Biomacromolecules 2008, 9, 1637–1642
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Synthesis of Biocompatible Polymeric Hydrogels with Tunable Adhesion to both Hydrophobic and Hydrophilic Surfaces Xuhong Guo,† Frank Deng,‡ Li Li,§ and Robert K. Prud’homme*,| State Key Laboratory of Chemical Engineering, East China University of Science and Technology, Shanghai 200237, People’s Republic of China, GlaxoSmithKline, Parsippany, New Jersey 07054, Department of Product Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai 200237, People’s Republic of China, and Department of Chemical Engineering, Princeton University, Princeton, New Jersey 08544 Received February 11, 2008
We report the synthesis of biocompatible polymeric hydrogels based on poly(vinyl acetate) (PVAc) and poly(methyl vinyl ether-co-maleic anhydride) (PMVE-MA). These polymeric hydrogels show strong and tunable adhesion to both hydrophobic and hydrophilic surfaces and should be ideal candidates as bioadhesives for applications such as denture adhesion. PVAc was partially hydrolyzed and then mixed with PMVE-MA. Crosslinking between these two polymers through reactions between hydroxyl groups in partially hydrolyzed PVAc and maleic anhydride groups in PMVE-MA increased their compatibility and prevented phase separation so transparent hydrogels were formed. The adhesion of these polymeric hydrogels to hydrophobic and hydrophilic surfaces was tailored by regulating the degree of hydrolysis of PVAc and the molecular weights of the polymers. In the vicinity of critical gel point, where the elastic modulus G′ and the viscous modulus G′′ scale as G′ ∼ G′′ ∼ ω0.3, polymeric hydrogels show optimal adhesion. Transparent gels are formed in mixed solvents of water and ethanol. The content of ethanol in the mixed solvent can be partially replaced by propylene glycol, glycerol, or poly(ethenyl glycol)-400, and the composition of appropriate mixed solvents can be determined by the calculation of solubility parameters.
Introduction Polymeric hydrogels have received considerable attention in a wide variety of biomedical applications since Wichterle et al. first proposed the use of poly(2-hydroxyethylmethacrylate) in contact lenses.1 The high water content and tissue-like flexibility promote the biocompatibility of polymeric hydrogels.2 Their potential applications are extensive, including tissue adhesives,3 dermatological patches,4 drug delivery carriers,5–7 and denture adhesives.8–10 The requirements for a denture adhesive is that it should bind strongly to both the hydrophilic oral tissue surface and the hydrophobic poly(methyl methacrylate) (PMMA) surface of a denture. Commercial denture adhesives attempt to create this dual adhesion by creating two-phase pastes with a hydrophobic external oil phase and a hydrophilic dispersed phase of water swellable polymer. These creams are activated by water to form a biphasic, rubber-like adhesive. There have been no homogeneous, single-phase adhesives that are substantive to both hydrophilic and hydrophobic surfaces. In this paper, we report the preparation of single-phase, transparent, biocompatible polymeric hydrogels based on PVAc and PMVE-MA in mixed solvents. The unique adhesion of this new material is obtained by combining both hydrophilic and hydrophobic polymers and preventing phase separation by partial hydrolysis of PVAc to poly(vinyl alcohol) (PVA) and reacting the resultant hydroxyl groups with maleic anhydride groups in PMVEMA to form crosslinks between the two polymers. Light crosslink* To whom correspondence should be addressed. E-mail: prudhomm@ princeton.edu. † State Key Laboratory of Chemical Engineering, East China University of Science and Technology. ‡ GlaxoSmithKline. § Department of Product Engineering, School of Chemical Engineering, East China University of Science and Technology. | Princeton University.
Figure 1. Controlled hydrolysis of PVAc catalyzed by HCl.
ing increases their compatibility significantly, but overcrosslinking compromises the adhesion to surfaces. Transparent polymeric hydrogels are thus prepared in a mixed solvent mainly consisting of water and ethanol, which show strong and tunable adhesion to both hydrophobic and hydrophilic surfaces. They should be ideal candidates for a new generation of denture adhesive.
Experimental Section Chemicals. Poly(vinyl acetate) (PVAc) (Mw ) 12.8 and 500 kg/ mol), hydrochloric acid (HCl; 37%), and glycerol (99+%) were purchased from Aldrich. Ethanol (absolute) was obtained from AAPER Alcohol and Chemical Co. Poly(ethylene glycol) 400 (PEG-400; Mw ) 400 g/mol) was obtained from Fluka. Poly(methyl vinyl ether-comaleic anhydride) (PMVE-MA), including Gantrez AN-169 (Mw ) 1980 kg/mol) and Gantrez AN-119 (Mw ) 216 kg/mol), were kindly provided by ISP Technologies Inc. All chemicals were used as obtained without further purification. Synthesis. Partial hydrolysis of PVAc (Figure 1): In a typical run, 25 g of ethanol, 25 g of deionized (DI) water, and 0.27 g of HCl were added to a reactor equipped with a Teflon stirrer. To avoid clumping, 25 g of PVAc was added slowly while stirring. The mixture was heated to 70 ( 2 °C and fluxed for 2 h. The hydrolysis degree of PVAc was determined by 1H NMR. Mixing with PMVE-MA: The partially hydrolyzed PVAc solution was cooled to room temperature and 25 g of PMVE-MA was introduced while stirring. The mixture was heated to 78 ( 2 °C and fluxed for 60 min. The maleic anhydride groups in PMVE-MA can be opened by hydroxyl groups from water (Figure 2a), ethanol (Figure 2b), and the
10.1021/bm800142z CCC: $40.75 2008 American Chemical Society Published on Web 05/23/2008
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Figure 2. Reactions during mixing of partially hydrolyzed PVAc and PMVE-MA. (a) PMVE-MA with water; (b) PMVE-MA with ethanol; (c) PMVEMA with partially hydrolyzed PVAc; (c) esterification reaction; (d) ester exchange reaction.
partially hydrolyzed PVAc (Figure 2c). The expected crosslinking between the two polymers comes from the chemical reactions between hydroxyl group in partially hydrolyzed PVAc with either maleic anhydride groups directly (Figure 2c) or carboxyl groups (Figure 2d) and ethyl ester groups (Figure 2e) from PMVE-MA. Characterization. 1H NMR spectra of partially hydrolyzed PVAc were obtained on a Varian Inova-400 spectrometer at room temperature. Samples were dissolved in acetone-d6 at about 2 wt %. The degree of hydrolysis was calculated from the 1H NMR spectrum (Figure 3) according to eq 1
hydrolysis(mol % ) )
AH4 2 AH4 + AH1 2
× 100
(1)
where AH4 denotes the peak areas of CH2 protons from the poly(vinyl alcohol) (PVA) and AH1 is the peak areas of CH proton from unhydrolyzed PVAc (Figure 3).
The rheological measurements were performed on a Physica MCR 501 (Anton Paar GmbH) rheometer with 25 cm parallel plate geometry and a gap of 1 mm. The temperature was controlled to 25 ( 0.1 °C by a Peltier plate. The 180° peel test followed ASTM D903-49. Cloth was fastened to the poly(methyl methacrylate) (PMMA) plate with the adhesive to serve as a mimic for the hydrophilic gingival tissue.
Results and Discussion Controlled Hydrolysis of PVAc. Enhancing the compatibility of PVAc and PMVE-MA tailors the adhesion to both hydrophobic and hydrophilic surfaces. Controlled hydrolysis of PVAc to form a random copolymer of vinyl acetate and vinyl alcohol poly(VAc-VA) produces hydroxyl groups to crosslink with PMVE-MA. PVAc hydrolysis was conducted without catalyst in a mixed solvent of 50:50 ethanol/water (weight) with a weight concentration of 33% PVAc at 78 °C. The hydrolysis
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Figure 3. 1H NMR spectrum of hydrolyzed PVAc in acetone-d6.
Figure 4. PVAc (Mw ) 12.8 kg/mol) hydrolysis degree as a function of time in 50:50 water/ethanol (weight) solution with a concentration of 33 wt % at 78 °C with and without catalyst HCl.
degree (d) of PVAc follows approximately an exponential function with reaction time (t; Figure 4).
d ) 0.797t0.389 + 3.29
(without HCl)
Figure 5. Viscosity as function of shear rate for sample 1 (Table 1). The changing parameter is the mixing time of partially hydrolyzed PVAc solution and PMVE-MA: (O) 33 wt % partially hydrolyzed PVAc (Mw ) 12.8 kg/mol) solution before mixing; (0) after 35 min mixing with Gantrez AN-119; (∇) after 60 min mixing.
(2)
It takes about 20 h to reach a hydrolysis degree of 5 mol %. To accelerate the PVAc hydrolysis reaction, hydrochloric acid (HCl) was added as a catalyst. Acid, rather than base hydrolysis, was chosen because alkaline hydrolysis of PVAc leads to blocky copolymers, while random copolymers result from acidcatalyzed hydrolysis.11–13 Upon addition of 0.03 wt % HCl, the hydrolysis reaction of PVAc accelerated significantly, and higher concentrations of HCl (0.06 wt %) led to faster hydrolysis (Figure 4). The hydrolysis degree as function of time followed.
d ) 0.889t0.561 + 4.78
(with 0.03 wt % HCl)
(3)
d ) 1.70t0.738 + 3.36
(with 0.06 wt % HCl)
(4)
Mixing of Poly(VAc-VA) and PMVE-MA. As shown in Figure 2, upon addition of PMVE-MA to poly(VAc-VA) solution, the anhydride groups react with hydroxyl groups from water, ethanol, and PVA. Reactions during mixing poly(VAcVA) and PMVE-MA were observed by rheology (Figure 5). After mixing of the poly(VAc-VA) solution with a hydrolysis degree of 6 mol % and PMVE-MA (Gantrez AN-119) powder at 78 °C under reflux for 35 min, a transparent polymeric hydrogel was formed with a zero shear viscosity of ∼2000 Pa · s. The viscosity of the mixture increased by about 1 order of magnitude (Figure 5) after 60 min of reaction. Crosslinking
Figure 6. Elastic modulus (G′) and viscous modulus (G′′) as function of frequency for sample 1 (Table 1). The changing parameter is mixing time of partially hydrolyzed PVAc (Mw ) 12.8 kg/mol) solution and PMVE-MA: (O), (b) G′ and G′′ of 33 wt % partially hydrolyzed PVAc solution; (0), (9) G′ and G′′ of mixture after 35 min reaction; (∇), (1) G′ and G′′ of mixture after a 60 min reaction.
between poly(VAc-VA) and PMVE-MA molecules is confirmed by the dynamic rheological results in Figure 6, where both the elastic modulus G′ and viscous modulus G′′ increased significantly when reaction time increased from 35 min to 1 h. For partially hydrolyzed PVAc solutions, the loss modulus G′′, indicating viscous response, is above the elastic moduli G′, which demonstrates the relative fluidity of the system (Figure 6). After mixing with PMVE-MA and increasing the reaction
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Table 1. Adhesion of Polymeric Hydrogels sample 1 2 3 4
PVAc Mw PMVE-MA Mw 180° peel (kg/mol) (kg/mol) strength (N/cm) appearance 12.8 12.8 500 500
216 1980 216 1980
1.8 7.7 15.4 9.7
transparent transparent transparent opaque
Figure 8. Elastic modulus (G′) and viscous modulus (G′′) as function of frequency. Comparison of the three samples listed in Table 1: (O), (b) G′ and G′′ of sample 1; (0), (9) G′ and G′′ of sample 3; (∆), (2) G′ and G′′ of sample 4.
Figure 7. Viscosity as function of shear rate. Comparison of the four samples listed in Table 1: (O) sample 1; (0) sample 2; (3) sample 3; (∆) sample 4.
time, G′ approaches G′′ and almost overlaps at 35 min. Further reaction leads to G′ at low frequency, being larger than G′′ after an hour (Figure 6). Winter’s definition of a critical gel occurs when G′ parallels G′′.14 Therefore, the overlapping of G′ and G′′ at 35 min is a rheological symbol for crosslinking between poly(VAc-VA) and PMVE-MA to form a critical polymeric gel. Longer reaction time results in a higher crosslinking degree. The 180° peel strength of this polymeric hydrogel after mixing for 35 min was 1.8 N/cm, but decreased to 1.1 N/cm for the gel after 1 h reaction time. When hydrogels are used as adhesives, a balance between cohesion and fluidity is required to obtain optimized adhesion. Critical gels are known to provide optimum adhesion in pressure-sensitive adhesive applications. If G′ < G′′ then the material will not have adequate (cohesive) strength, and if G′ > G′′, then the material is too rigid to conform easily to a surface (inadequate adhesive strength). Thus, the overlapping of G′ and G′′ of the polymeric gel can be used to estimate the suitability for an adhesive for this application. Effect of Molecular Weight on Adhesion. The adhesion to both hydrophobic and hydrophilic surfaces was characterized by 180° peel strength, which tests followed ASTM D903-49. Table 1 lists the experimental results for polymeric hydrogels prepared from PVAc and PMVE-MA with different molecular weights. PVAc and PMVE-MA were mixed with a weight ratio of 1:1 and dissolved in mixed solvent of 50:50 water/ethanol (weight) with a polymer concentration of 50 wt %. As shown in Table 1, for low molecular weight PVAc (12.8 kg/mol), the peel strength increased significantly with increasing PMVE-MA molecular weight and the polymeric hydrogels were transparent. But for high molecular weight PVAc (500 kg/mol) and high molecular weight PMVE-MA (1980 kg/mol), opaque polymer hydrogels result (sample 4) with lower peel strength than that of sample 3 from PMVE-MA, with a molecular weight of 216 kg/mol. The failure was an adhesive failure at the interface. Therefore, although the viscosity (Figure 7) as well as G′ and G′′ (Figure 8) of sample 4 are higher than those of sample 3 adhesion did not result. Appropriate rheology is a necessary condition for adhesion but not a sufficient condition.
This reinforces the notion that pressure sensitive adhesives require both appropriate rheology and interfacial energy. The increase of viscosity in Figure 7 was due to the increased entanglement of polymer chains with increasing molecular weights of PVAc and PMVE-MA. But the flowability becomes worse upon increasing polymer molecular weights, as shown by the increasing values of G′′ at low frequencies (Figure 8). The increase of polymer molecular weight improved the cohesion, but phase separation produced an interfacial liquid layer that afforded poor surface adhesion. The best balance is reached in sample 3. Solvent Choice. To obtain transparent polymeric hydrogels, the composition of the mixed solvent is critical. Because the polymeric hydrogels contain both hydrophobic and hydrophilic domains, solubilization requires a mixed solvent. A mixture of 50/50 water/ethanol by weight proved to be a good solvent for the polymer mixtures and produced transparent polymeric hydrogels. Opacity of the gel indicates either inadequate solubilization of the hydrophilic PMVE-MA or hydrophobic PVAc components. Ethanol is a good solvent for hydrophobic PVAc sections, but ethanol concentrations above 12% produce irritation to mucosal tissue and cannot be used in denture adhesives. To minimize ethanol concentration, ethanol was replaced by propylene glycol, glycerol, or PEG-400 in a mixed solvent formation. Solubility parameters were used to calculate mixed solvent compositions equivalent to the 50:50 (wt) ethanol/water system.15 The Hildebrand and Hansen solubility parameters of water, ethanol, propylene glycol, and glycerol can be found in the literature, while those for PEG-400 have to be calculated from its structure using group contribution theory.15 All the solubility parameters of solvents used in this paper were listed in Table 2. The components of four mixed solvents with the same solubility as the 50:50 water/ethanol solvent were calculated according to following equations
δt2 ) δ2d + δ2p + δ2h
∑ δdiΦVi δpm ) ∑ δpiΦVi δhm ) ∑ δhiΦVi δdm )
(5) (6) (7) (8)
where δdm, δpm, and δhm are dispersion, polar, and hydrogen bonding components of the Hildebrand parameters for mixed solvent, respectively; ΦVi is the volume fraction of each solvent
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Table 2. Hildebrand and Hansen Solubility Parameters of Solventsa solvent
Mn (g/mol)
density (g/mL)
δd (MPa1/2)
δp (MPa1/2)
δh (MPa1/2)
δt (MPa1/2)
water ethanol propylene glycol glycerol PEG-400
18.02 46.1 76.1 92.1 400
0.997 0.785 1.033 1.258 1.125
12.2 12.6 11.8 9.3 16.6
22.8 11.2 13.3 15.4 10.4
40.4 20.0 25.0 31.4 18.8
48.0 26.1 30.7 36.2 27.2
a
δt, the total Hildebrand parameter; δd, the dispersion component; δp, the polar component; and δh, the hydrogen bonding component.
Table 3. Solvent Mixtures with Same Solubility mixed solvent
water (wt %)
ethanol (wt %)
1 2 3 4
25.0 19.0 14.5 22.0
25.0 14.5 19.0 11.5
propyl glycol (wt %)
glycerine (wt %)
PEG-400 (wt %)
16.5 16.5 16.5
component; and δdi, δpi, and δhi denote to parameters of each solvent component. The calculated compositions of four mixed solvents were listed in Table 3. The solubility was observed visually by redissolving the dried polymer hydrogel sample 2 (Table 1) in each mixed solvent at the same 50 wt % concentration. As shown in Figure 9, all the four mixed solvents could redissolve the dried polymeric hydrogel sample 2. But mixed solvents 1 and 2 led to transparent hydrogels, while translucent polymeric hydrogels resulted for mixed solvents 3 and 4. But because both propylene glycol and glycerine contain many more hydroxyl groups than PEG-400, they might be expected to interact with the crosslinking process and create crosslinks. Therefore, PEG-400 was selected as the solvent to replace ethanol among the three solvents.
Conclusions Transparent polymeric hydrogels based on poly(vinyl acetate) (PVAc) and poly(methyl vinyl ether-co-maleic anhydride) (PMVE-MA) in mixed solvents were prepared by partial hydrolysis of PVAc and crosslinking between these two polymers. These biocompatible polymeric hydrogels showed strong and tunable adhesion to both hydrophobic and hydrophilic
surfaces due to the coexistence of hydrophobic PVAc domains and hydrophilic domains from PMVE-MA. The hydrolysis of PVAc accelerated with the addition of HCl as a catalyst and the hydrolysis degree followed an exponential function with hydrolysis time. Therefore, the hydrolysis degree of PVAc was easily controlled by catalyst HCl amount and reaction time. During the mixing of partially hydrolyzed PVAc and PMVEMA, these two polymers crosslink by reactions between hydroxyl groups and maleic anhydride groups. The crosslinking, which was confirmed by the increase of viscosity and elastic modulus G′, as observed by rheology, increased the compatibility of the two polymers and led to transparent hydrogels in a mixed water and ethanol solvent. The adhesion of these polymeric hydrogel was determined by a balance between cohesion (crosslinking) and flowability. At the vicinity of the critical gel point, where the elastic modulus G′ and the viscous modulus G′′ overlapped, the polymeric hydrogels show optimal adhesion. Therefore, the overlapping of G′ and G′′ is a rheological prerequisite of good adhesion for polymeric hydrogels. The adhesion of polymeric hydrogels can be tailored by regulating the degree of hydrolysis of PVAc as well as the molecular weights of both PVAc and PMVE-MA. The adhesion did not increase monotonically with increasing the molecular weights of the two polymers. The best adhesion appeared at the mixture of PVAc with a molecular weight of 500 kg/mol and PMVE-MA with a molecular weight of 216 kg/mol due to the balance of entanglement and flow. The ethanol in the mixed solvent can be partially replaced by propylene glycol, glycerol, or poly(ethylene glycol) (PEG400) whose compositions can be calculated from solubility parameter methods. PEG-400 is the best candidate to partially replace ethanol. Due to the tunable adhesion to both hydrophobic
Figure 9. Photos of dried polymeric hydrogel sample 2 (Table 1) redissolved in various mixed solvents. (a) Mixed solvent 1 (Table 3); (b) mixed solvent 2; (c) mixed solvent 3; (d) mixed solvent 4.
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and hydrophilic surfaces, these biocompatible polymeric hydrogels should be ideal candidates for the new generation of denture adhesives. Acknowledgment. We gratefully acknowledge support from GlaxoSmithKline. Xuhong Guo acknowledges partial support of this work from Shanghai Shuguang Plan Project 06SG35 and Shanghai Pujiang Talent Project 07PJ14022.
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Guo et al. (5) Am Ende, M. T.; Peppas, N. A. Pharm. Res. 1995, 12, 2030–2035. (6) Jones, D. S.; Lawlor, M. S.; Woolfson, A. D. J. Pharm. Sci. 2003, 92, 995–1007. (7) McCarron, P. A.; Woolfson, A. D.; Donnelly, R. F.; Andrews, G. P.; Zawislak, A.; Price, J. H. J. Appl. Polym. Sci. 2003, 91, 1576–1589. (8) Zhao, K.; Cheng, X. R.; Chao, Y. L.; Li, Z. A.; Han, G. L. Dent. Mater. 2004, 20, 419–424. (9) Ozcan, M.; Kulak, Y.; De Baat, C.; Arikan, A.; Ucankale, M. J. Prosthodontics 2005, 14, 122–126. (10) Koppang, R.; Berg, E.; Dahm, S.; Floystrand, F. J. Prosthet. Dent. 1995, 73, 486–491. (11) Arranz, F.; Sanchez-Chaves, M.; Riofrio, A. Makromol. Chem. 1986, 185, 1215–1228. (12) Moritani, T.; Fujiwara, Y. Macromolecules 1977, 10, 532–535. (13) Tubbs, R. K. J. Polym. Sci., Part A: Polym Chem. 1966, 4, 623–629. (14) Chambon, F.; Petrovic, Z. S.; MacKnight, W. J.; Winter, H. H. Macromolecules 1986, 19, 2146–2149. (15) Barton, A. F. M., Ed. CRC handbook of solubility parameters and other cohesion parameters; CRC Press: Boca Raton, FL, 1991.
BM800142Z
