental monomers was evaluated to establish an appropriate concentration range for genotoxic evaluations. HGFs (2 x 10⁴) were pre-attached to a 96 well plate for 24 h. Following attachment, cells were subjected to test concentrations of resin monomers diluted with media and incubated for 24 hrs. For cured resin specimens, the viability HGFs cultured was evaluated by adding 150 pL of HGF cell suspension (2 x 10⁴) to each preconditioned well for 48 hrs. For both sets of experiments, positive control wells were included with 20 vol% DMSO, and negative control wells contained and media with 0.05 vol% DMSO. Both experiments were repeated three times (n = 12 per formulation in total).

Water-soluble tetrazolium (WST)-1 assay

To evaluate the cytotoxicity of resin monomers and cured resin discs, the metabolic activity of HGFs was quantified using a WST-1 assay (Roche Diagnostics, Laval, Quebec, Canada). First, the WST-1 reagent was prepared in a 1 :10 dilution with DMEM. Following aspiration of the media from each well, 10 pL of WST-1 solution was added to the 96-well plate. The plate was then incubated at 37°C with 5% CO2 for 1 h. Following incubation, the plate was read using the VersaMax™ tunable microplate reader at an absorbance of 450 nm and a background reading of 650 nm. The absorbance from the control wells was subtracted from all readings.

Statistical Analysis

Statistical analysis was performed using Graphpad Prism Software v 8.3.2 (GraphPad Software, San Diego, California, USA). All data were, first, evaluated for normality using a Shapiro-Wilk test, before groupwise comparisons using one-way ANOVA, and post-hoc analysis using Tukey’s test with all tests being performed at a significance level of a = 0.05. All data are reported as mean ±standard deviation (SD).

Results and Discussion

Synthesis and Formulation

In this work, novel acrylamide monomers were conceptualized, and successfully synthesized in a reproducible manner. Preliminarily functional performance was investigated (Figure 2). Acrylamides were chosen as prospective crosslinking moieties due to their greater resistance to hydrolysis compared to their acrylate analogs. This is driven by the fundamental chemical state of compounds bearing carbonyl (C=O) groups, where the adjacent substituents greatly effect the rate of hydrolytic cleavage. Higher substituted tertiary amides have proven even more difficult to hydrolyze and often require stronger conditions when compared to primary and secondary amides²⁶. This trait of amide-containing moieties (such as in the case of acrylamides) has been utilized consistently for pharmaceutical agents and biomedical devices to modulate drug release and degradation rate²⁷²⁸. For the design of dental resin monomers, which should ideally have a lifespan longer than that of the patient, the use of optimally stable tertiary acrylamides should provide minimal reactivity via catalyzed hydrolysis. Additionally, acrylamides were chosen over methacrylamides as methacrylamides would preclude the use of the stable tertiary amide moieties, given their ability to effect reactivity due to steric effects.

Initial characterization of monomers involved a screening of defined properties, involving chemical state, structure, purity, and monomer miscibility. Structural monomers were assessed for their ability to be miscible or soluble (depending on physical state) with developed diluent monomers. Diluent monomers were assessed for their physical state - as they would only be practical for clinical use if in a flowable state. Monomers 3BM, 3BE, 3TE and DEPBAM were fluid at room temperature and miscible with one another, forming clear liquid states.

2TE was synthesized to evaluate the physical differences between secondary (2TE) and tertiary (3TE) acrylamides, but each having similar backbones. 2TE, a secondary acrylamide with two H-bonding sites proved to be solid at room temperature, whereas 3TE was a low viscosity fluid at room temperature. The state difference of these two monomers illustrates the importance N-alkylation in the development of acrylamide-based diluents.

The structural monomer 3BLDI was a solid at room temperature and poorly soluble in all acrylamide diluents. The solid nature of the monomer was attributed to its strong H bonding character and bulky structure.

Based on the above practical analysis, both 2TE and 3BLDI were precluded from the remainder of the characterization studies as they were both solids at room temperature and poorly miscible with the other acrylamide monomers, failing the first stage of our screening protocol²³.

Degree of Conversion

The degree of double bond conversion (DC) was used to assess the network formation for cured resin specimens developed in this study. A low DC is indicative of poor network formation and may lead to poor mechanical properties and monomer leaching from cured materials. It has been well documented that the advancement of novel clinical dental materials has been challenged by trying to advance candidate materials that had poor potential for readily achieving good DC²³. The degree of conversion for eight synthesized resin combinations were evaluated and are summarized in Figure 3A. All single component resins had a statistically similar (p > 0.05) DC (69-77%), despite their varying chemistries. Resins composed solely of bulky structural monomers (such as 3BM and 3BE) were quite viscous and were anticipated, based on previous literature, to exhibit poor monomer mobility during curing²⁹. On the other hand, resins composed solely of highly flowable diluent monomers (TEGDMA (commercial control), DEPBAM, 3TE) were expected to show a rapid onset of vitrification which would also limit high DC. Multi-monomer resins are featured in almost all commercial resin-based products in order to tailor handling characteristics, curing performance, and the final properties of cured resin specimens. Accordingly, two component resins (Bis/TEGDMA (commercial control), 3BE + DEPBAM, 3BE + 3TE) consisting of structural and diluent monomers were evaluated as well. While the combination resin 3BE + DEPBAM cured similarly (70%, p > 0.05) to its single monomer constituents, 3BE + 3TE had a statistically higher DC (87%), when compared to its single monomer constituents (p < 0.05). The increase in DC found with the multimonomer 3BE+3TE resin can be explained by the increased molecular mobility and delayed vitrification found, contributed from 3TE, when combining suitable structural and rigid monomers. This effect has previously been reported on when blending MA monomers such as BisGMA, where the addition of diluents (such as TEGDMA) has increased the DC of cured materials. In the current study, a higher average DC for Bis/TEGDMA (84%) (60:40 ratio of BisGMA and TEGDMA respectively) was observed when compared to the single component resin TEGDMA (76%), although the results were not statistically significant.

Increasing the degree of alkylation of 3AA structures beyond ethyl (propyl, isopropyl, and butyl, for 3T_P, 3T_iP and 3T_B, respectively) led to a similar degree of double bond conversion as 3TE, with the exception of 3T_P (Figure 3B). Despite the similar degree of conversion, qualitatively these polymerized materials were significantly more “gel-like”, likely due to lower intermolecular bonding with the added alkylation (summarized in TABLE 1 below). Such materials were precluded from the remainder of this study but may be useful in other applications.

TABLE 1

Water Contact Angle and Water Uptake

Dental restoratives are applied in hydrated environments, therefore, developed resin specimens should be evaluated for the interactions with water. In this study, hydrophilicity was used as a proxy to evaluate the surface energy presented by cured materials, and water uptake was used to evaluate resin network stability in hydrated environments (Figure 4A and 4B). Highly wettable materials can promote surface pellicle and bacteria colonization, and materials that take up excessive water are more susceptible to monomer leaching and compromised mechanical properties.

Single component resins specimens of DEPBAM and 3BM presented the most wettable surfaces and the highest degree of water uptake, with an average WCA of 29 and 32°, and average water uptake of 22 and 21 %, respectively. 3BE was the most water-stable single component resin evaluated, presenting a WCA and water uptake (43° and 3%, respectively) (p > 0.05) similar to MA resin specimens Bis/TEGDMA, and TEGDMA. The two-component resin 3BE+3TE presented the highest WCA (54°) and lowest water uptake (3%) of the resins developed in this study, also performing similarly to MA resin specimens. Conversely, two-component resin specimens composed of 3BE + DEPBAM, while presenting a moderate WCA (37°), expressed a high degree of water uptake (16%), despite being blended with the most hydrophobic monomer being tested. The high water uptake and hydrophilicity of DEPBAM-containing resins has previously been found³⁰. Under conditions of high water uptake, resin materials are plasticized allowing for the penetration of water into the bulk polymeric network.

The extent and rate of plasticization is related to both the density of the polymeric network and to the addition of hydrophilic/polar chemistries, which was shown to lead to increased sorption through “water treeing”. For this reason, resin compositions comprising of 3BM and/or DEPBAM were excluded from subsequent evaluations due to their high swelling and general affinity for water, which makes them unsuitable for use in bulk resin restorative or adhesive materials. The decreased water uptake experienced by the 3BE + 3TE resin can be explained by both the hydrophobic alkyl core of 3BE and, the high crosslinking density (DC) of the combination resin. Given the enhanced performance of the 3BE and 3TE resins, the remainder of this study focused on the development of resin formulations comprised of these favorable monomers.

Knoop Surface Hardness

Bulk restoratives are subjected to the forces of mastication which can exceed over 700 N³¹. Therefore, the durability and resistance to wear are an important design criteria. Measures of surface hardness have been shown to correlate well with several properties of cured resins including DC, abrasion resistance, and compressive strength. In this work the Knoop microhardness values (KHV) of cured resin specimens were used as a proxy for the potential mechanical properties of cured resin specimens. The surface hardness values of the five resin specimens evaluated are summarized in Figure 5. The two component resins Bis/TEGDMA and 3BE+3TE had KHV of 31 and 36, respectively. These resins had statistically higher KHV (p < 0.05) than the single component diluent resins of TEGDMA and 3TE, that had an average KHV of 17 and 16, respectively. This was in agreement with theoretical predictions based on the potential for polymer chain interactions and freedom to move under applied force, as the two component resins had statistically higher DC when compared to their one component diluent resins. Along with an increased DC, the addition of structurally rigid monomers (such as BisGMA and 3BE) to resin blends has been shown to increase surface hardness. Despite the increased rigidity of the monomer structure, single component 3BE resins had statistically similar (p > 0.05) hardness (23 KHV) to that of flexible single component 3TE resins and TEGDMA, and this can be most likely explained by their statistically similar DC.

Biodegradation

Several studies have shown that the esterase levels present in human saliva are capable of catalyzing the degradation of MA-based restoratives^32-34. Degradation of such cured resin specimens has been shown to render the materials more prone to mechanical wear, as a result of surface softening. Over time, through progressive surface wear, subsequent layers of restorative materials are exposed to saliva, resulting in further chemical degradation and surface softening. This progressive wear can lead to breakdown at the marginal interface of the restorative, allowing for the microleakage of bacteria into the restorations’ margins; shown to be accelerated by infiltration of salivary enzymes. In this work, the effect of SHSE on newly developed monomers and cured resins specimens was evaluated and compared to MA-derivatives controls (Figures 6A and 6B). Monomers subjected to SHSE were assessed for their degradation and degradation by-products using UPLC. For cured resin specimens, the hardness was evaluated pre- and post-immersion as a measure of surface softening.

All developed 3AA systems remained biostable under enzymatic challenges (Figures 6A and 6B). Compared to the control MA monomer BisGMA, 3AA monomers (3BE and 3TE) remained stable following SHSE enzymatic challenge over a 3-day period whereas the control MA monomer (BisGMA) had < 5% of residual monomer remaining following just 2-days immersion in SHSE (Figure 6A). This was in line with the published literature, as numerous studies have shown the breakdown of BisGMA in the presence of esterases produces BisHPPP, the degradation product at the MA junction (Figure 1). BisHPPP was the primary degradation product of BisGMA, whereas both 3BE and 3TE presented no major degradation products.

Further, the 3AA cured resins displayed no decrease in surface hardness following 14-day immersion in SHSE, whereas the control BisGMA/TEGDMA system experienced >90% decrease in surface hardness during the same incubation period (Figure 6B).

Cytotoxicity and Genotoxicity

Several studies have been established for both the potential cyto- and genotoxic effects of contemporary dental resin monomers and polymer degradation products on human cell lines. Both evaluation metrics provide justification for resin biocompatibility - lending to their ability to measure the irreversible disturbance of cellular function. In restorative dentistry, HGFs have been commonly utilized as a model cell line to compare and quantify the toxicities of such resin substances given their physiological proximity to both eluted monomers and degradation by- products from restorative materials in vivo. However, HGF cultures isolated from different human donors have been shown to have different absolute sensitivities to resin monomers - necessitating the evaluation of toxicity thresholds of well studied monomers (such as BisGMA and TEGDMA) in addition to experimental systems before conducting genotoxic studies³⁵.

The cytotoxic effects of resin monomers were evaluated using a metabolic WST-1 assay (Figure 7). There was no significant difference (p > 0.05) between the experimental groups and the growth media control culture for the cured resin discs the metabolic activity of cells was assayed in parallel with DNA content as a measure of cell growth, independent of metabolic changes to control for potential cell interactions with the cured resin discs. The cellularity (DNA content) of the samples’ wells was expressed as a percent of growth media control culture. All sample wells had statistically similar DNA content and were clearly differentiated from the DMSO control (data not shown).

The genotoxic effects of resin monomers on HGFs were assessed using a well-established MN assay. The dual-staining method employing both Hoechst 33258 and Acridine Orange stains enabled both accurate and efficient visible identification of fixed bi- and multinucleated HGFs. All monomers evaluated presented a dose-dependent cytostatic response following a 24-hour exposure period (Figure 8A). While elevated levels of MN (compared to control) were found for both BisGMA and TEGDMA following exposure, only BisGMA displayed a dosedependent increase in MN frequency with elevated concentrations being statistically different (p < 0.05) from that of the negative control well (Figure 8B, 12 and 25 pM). BisGMA has been previously identified as a potential genotoxic agent, being shown to cause elevated cytotoxicity and genotoxicity to that of other traditionally used water-soluble MA monomers such as TEGDMA. Both experimental monomers (3BE and 3TE) did not present a dose-dependent or statistically greater MN frequency at any tested concentrations following 24-hour exposure period indicating that they are unlikely to be genotoxic.

Monomers were developed based on ester-free and hydrolytically stable chemistries which could be used in the development of novel resin formulations and their related composites. Two of the developed monomers (3BE and 3TE) showed significant promise as alternative resins to that of MA controls BisGMA and TEGMDA. 3BE+3TE resins cured resins had statistically similar (p < 0.05) DC, WCA, water uptake, surface hardness, and cytocompatibility compared to traditional MA derivatives controls, but were far more stable in the presence of SHSE. 3BE and 3TE monomers remained stable and cured resin specimens maintained surface hardness under enzymatic challenge, whereas MA controls suffered significant monomer and surface degradation.

Monomers developed in this study were found to be less cytotoxic than BisGMA (p < 0.05) and are unlikely to be genotoxic at all tested concentrations (Figure 7). Therefore, the biostable resins developed in this study have the potential to significantly improve the clinical service life of restorative materials (composites, fissure sealants, adhesives, and other different formulations of dental materials containing such monomeric or oligomeric resins) by minimizing surface degradation, and potentially delaying the propensity for oral micro-organism infiltration within tooth structures and restoration, without compromising the most fundamental design aspects of the resins (DC; water uptake; hardness; handling; reproducibly synthesizable; biostability)²³. On-going work is investigating the stability of these resin specimens and composites when subjected to biofilm stress and mechanical testing protocols such as three-point bending studies. Examples of formulations for resins in typical practical use within the dental practice are provided in the form of some composite and adhesive systems (Figures 9A, 9B, 10A, and 10B below) but by no means restrict the use of the invented materials to such applications. Another example of dental materials formulations that contain resins blended with a range of other agents includes fissure sealants, see https://www.ada.org/en/resources/research/science-and-research-institute/oral-health- topics/dentai-seaiants which range in concentrations of monomeric/oligomeric resins to achieve very low viscosity materials that can penetrate into the crevices of tooth surface fissures, typically in one of three formulation types: 1 ) Resin modified glass ionomers (composites or resins containing classical fluoride based glass ionomers, typically with more ionomer than resin component); 2) Poly-acid modified resins, where monomers of the type described in this current disclosure are covalently coupled to the ionomeric oligomers; 3) pure composite resin based systems which contain little or no ionomeric materials, are formulated with resins of types described in this disclosure, but have antimicrobial agents such as fluoride releasing agents within them, and very low (<50% by weight), depending on the formulation.

Monomers used in composites (filler+experimental resins) yield comparable flexural strength and flexural modulus (measured by three-point bending test) to those of an in-house simulation of commercial monomers (In-house methacrylate (MA) composite was formulated using BisGMA and TEGDMA) with identical filler loading and type (microfill, 60 wt%) to that of the experimental composite. This indicates that by incorporating the new low-hydrolysable monomers we did not compromise flexural and strength and modulus of the composites. (Figures 9A and 9B).

Monomers used in adhesive system examples of the invention, i.e. experimental adhesive (EA), made from 3BE/3EM/3TE (50/10/40) + EtOH (20%), showed statistically similar (p > 0.05) pTBS and IFT to that of the commercial adhesive system (AS), indicating that by incorporating the new low-hydrolysable monomers we did not compromise adhesive strength and illustrated improved bonding performance over long-term physiologically relevant enzymatic aging. (Figs 10A and B).

According to an embodiment, the novel monomeric compound has the genus structure of formula (I), wherein R1 and R2 are independently alkyl and X1 has either structure (A) or structure (B):

Formula (I) According to an embodiment, R1 and R2 may be independently C1 , C2, C3 or C4 alkyl. The alkyl may be linear or branched. Furthermore, R1 and R2 may be distinct or alternatively the same alkyl.

According to an embodiment, R1 and R2 are C1 alkyl and X1 is A resulting in compound 3BM.

According to an embodiment, R1 and R2 are C2 alkyl and X1 is A resulting in compound 3BE.

According to an embodiment, R1 and R2 are C1 alkyl and X1 is B resulting in compound 3BLDI.

According to an embodiment, R1 and R2 may be C2 and X1 may be B resulting in the following compound.

According to an embodiment, R1 and R2 may be C3 and X1 may be A resulting in the following compound.

According to an embodiment, R1 and R2 may be linear C4 and X1 may be A resulting in the following compound.

According to an embodiment, R1 and R2 may be branched C4 and X1 may be A resulting in the following compound.

According to an embodiment, R1 and R2 may be C3 and X1 may be B resulting in the following compound.

According to an embodiment, R1 and R2 may be linear C4 and X1 may be B resulting in the following compound,

According to an embodiment, R1 and R2 may be branched C4 and X1 may be B resulting in the following compound.

According to an embodiment, the novel monomeric compound has the genus structure of formula (II), wherein R1 and R2 are independently alkyl and n is in a range from 1 to about 5.

Formula (II)

According to an embodiment, R1 and R2 may be independently C1 , C2, C3 or C4 alkyl. The alkyl may be linear or branched. Furthermore, R1 and R2 may be distinct or alternatively the same alkyl.

According to an embodiment, R1 and R2 are C2 alkyl and n is 2 resulting in compound 3TE

According to an embodiment, R1 and R2 may be C1 alkyl and n may be 1 resulting in the following compound.

According to an embodiment, R1 and R2 may be C1 alkyl and n may be 2 resulting in the following compound.

According to an embodiment, R1 and R2 may be C1 alkyl and n may be 3 resulting in the following compound.

According to an embodiment, R1 and R2 may be C1 alkyl and n may be 4 resulting in the following compound.

According to an embodiment, R1 and R2 may be C1 alkyl and n may be 5 resulting in the following compound.

According to an embodiment, R1 and R2 may be C2 alkyl and n may be 1 resulting in the following compound.

According to an embodiment, R1 and R2 may be C2 alkyl and may be 2 resulting in the following compound.

According to an embodiment, R1 and R2 may be C2 alkyl and may be 3 resulting in the following compound.

According to an embodiment, R1 and R2 may be C2 alkyl and may be 4 resulting in compound:

According to an embodiment, R1 and R2 may be C2 alkyl and n may be 5 resulting in the following compound.

According to an embodiment, R1 and R2 may be C3 alkyl and n may be 1 resulting in the following compound.

According to an embodiment, R1 and R2 may be C3 alkyl and n may be 2 resulting in the following compound.

According to an embodiment, R1 and R2 may be C3 alkyl and n may be 3 resulting in the following compound.

According to an embodiment, R1 and R2 may be C3 alkyl and n may be 4 resulting in the following compound.

According to an embodiment, R1 and R2 may be C3 alkyl and n may be 5 resulting in compound:

According to an embodiment, R1 and R2 may be linear C4 alkyl and n may be 1 resulting in the following compound.

According to an embodiment, R1 and R2 may be linear C4 alkyl and n may be 2 resulting in the following compound.

According to an embodiment, R1 and R2 may be linear C4 alkyl and n may be 3 resulting in the following compound.

According to an embodiment, R1 and R2 may be linear C4 alkyl and n may be 4 resulting in the following compound.

According to an embodiment, R1 and R2 may be C4 linear alkyl and n may be 5 resulting in the following compound.

According to an embodiment, R1 and R2 may be branched C4 alkyl and n may be 1 resulting in the following compound.

According to an embodiment, R1 and R2 may be branched C4 alkyl and n may be 2 resulting in the following compound.

According to an embodiment, R1 and R2 may be branched C4 alkyl and n may be 3 resulting in the following compound.

According to an embodiment, R1 and R2 may be branched C4 alkyl and n may be 4 resulting in the following compound.

According to an embodiment, R1 and R2 may be C4 branched alkyl and n may be 5 resulting in the following compound.

According to an embodiment, although not schematically illustrated, the monomers of formula I and formula II may have R1 or R2 that are distinct from each other. According to an embodiment, a dental resin may comprise at least one monomeric compound of Formula I and/or one monomeric compound or formula II.

According to an embodiment, a dental resin may comprise at least one monomeric compound of Formula I in combination with one monomeric compound of Formula II. According to an embodiment, the dental resin comprises at least one monomeric compound of Formula I selected within the group consisting of

In combination with

According to an embodiment, the dental resin may comprise 3BM alone, 3BE alone, 3BLDI alone, combination of 3BM and 3BE, combination of 3BM and 3BLDI, combination of 3BE and 3BLDI or combination of 3BM, 3BE and 3BLDI.

According to an embodiment, the dental resin may comprise at least one monomeric compound of formula I 1 is 3BE, 3TE or a combination thereof.

According to an embodiment, the dental resin may further comprise one or more polymerization initiators.The polymerization initiators may be selected from the the group of camphorquinone (CQ); trimethylbenzoyl-diphenyl-phosphine oxide (TPO); Ethyl-4-dimethylamino benzoate (EDMAB); 2,2-Dimethoxy-2- phenylacetophenone (DMPA); Bisacylphosphine oxide (BAPO); 1-Phenyl-1 ,2- propanedione (PPD); phosphine oxide compounds, including naphthacene (APO), 9-anthracene (APO), and bisacylphosphine oxide (BAPO); 1 -phenyl-1 ,2- propanedione (PPD); thioxanthone (TX) and its derivatives; a dibenzoyl germanium derivative, benzoyltrimethylgermane (BTG), dibenzoyldiethylgermane; hexaarylbiimidazole derivatives; a silane based derivative;

(diethylgermanediyl)bis((4-methoxyphenyl)methanone); benzenesulfinic acid sodium salt (BS); a diaryliodonium salt, diphenyliodonium chloride or iodonium salt [diphenyliodonium hexafluorophosphate (DPIHP or DPI-PF6))], bromide, iodide, or hexafluorophosphate; and benzoyl peroxide (BPO).

According to another embodiment, the one or more polymerization initiators may be combination of polymerization initiators selected from the group consisting of of camphorquinone/ethyl-4-(dimethylamino)benzoate (EDMAB), camphorquinone/2-(dimethylamino)ethyl methacrylate (DMAEMA)), DMPA/DPI- PF6, CQ/PPD, CQ/DMAEMA, CQ/EDMAB, CQ/DMAEMA/PDIHP, CQ/EDMAB/DPIHP or initiators containing ,bis-(4-methoxybenzoyl)diethyl germane, or phenylbis(2,4,6-trimethylbenzoyl) phosphine oxide (BAPO).

According to an embodiment, the dental resin may further comprise at least one polymerization inhibitor and/or stabilizer. The one or more polymerization inhibitors are selected from the group consisting 4-tert-butylcatechol (TBC), 4- methoxyphenol (MEHQ), butylated hydroxytoluene (BHT) and hydroquinone (HQ), inhibitors of the class of phenols, aryl amines, phenylenediamines, N,N- dialkylhydroxylamines, m-nitro-p-cresol, 2,6-dinitro-p-cresol, and nitroxides,

2.2.6.6-tetramethylpiperidin- 1 -yl)oxyl or (2, 2, 6, 6-tetramethylpiperidin- 1 - yl)oxidanyl),2,4-dinitrophenol (DNP) and 2,4-dinitro-6-sec-butyl phenol (DNBP), and wherein the one or more stabilizers are selected from the group consisting of

2.6-di-tert-butyl-p-cresol, hydroquinone, 4-methoxyphenol, 4-tert- butylpyrocatechol,tert-butylhydroquinone,n2-tert-butyl-1 ,4-benzoquinone, copper(ii) dibutyldithiocarbamate, 2,6-di-tert-butylphenol, 2-[1-(2-hydroxy-3,5-di-tert- pentylphenyl)ethyl]-4,6-di-tert-pentylphenyl acrylate, phenothiazine, 1 , 1 -diphenyl-2- picrylhydrazyl free radical, 1 ,4-benzoquinone, 6-tert-butyl-2,4-xylenol. According to an embodiment, the dental resin composition may further comprise plurifuntionalized methacrylate monomers and/or methacrylate oligomers. According to another embodiment, the plurifunctionalized methacrylate monomers may be dental-based plurifunctionalized methacrylate monomers. The dental based plurifuntionalized methacrylate monomers may be any one or combination of bisphenol A-glycidyl methacrylate (BisGMA), ethoxylated bisphenol A glycol dimethacrylate (BisEMA), urethane dimethacrylate (UDMA), triethylene glycol dimethacrylate (TEGDMA), 2-hydroxyethyl methacrylate (HEMA).

According to an embodiment, the dental resin may be combined with a solvent resulting in a dental adhesive composition. The solvent may be any one or combination of water, ethanol, acetone, DMSO.

According to an embodiment, filler materials may be combined with the dental resin resulting in a dental filler composite. The filler materials may be inorganic filler materials, organic filler materials or a combination thereof.

According to an embodiment, a dental adhesive composition may comprise at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

one or more polymerization initiators, at least one polymerization inhibitor and/or stabilizer; dental based plurifuntionalized methacrylate monomers and/or methacrylate oligomers; and a solvent.

According to an embodiment, the dental adhesive composition may further comprise a monomeric compound of formula (II):

According to an embodiment, a dental filler composite may comprise at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

one or more polymerization initiators; at least one polymerization inhibitor and/or stabilizer, dental based plurifuntionalized methacrylate monomers and/or methacrylate oligomers and inorganic and/or organic filler materials.

According to an embodiment, the dental filler may further comprise a monomeric compound of formula (II):

According to an embodiment, the dental resin composition may be combined with a solvent resulting in a dental sealant composition. The dental sealant composition may further comprise up to 60 wt% or less of inorganic and/or organic filler materials. Alternatively, the dental sealant composition may comprise fillers in the amount of 50% or less, 40% or less, 30% or less, 20 % or less, 10% or less, or 5% or less. According to an embodiment, a dental sealant composition may comprise at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

(A), or

one or more polymerization initiators, at least one polymerization inhibitor and/or stabilizer, dental based plurifuntionalized methacrylate monomers and/or methacrylate oligomers, and a solvent. According to an embodiment, the dental sealant may further comprise a monomeric compound of formula (II):

wherein O is oxygen, N is nitrogen, R1 and R2 are alkyl; and n is in a range from 1 to about 5. According to an embodiment, the dental sealant composition may further comprise up to 60 wt% or less of inorganic and/or organic filler materials. Alternatively, the dental sealant composition may comprise fillers in the amount of 50% or less, 40% or less, 30% or less, 20 % or less, 10% or less, or 5% or less. The skilled person in the field will understand that the various formulations comprising monomers of formula I and/or formula II may be tailored/adjusted using the general knowledge in the art such as disclosed in the following references: Phillips' Science of Dental Materials, 13th Edition by Chiayi Shen, H. Ralph Rawls and Josephine F. Esquivel-Upshaw (2022); Delaviz Y, et al. (2014) Dental Materials, 30(1): 16-32 entitled Biodegradation of resin composites and adhesives by oral bacteria and saliva: A rationale for new material designs that consider the clinical environment and treatment challenges; Bourbia M, Finer Y, (2018) J Can Dent Assoc;84 (11) entitled Biochemical Stability and Interactions of Dental Resin Composites and Adhesives with Host and Bacteria in the Oral Cavity: A Review;

Stewart CA, Finer Y (2019) Dental Materials, 35(1): 36-52 entitled Biostable, antidegradative and antimicrobial restorative systems based on host-biomaterials and microbial interactions; and Desai H et al, (2021) Dent. J.9(12), 147 entitled Minimally Invasive Therapies for the Management of Dental Caries — A Literature Review which are here incorporated by reference to the current description of the present invention.

Embodiments

Embodiment 1 . A monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

Embodiment 2. The monomeric compound of embodiment 1 wherein R1 and

R2 are different alkyl.

Embodiment 3. The monomeric compound of embodiment 1 wherein R1 and

R2 are the same alkyl.

Embodiment 4. The monomeric compound of embodiment 1 wherein R1 and

R2 are independently C1 , C2, C3 or C4 alkyl.

Embodiment 5. The monomeric compound of embodiment 1 , wherein for R1 and R2 are C1 and X1 is (A), the compound is:

Embodiment 6. The monomeric compound of embodiment 1 , wherein for R1 and R2 are C2 and X1 is (A), the compound is:

Embodiment 7. The monomeric compound of embodiment 1 , wherein for R1 and R2 are C1 and X1 is (B), the compound is:

Embodiment 8. The monomeric compound of embodiment 1 , wherein for R1 and R2 are C2 and X1 is (B), the compound is:

Embodiment 9. The monomeric compound of embodiment 1 , wherein for R1 and R2 are C3 and X1 is (A), the compound is:

Embodiment 10. The monomeric compound of embodiment 1 , wherein for R1 and R2 are linear C4 and X1 is (A), the compound is:

Embodiment 11 . The monomeric compound of embodiment 1 , wherein for R1 and R2 are branched C4 and X1 is (A), the compound is:

Embodiment 12. The monomeric compound of embodiment 1 , wherein for R1 and R2 are C3 and X1 is (B), the compound is:

Embodiment 13. The monomeric compound of embodiment 1 , wherein for R1 and R2 are linear C4 and X1 is (B), the compound is:

Embodiment 14. The monomeric compound of embodiment 1 , wherein for R1 and R2 are branched C4 and X1 is (B), the compound is:

Embodiment 15. A monomeric compound of formula (II):

wherein O is oxygen, N is nitrogen, R1 and R2 are alky, and n is in a range from 1 to about 5. Embodiment 16. The monomeric compound of embodiment 15 wherein R1 and

R2 are independently C2, C3, C4 alkyl.

Embodiment 17. The monomeric compound of embodiment 16 wherein R1 and R2 are different alkyl.

Embodiment 18. The monomeric compound of embodiment 16 wherein R1 and R2 are the same alkyl.

Embodiment 19. The monomeric compound of embodiment 15 wherein R1 and

R2 are C2 alkyl and n is 2, the compound is:

Embodiment 20. The monomeric compound of embodiment 15 wherein R1 and

R2 are C1 alkyl and n is 1 , the compound is:

Embodiment 21 . The monomeric compound of embodiment 15 wherein R1 and

R2 are C1 alkyl and n is 2, the compound is:

Embodiment 22. The monomeric compound of embodiment 15 wherein R1 and

R2 are C1 alkyl and n is 3, the compound is:

Embodiment 23. The monomeric compound of embodiment 15 wherein R1 and

R2 are C1 alkyl and n is 4, the compound is:

Embodiment 24. The monomeric compound of embodiment 15 wherein R1 and

R2 are C1 alkyl and n is 5, the compound is:

Embodiment 25. The monomeric compound of embodiment 15 wherein R1 and

R2 are C2 alkyl and n is 1 , the compound is:

Embodiment 26. The monomeric compound of embodiment 15 wherein R1 and

R2 are C2 alkyl and n is 2, the compound is:

Embodiment 27. The monomeric compound of embodiment 15 wherein R1 and

R2 are C2 alkyl and n is 3, the compound is:

Embodiment 28. The monomeric compound of embodiment 15 wherein R1 and

R2 are C2 alkyl and n is 4, the compound is:

Embodiment 29. The monomeric compound of embodiment 15 wherein R1 and R2 are C2 alkyl and n is 5, the compound is:

Embodiment 30. The monomeric compound of embodiment 15 wherein R1 and

R2 are C3 alkyl and n is 1 , the compound is:

Embodiment 31. The monomeric compound of embodiment 15 wherein R1 and

R2 are C3 alkyl and n is 2, the compound is:

Embodiment 32. The monomeric compound of embodiment 15 wherein R1 and

R2 are C3 alkyl and n is 3, the compound is:

Embodiment 33. The monomeric compound of embodiment 15 wherein R1 and

R2 are C3 alkyl and n is 4, the compound is:

Embodiment 34. The monomeric compound of embodiment 15 wherein R1 and

R2 are C3 alkyl and n is 5, the compound is:

Embodiment 35. The monomeric compound of embodiment 15 wherein R1 and R2 are linear C4 alkyl and n is 1 , the compound is:

Embodiment 36. The monomeric compound of embodiment 15 wherein R1 and

R2 are linear C4 alkyl and n is 2, the compound is:

Embodiment 37. The monomeric compound of embodiment 15 wherein R1 and

R2 are linear C4 alkyl and n is 3, the compound is:

Embodiment 38. The monomeric compound of embodiment 15 wherein R1 and

R2 are linear C4 alkyl and n is 4, the compound is:

Embodiment 39. The monomeric compound of embodiment 15 wherein R1 and

R2 are linear C4 alkyl and n is 5, the compound is:

Embodiment 40. The monomeric compound of embodiment 15 wherein R1 and

R2 are branched C4 alkyl and n is 1 , the compound is:

Embodiment 41 . The monomeric compound of embodiment 15 wherein R1 and R2 are branched C4 alkyl and n is 2, the compound is:

Embodiment 42. The monomeric compound of embodiment 15 wherein R1 and

R2 are branched C4 alkyl and n is 3, the compound is:

Embodiment 43. The monomeric compound of embodiment 15 wherein R1 and

R2 are branched C4 alkyl and n is 4, the compound is:

Embodiment 44. The monomeric compound of embodiment 15 wherein R1 and

R2 are branched C4 alkyl and n is 5, the compound is:

Embodiment 45. A dental resin composition comprising at least one monomeric compound of embodiment 1 and/or embodiment 15.

Embodiment 46. The dental resin of embodiment 13 comprising at least on monomeric compound of embodiment 1 and the compound of embodiment 15.

Embodiment 47. The dental resin of embodiment 46 wherein the at least one monomeric compound of embodiment 1 is selected within the group consisting of

the compound of embodiment 15 is

Embodiment 48. The dental resin of embodiment 47 wherein the at least one monomeric compound of embodiment 1 is 3BM alone, 3BE alone, 3BLDI alone, combination of 3BM and 3BE, combination of 3BM and 3BLDI, combination of 3BE and 3BLDI or combination of 3BM, 3BE and 3BLDI.

Embodiment 49. The dental resin of embodiment 48 wherein the at least one monomeric compound of embodiment 1 is 3BE, 3TE or a combination thereof. Embodiment 50. The dental resin composition of embodiment 15 further comprising one or more polymerization initiators.

Embodiment 51 . The dental resin composition of embodiment 50, further comprising at least one polymerization inhibitor and/or stabilizer.

Embodiment 52. The dental resin composition of embodiments 50 or 51 , wherein the one or more polymerization initiators are selected from the group of camphorquinone (CQ); trimethylbenzoyl-diphenyl-phosphine oxide (TPO); Ethyl-4- dimethylamino benzoate (EDMAB); 2,2-Dimethoxy-2-phenylacetophenone (DMPA); Bisacylphosphine oxide (BAPO); 1-Phenyl-1 ,2-propanedione (PPD); phosphine oxide compounds, including naphthacene (APO), 9-anthracene (APO), and bisacylphosphine oxide (BAPO); 1-phenyl-1 ,2-propanedione (PPD); thioxanthone (TX) and its derivatives; a dibenzoyl germanium derivative, benzoyltrimethylgermane (BTG), dibenzoyldiethylgermane; hexaarylbiimidazole derivatives; a silane based derivative; (diethylgermanediyl)bis((4- methoxyphenyl)methanone); benzenesulfinic acid sodium salt (BS); a diaryliodonium salt, diphenyliodonium chloride or iodonium salt [diphenyliodonium hexafluorophosphate (DPIHP or DPI-PF6))], bromide, iodide, or hexafluorophosphate; and benzoyl peroxide (BPO).

Embodiment 53. The dental resin composition of embodiments 50 or 51 , wherein the one or more polymerization initiators is a combination of polymerization initiators selected from the group consisting of of camphorquinone/ethyl-4- (dimethylamino)benzoate (EDMAB), camphorquinone/2-(dimethylamino)ethyl methacrylate (DMAEMA)), DMPA/DPI-PF6, CQ/PPD, CQ/DMAEMA, CQ/EDMAB, CQ/DMAEMA/PDIHP, CQ/EDMAB/DPIHP or initiators containing ,bis-(4- methoxybenzoyl)diethyl germane, or phenylbis(2,4,6-trimethylbenzoyl) phosphine oxide (BAPO )..

Embodiment 54. The dental resin composition of embodiment 51 , wherein the one or more polymerization inhibitors are selected from the group consisting 4-tert- butylcatechol (TBC), 4-methoxyphenol (MEHQ), butylated hydroxytoluene (BHT) and hydroquinone (HQ), inhibitors of the class of phenols, aryl amines, phenylenediamines, N,N-dialkylhydroxylamines, m-nitro-p-cresol, 2,6-dinitro-p- cresol, and nitroxides, 2,2,6,6-tetramethylpiperidin-1-yl)oxyl or (2, 2,6,6- tetramethylpiperidin-1-yl)oxidanyl),2,4-dinitrophenol (DNP) and 2,4-dinitro-6-sec- butyl phenol (DNBP), and wherein the one or more stabilizers are selected from the group consisting of 2,6-di-tert-butyl-p-cresol, hydroquinone, 4-methoxyphenol, 4- tert-butylpyrocatechol,tert-butylhydroquinone,n2-tert-butyl-1 ,4-benzoquinone, copper(ii) dibutyldithiocarbamate, 2,6-di-tert-butylphenol, 2-[1-(2-hydroxy-3,5-di- tert-pentylphenyl)ethyl]-4,6-di-tert-pentylphenyl acrylate, phenothiazine, 1 ,1- diphenyl-2-picrylhydrazyl free radical, 1 ,4-benzoquinone, 6-tert-butyl-2,4-xylenol.

Embodiment 55. The dental resin composition of any one of embodiments 45 to 54, further comprising dental based plurifuntionalized methacrylate monomers and/or methacrylate oligomers.

Embodiment 56. The dental resin composition of embodiment 55, wherein the dental based plurifuntionalized methacrylate monomers are any one or combination of bisphenol A-glycidyl methacrylate (BisGMA), ethoxylated bisphenol A glycol dimethacrylate (BisEMA), urethane dimethacrylate (UDMA), triethylene glycol dimethacrylate (TEGDMA), 2-hydroxyethyl methacrylate (HEMA).

Embodiment 57. A dental adhesive composition comprising a dental resin composition of any one of embodiments 45 to 56 and a solvent.

Embodiment 58. The dental adhesive composition of embodiment 57, wherein the solvent is any one or combination of water, ethanol, acetone, DMSO.

Embodiment 59. A dental filler composite comprising a dental resin composition of any one of embodiment 45 to 56 and filler materials.

Embodiment 60. The dental filler composite of embodiment 59 wherein the filler materials is inorganic filler materials, organic filler materials or a combination thereof.

Embodiment 61 . A dental adhesive composition comprising: at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

Embodiment 62. The dental adhesive composition of embodiment 61 further comprising a monomeric compound of formula (II):

Embodiment 63. A dental filler composite comprising: at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

one or more polymerization initiators; at least one polymerization inhibitor and/or stabilizer; dental based plurifuntionalized methacrylate monomers and/or methacrylate oligomers; and inorganic and/or organic filler materials.

Embodiment 64. The dental filler composite of embodiment 63, further comprising: a monomeric compound of formula (II):

Embodiment 65. A dental sealant composition comprising a dental resin composition of any one of embodiments 45 to 56 and a solvent.

Embodiment 66. The dental sealant composition of embodiment 65 further comprising up to about 60 wt% or less of inorganic and/or organic filler materials. Embodiment 67. The dental sealant composition of embodiment 66 wherein the amount of filler is 50% or less, 40% or less, 30% or less, 20 % or less, 10% or less, or 5% or less.

Embodiment 68. A dental sealant composite comprising: at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

(A), or

Embodiment 69. The dental sealant of embodiment 68 further comprising: a monomeric compound of formula (II):

Embodiment 70. The dental sealant composition of embodiment 68 or 69 further comprising up to 60 wt% or less of inorganic and/or organic filler materials. Embodiment 71 . The dental sealant composition of embodiment 70 wherein the amount of filler is 50% or less, 40% or less, 30% or less, 20 % or less, 10% or less, or 5% or less.

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Claims

THEREFORE WHAT IS CLAIMED IS:

1 . A monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

2. The monomeric compound of claim 1 wherein R1 and R2 are different alkyl or the same alkyl.

3 The monomeric compound of claim 1 wherein R1 and R2 are independently

C1 , C2, C3 or C4 alkyl.

4. The monomeric compound of claim 1 , wherein for R1 and R2 are C1 and X1 is

(A), the compound is:

5. The monomeric compound of claim 1 , wherein for R1 and R2 are C2 and X1 is

(A), the compound is:

3BE

6. The monomeric compound of claim 1 , wherein for R1 and R2 are C1 and X1 is

(B), the compound is:

7. A monomeric compound of formula (II):

wherein 0 is oxygen, N is nitrogen, R1 and R2 are alky, and n is in a range from 1 to about 5.

8. The monomeric compound of claim 7 wherein R1 and R2 are independently C2, C3, C4 alkyl.

9. The monomeric compound of claim 8 wherein R1 and R2 are different alkyl or the same alkyl.

10. The monomeric compound of claim 7 wherein R1 and R2 are C2 alkyl and n is 2, the compound is:

11. A dental resin composition comprising at least one monomeric compound of claim 1 and/or claim 7.

12. The dental resin of claim 11 wherein the at least one monomeric compound of claim 1 is selected within the group consisting of

13. The dental resin of claim 12 wherein the at least one monomeric compound of claim 1 is 3BM alone, 3BE alone, 3BLDI alone, combination of 3BM and 3BE, combination of 3BM and 3BLDI, combination of 3BE and 3BLDI or combination of 3BM, 3BE and 3BLDI.

14. The dental resin composition of claim 7 further comprising one or more polymerization initiators.

15. The dental resin composition of claim 14, further comprising at least one polymerization inhibitor and/or stabilizer.

16. The dental resin composition of any one of claims 11 to 15, further comprising dental based plurifuntionalized methacrylate monomers and/or methacrylate oligomers.

17. A dental adhesive composition comprising a dental resin composition of any one of claims 11 to 16 and a solvent.

18. A dental filler composite comprising a dental resin composition of any one of claim 11 to 16 and filler materials.

19. A dental adhesive composition comprising: at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

one or more polymerization initiators; at least one polymerization inhibitor and/or stabilizer; dental based plurifuntionalized methacrylate monomers and/or methacrylate oligomers; a solvent; and optionally a monomeric compound of formula (II):

wherein 0 is oxygen, N is nitrogen, R1 and R2 are alkyl; and n is in a range from 1 to about 5.

20. A dental filler composite comprising: at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

one or more polymerization initiators; at least one polymerization inhibitor and/or stabilizer; dental based plurifuntionalized methacrylate monomers and/or methacrylate oligomers; inorganic and/or organic filler materials; and optionally a monomeric compound of formula (II):

21 . A dental sealant composition comprising a dental resin composition of any one of claims 11 to 16 and a solvent.

22. The dental sealant composition of claim 65 further comprising up to about 60 wt% or less of inorganic and/or organic filler materials.

23. A dental sealant composite comprising: at least one monomeric compound of formula (I)

wherein R1 and R2 are independently alkyl and X1 is

24. The dental sealant composition of claim 23 further comprising up to 60 wt% or less of inorganic and/or organic filler materials.