Polym. Bull. DOI 10.1007/s00289-013-0995-z ORIGINAL PAPER

Hemocompatibility, swelling and thermal properties of hydrogels based on 2-hydroxyethyl acrylate, itaconic acid and poly(ethylene glycol) dimethacrylate Simonida Lj. Tomic´ • Jovana S. Jovasˇevic´ Jovanka M. Filipovic´

•

Received: 12 September 2012 / Accepted: 27 June 2013 Ó Springer-Verlag Berlin Heidelberg 2013

Abstract Two series of novel hydrogels, based on 2-hydroxyethyl acrylate (HEA), itaconic acid (IA), and two poly(ethylene glycol) dimethacrylates (PEGDMA), of different ethylene glycol chain lengths, were prepared by free radical crosslinking copolymerization. The influence of different ethylene glycol chain lengths and concentration in P(HEA/IA/PEGDMA) hydrogels on biocompatibility, swelling and thermal properties was investigated. All samples in contact with blood showed a mean hemolysis value \1.0 % in the direct contact assay, and even \0.5 % in the indirect contact assay, for in vitro testing conditions. Swelling studies, conducted in a physiological pH and temperature range, showed pH sensitivity and relatively small changes of equilibrium swelling with temperature, which varied with PEGDMA molecular weight. The glass transition temperatures (Tg) of P(HEA/IA/PEGDMA) networks were in the range 28.1–36.9 °C, respectively, and also dependent on copolymer composition. Due to good biocompatibility, favorable swelling, and thermal properties these hydrogels show good potential for biomedical uses. Keywords Hydrogel  2-Hydroxyethyl acrylate  Itaconic acid  Poly(ethylene glycol) dimethacrylate  Hemocompatibility  pH-sensitive and temperature-dependent swelling  Network parameters  Thermal properties  Glass transition temperature

Introduction Special types of hydrogels known as stimuli-responsive have been investigated for the development of ‘‘smart’’ materials in various fields. The term ‘‘stimuli-responsive’’ S. Lj. Tomic´ (&)  J. S. Jovasˇevic´  J. M. Filipovic´ Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4/V, Belgrade, Serbia e-mail: [email protected]

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implies that significant changes of key properties can be induced by an external stimulus, such as pH value, temperature, ionic strength, pressure, light, or electrical and magnetic fields [1–3]. Studies performed by many authors showed that 2-hydroxyethyl methacrylate (HEMA), 2-hydroxyethyl acrylate) (HEA), itaconic acid (IA) and poly(ethylene glycol) dimethacrylate (PEGDMA), due to their excellent characteristics, are favorable as components of a pH-sensitive ‘‘smart’’ material [4–9]. Poly(2-hydroxyethyl methacrylate) (PHEMA) and its acrylate analogue poly(2hydroxyethyl acrylate) (PHEA) are hydroxyl functionalized polymers with similar biocompatibility, cytotoxicity, low thrombogenicity, and cell compatibility. The hydroxyl groups are attractive as the functionality in polymers because they offer hydrophilic properties, but they can also undergo a wide variety of reactions and act as initiation sites for ring opening polymerization (ROP) of cyclic esters thus, allowing easy access to complex biodegradable polymers [10]. The PHEMA has been widely used to make contact lenses, intraocular lenses, dental fillings, surgical implants, tissue engineering scaffolds, biosensors, prosthetic vascular implants, catheters, hemodialysis membranes, wound dressings and for the immobilization of drugs, cells, and enzymes [11, 12]. Numerous studies have been conducted to modify PHEMA with the aim of improving swelling, mechanical properties and of eliciting better physiological responses to design stimuli-responsive hydrogels [13–20]. Compared to PHEMA, PHEA is a less frequently studied polymer. Since PHEA has higher water sorption capacity than PHEMA, it seems to be a better option for the uses where higher swelling is required [21]. Therefore, it would be interesting to evaluate HEA polymer and copolymers as potential biomaterials. The PEGDMAs, polymers, obtained by substituting PEG terminal hydroxyl groups with methacrylates, are versatile building blocks for the preparation of ‘‘smart’’ biomaterials. PEG-based hydrogels, have been widely investigated due to good biocompatibility and flexibility. Besides, they are considered ‘‘stealth’’ systems due to their high water content and the presence of PEG chains which exhibit high biocompatibility. The biocompatibility of PEG stems from its ability to repel protein adsorption, that is once it is attached to certain formulations, allows slow release of the formulation, thus enabling controlled release, as well as reduced uptake of harmful immunoglobulins, due to the hydrophilic nature of the polymer [22, 23]. Hydrogels containing PEGDMA crosslinkers are highly tunable: the mesh size and swelling ratio of these hydrogels can be controlled by varying the molecular weight and/or concentration of PEGDMA [24–28]. The IA easily copolymerizes and provides polymer chains with carboxylic side groups, which are highly hydrophilic and able to form hydrogen bonds with corresponding groups or ionize in aqueous solutions of appropriate pH. The addition of very small amounts of IA to HEMA or HEA hydrogels renders good pH sensitivity and increases the degree of hydrogel swelling [8, 29, 30]. Owing to the fact that pH-sensitive hydrogels can conveniently change their volume in response to the environmental stimuli of different pH values they have been extensively investigated as drug carriers. Furthermore, IA is expected to show high biocompatibility because of its natural source [31]. We prepared two series of copolymeric hydrogels, based on 2-hydroxyethyl acrylate, IA, and two different types of PEGDMA, by free radical crosslinking

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copolymerization. Due to very good biocompatibility of all the ingredients and high water sorption capacity of HEA, the polymer network built up with such monomers was supposed to be a good matrix for wound dressing materials. In our previous paper [9], we investigated P(HEMA/IA/PEGDMA) copolymers and some of the obtained results are presented in this paper to illustrate the advantages of substituting HEMA with HEA, in the copolymers with the same comonomer ratio. The differences between acrylates and methacrylates were our guidelines for this substitution. Firstly, HEA (acrylate) is more hydrophilic and swells more than PHEMA component. Secondly, HEA polymers have lower glass transition temperatures than those with HEMA, which can translate into greater impact resistance and flexibility. The IA was chosen to introduce higher swelling and pH sensitivity, while PEGDMA polymers were introduced as segments which impart ‘‘stealth’’ properties and control copolymer flexibility and biocompatibility. The influence of ethylene glycol chain lengths and concentration on hemocompatibility, glass transition temperatures and swelling degrees of hydrogels was tested using direct and indirect contact blood assay, differential scanning calorimetry (DSC) measurements, and swelling studies in the physiological pH and temperature range. The results were compared with those for P(HEMA/IA/PEGDMA) copolymers. These hydrogels can be used as potential carriers of various antibiotics or antimicrobials in controlled release systems for wound dressing materials. The good hemocompatibility as well as the high ability to absorb fluids imparts humectants properties such that the wound is kept hydrated, and on the other hand, the absorption of secretion by expansion of the crosslinks in the polymer chain, is making room for the inclusion of foreign bodies such as bacteria detritus and odor molecules that are irreversibly taken up along the liquid [32].

Materials and methods Materials 2-Hydroxyethyl acrylate (HEA, Aldrich), itaconic acid (IA, Fluka), and poly(ethylene glycol) dimethacrylate (Mn 550 and 875; PEGDMA, Aldrich), were the components used in this study (Scheme 1). Ethyleneglycol dimethacrylate (EGDMA, Aldrich), as crosslinking agent, potassium persulfate (KPS, Fluka), as initiator, and N, N, N0 , N0 -tetramethylethylene diamine (TEMED, Aldrich), as activator, were used in all polymerizations performed in a mixture of water/ethanol as solvent. Buffer solutions with different pH values were prepared using hydrochloric acid (La Chema), potassium chloride (Fluka), potassium mono- and dihydrogenphosphate (Fluka) and sodium hydroxide (Fluka). Demineralized water was used for all polymerizations and the preparation of buffer solutions. Hydrogel synthesis The P(HEA/IA/PEGDMA) copolymeric hydrogels were obtained by in situ radical copolymerization. The reactants were dissolved in water/ethanol mixture (ratio 1:1). Four series of hydrogels were synthesized using constant HEA/IA ratio with

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Scheme 1 Hydrogel synthesis

variable PEGDMA molecular weight (Mn = 550 and 875), and mole fraction (5, 10 or 15). The samples were designated, according to the monomers used and the PEGDMA molecular weight and content. Initiator, activator, and crosslinker were added to the monomer feed mixture. Prior to polymerization, the reaction mixture was degassed and placed between two glass plates sealed with a rubber spacer (2mm thick). The polymerization was carried out at 50 °C for 24 h. After the reaction, the gels were cut into discs and immersed in water for a week to remove unreacted chemicals. The water was changed daily. Finally, the discs were dried to obtain xerogels (1-mm thick and 5 mm in diameter). The total amount of water used (350 ml) to remove unreacted chemicals was reduced in rotary evaporator to 50 ml. The amount of uncrosslinked HEA, and PEGDMA was determined using UV spectroscopy. On the other hand, the amount of uncrosslinked IA was determined by titration of extract against NaOH (0.05 mol/l) to phenolphthalein endpoint. All results indicate that the conversion during crosslinking reaction was nearly complete. The yields of P(HEA/IA/PEGDMA) copolymeric hydrogels of various compositions were above 99 %. All prepared hydrogels were transparent, flexible discs with variable fluid absorption capability. Hemolytic assay The hemolytic assay was determined in terms of hemolytic activity of the hydrogels by the direct and indirect contact methods, according to ISO 10 993-4 (1992) [33]. In the direct method, the hydrogel discs were immersed in 5 ml of a physiological solution (PS) to which 0.25 ml of whole rat blood had been added. The PS and distilled water were used as the negative and the positive control, respectively. Then

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the contents of the tubes were gently mixed and incubated in a water bath at 37 °C for 1 h. Subsequently, the absorbance of the supernatant liquid in each tube was determined at 545 nm using a Pharmacia LKB Ultrospec Plus UV/VIS spectrophotometer and the percentage of hemolysis was calculated. The mean hemolysis value of 1 % or less variation from two tests is considered acceptable [34, 35]. In the indirect contact method 5 ml of an isotonic aqueous extract from a hydrogel disc was used with 0.25 ml of a 10 % suspension of rat erythrocytes. To prepare the isotonic aqueous extracts, pieces of each disc were kept for 72 h at 37 °C in 100 ml of sterilized bidistilled water and then 0.9 g NaCl was added. The negative control was 0.9 % NaCl solution and 100 % hemolysis was obtained in bidistilled water. After incubation at 37 °C for 24 h, the absorbance of the supernatant was measured at 545 nm and the percentage of hemolysis was calculated [36]. The results presented are the mean values of three independent measurements. Differential scanning calorimetry The glass transition temperatures of P(HEMA/IA/PEGDMA) [9] and P(HEA/IA/ PEGDMA) copolymeric networks were determined with a TA Instruments DSC Q10 system. The DSC was calibrated with metallic indium standards (99.9 % purity). The hydrogel samples were all desiccated for 24 h at 40 °C, and tested in crimped aluminium pans at a rate of 10 °C/min under nitrogen gas flow (50 ml/min) over a twostep heating/cooling cycle temperature range of 0 to 150 °C, to eliminate any residual water. The glass transition was determined by the midpoint of the initial transition slopes. The results presented are the mean value of three independent measurements. Swelling study Dynamic swelling measurements were performed in a range of pH values from 2.20 to 7.40 (simulated physiological fluids) and in the temperature range from 25 to 55 °C. Swollen gels were removed from the swelling medium at regular intervals, dried superfically with filter paper, weighed and placed in the same bath. The measurements were continued until constant weight was reached for each sample. The amount of fluid absorbed was monitored gravimetrically. The equilibrium degree of swelling (qe) was calculated as follows: qe ¼ ðMe  Mo Þ=Mo

ð1Þ

where Me is the weight of the swollen hydrogel at equilibrium, and Mo is the weight of the xerogel [37, 38]. All swelling experiments were performed in triplicate.

Results and discussion Hemolytic activity of P(HEA/IA/PEGDMA) hydrogels Biocompatibility testing is an important step in the development of polymeric materials for biomedical applications [39]. By definition, the biocompatible material

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(a) Indirect contact Direct contact )

A-5

DM

EG 50P

A/5

A/I

E P(H

)

-10

MA

D PEG

50

A/5

A/I

E P(H

5)

A-1

DM

G 0PE

5

A/5

A/I

E P(H

0.0

0.2

0.4

0.6

0.8

1.0

Hemolysis (%)

(b) Indirect contact Direct contact -5)

MA

GD

5PE

87 IA/

/

EA

P(H

)

-10

MA

5

/87

/IA

A (HE

D PEG

P

5)

A-1

P(H

E

75P

A/8

/I EA

M GD

0.0

0.2

0.4

0.6

0.8

1.0

Hemolysis (%) Fig. 1 Hemolytic activity of (a) (HEA/IA/550PEGDMA), and (b) P(HEA/IA/875PEGDMA) hydrogels

should not influence negatively the organism nor be influenced by the surrounding environment while performing a particular function [40–43]. Hemolysis is defined as the release of hemoglobin into plasma due to damage of erythrocyte membrane [44]. The hemocompatibility testing is necessary for medical devices intended for direct or indirect blood exposure. All P(HEA/IA/PEGDMA) hydrogels were characterized by hemolysis tests. For in vitro testing conditions, all samples in contact with blood showed a mean hemolysis value \1.0 % in the direct contact assay and even\0.5 % in the indirect contact assay. According to the results obtained, these gels exert a favorable hemolytic activity (Fig. 1a, b). From our

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earlier investigation [45] it is known that small amounts of IA, incorporated in hydrogels, improve the hemocompatibility of PHEMA-based biomaterials. On the other hand, PEGDMA polymers are also beneficial for favorable hemocompatible behavior [39]. Similar trends for P(HEA/IA/PEGDMA) hydrogels of the corresponding composition containing 550PEGDMA and 875PEGDMA can be observed from Fig. 1a, b. The results also indicate that hemocompatibility decreases with the increase of 550PEGDMA content, probably due to higher crosslinking ratio in the polymer network (Fig. 1a). The same trend was observed for P(HEA/IA/875PEGDMA) hydrogels (Fig. 1b). The results obtained for hemocompatibility of P(HEA/ IA/PEGDMA) hydrogels confirm their possible use for wound dressing [46]. Comparing contribution of HEMA [9] to HEA component, it could be said that more hydrophilic nature of HEA slightly improves the hemocompatibility of the samples. Swelling of P(HEA/IA/PEGDMA) hydrogels The swelling properties of P(HEA/IA/PEGDMA) hydrogels were investigated in dependence of pH and temperature, as main external stimuli influencing the hydrogel swelling/deswelling in contact with body fluids, in a physiologically important range of pH (2.20–7.40) and temperature (from 25 to 55 °C) values. The results are presented as the dependences of equilibrium swelling degree (qe) on the pH (Fig. 2a, b) and temperature (Fig. 3a, b) and compared with previously obtained corresponding results for P(HEMA/IA/PEGDMA) [9] hydrogels. All P(HEA/IA/PEGDMA) samples are pH sensitive, as expected, due to the presence of carboxyl groups from IA which are responsible for the anionic character of the hydrogels and consequently their pH-sensitive swelling behavior. They have very different equilibrium swelling degrees in various buffers, showing a sharp volume phase transition at pHs near pKa values for IA. The qe vs. pH dependences of P(HEA/IA/PEGDMA) hydrogels (Fig. 2a, b) have similar trend for all samples. At low pH values (around 2.20) the swelling degrees are low, due to the intermolecular physical crosslinks, via hydrogen bond formation, between carboxylic groups of IA with the hydroxyl groups of HEA or with ether groups of PEGDMA residues. The equilibrium swelling degrees increase with the increase of pH, reaching the maximum value in the pH range 5.60–6.20. When pH further increases (from 6.20 to 6.80) qe values slightly decrease and rise again in the pH range of 6.80–8.00. As the pH value of the surrounding medium raises above pKa values of both IA carboxyl groups, those groups are transformed to carboxylate anions, and the hydrogel swelling in that region is substantially higher. The variation of swelling degrees with PEGDMA content is pronounced in the case of P(HEA/IA/550PEGDMA) samples, while for case of P(HEA/IA/875PEGDMA) this effect is less pronounced. The change of qe values with temperature is also pronounced for P(HEA/IA/ PEGDMA) samples (Fig. 3a, b). The qe values of P(HEA/IA/PEGDMA) hydrogels change very little in the range of 25–37 °C. From 37 to 40 °C qe values decrease, then increase from 40 to 50 °C, probably due to the changes of hydrophilic/ hydrophobic balance of the system, and decrease again from 50 to 55 °C. P(HEA/

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Equilibrium degree of swelling, qe

(a)

16 14 12 10 8 6 4

P(HEA/IA/550PEGDMA-5) P(HEA/IA/550PEGDMA-10) P(HEA/IA/550PEGDMA-15)

2 0 2

3

4

5

6

7

8

pH

Equilibrium degree of swelling, qe

(b)

16 14 12 10 8 6 4

P(HEA/IA/875PEGDMA-5) P(HEA/IA/875PEGDMA-10) P(HEA/IA/875PEGDMA-15)

2 0 2

3

4

5

6

7

8

pH Fig. 2 pH-sensitive swelling behavior of (a) copolymer hydrogels with 550PEGDMA and (b) copolymer hydrogels with 875PEGDMA

IA/PEGDMA) samples with 550PEGDMA have a more pronounced difference in swelling with the change of temperature then those containing 875PEGDMA. It can be explained by the fact that longer 875PEGDMA chains are more flexible, therefore they are more capable to adjust to the temperature changes than 550PEGDMA chains to regulate hydrophilic/hydrophobic balance of the system. It can be concluded that P(HEA/IA/PEGDMA) hydrogels show temperature-dependent swelling, but they are not temperature sensitive. It should be noted that P(HEA/IA/PEGDMA) samples have distinctly higher qe values, compared to the corresponding samples containing HEMA, which is due to higher hydrophilicity of HEA residues in copolymers. Besides, the differences in swelling degrees between different copolymers at measured pH/temperature values

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(a)

16

Equilibrium degree of swelling, qe

Polym. Bull.

14 12 10 8 6 4

P(HEA/IA/550PEGDMA-5) P(HEA/IA/550PEGDMA-10) P(HEA/IA/550PEGDMA-15)

2 0 20

25

30

35

40

45

50

55

Temperature (°C)

Equilibrium degree of swelling, qe

(b) 16 14 12 10 8 6 4

P(HEA/IA/875PEGDMA-5) P(HEA/IA/875PEGDMA-10) P(HEA/IA/875PEGDMA-15)

2 0 20

25

30

35

40

45

50

55

Temperature (°C) Fig. 3 Temperature-dependent swelling behavior of (a) copolymer hydrogels with 550PEGDMA, and (b) copolymer hydrogels with 875PEGDMA

are far more pronounced in the case of P(HEA/IA/PEGDMA) compared to P(HEMA/IA/PEGDMA) samples [9]. Network parameters of P(HEA/IA/PEGDMA) hydrogels Properties of hydrogels with weak acid moieties depend on the network structure, which is controlled by the feed composition. The most important network parameters are the molar mass of the polymer chain between two neighboring crosslinking points (Mc), the effective crosslinking density (me ) and pore size (n). In order to determine Mc for hydrogels containing diprotic IA, Eq. (2) is used [47].

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V1 X 2 u22;s 2Ka1 Ka2 þ 10pH Ka1 2  4I Vr 2ð10pH Þ2 þ10pH Ka1 þ Ka1 Ka2

!2

h  i ð1 þ 2=/ÞV1 u2=3 u1=3  2;r 2;s ¼ ln 1  u2;s þ u2;s þ vu22;s þ mMc

ð2Þ

where Mc is the molar mass of the polymer chain between two neighboring crosslinking points, Ka1 and Ka2 are the first and second dissociation constants of a diprotic acid, X is the weight fraction of ionisable polymer in the system, I is ionic strength of the swelling medium, u2,s is the polymer volume fraction in the swollen gel, u2,r is the polymer volume fraction in the relaxed state, V1 is the molar volume of water, / is the crosslinking agent functionality, Vr is the average molar volume of polymer repeating units, v is the Flory polymer–solvent interaction parameter, and m is the specific volume of the polymer. The effective crosslinking density (me ) was calculated as me ¼ q=Mc , where q is the sample density. The pore size (n), an important parameter in analyzing crosslinked polymers which describes the available space for solute transport within the polymer network, was calculated according to Eq. (3) [48]:    c 1=2 2Cn M 1=3 n ¼ u2;s l ð3Þ Mr Here, Mr is the molecular weight of the repeating unit; l, the C–C bond length of ˚ ; and Cn, the characteristic ratio, M  c is the average of the molar mass of 1.54 A repeating unit [49]. Table 1 describes the various network parameters calculated for the hydrogel samples having different composition. It is clear that as the effective crosslink density of the network increases, the value of Mc decreases. Moreover, the number of elastically effective chains increases because it varies inversely with Mc. The calculation of network parameters was done for the data obtained at pH 7.40 and 37 °C. The network parameters for P(HEA/IA/PEGDMA) hydrogels depend on PEGDMA chain length (550 and 875) and content, which can be expected (Table 1). The pore size values obtained for P(HEA/IA/PEGDMA) copolymers are Table 1 Network parameters of P(HEA/IA/PEGDMA) hydrogels at pH 7.40 and 37 °C Sample

Mc 9 10-6 (g/mol)

me 9 103 (mol/dm3)

P(HEA/IA)

0.084

11.40

P(HEA/IA/550PEGDMA-5)

1.673

0.601

170.7

P(HEA/IA/550PEGDMA-10)

0.867

1.267

105.4

P(HEA/IA/550PEGDMA-15)

0.569

2.022

75.8

P(HEA/IA/875PEGDMA-5)

1.371

0.720

143.9

P(HEA/IA/875PEGDMA-10)

1.141

0.903

113.6

P(HEA/IA/875PEGDMA-15)

0.863

1.152

87.1

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n (nm) 35.6

Polym. Bull.

in the range 75.8–170.7 nm for P(HEA/IA/550PEGDMA) and 87.1–143.9 nm for P(HEA/IA/875PEGDMA) (microporous regime). The results for network parameters are in very good agreement with the swelling results (Figs. 2, 3). From the results presented in Table 1 it follows that the PEGDMA content determines hydrogel mesh size and swelling—with increasing PEGDMA content pore size decreases and hydrogels swell less. It can be concluded that PEGDMA component enables the control of the pore size and swelling of P(HEA/IA/PEGDMA) copolymers. Thermal properties of P(HEMA/IA/PEGDMA) and P(HEA/IA/PEGDMA) hydrogels The glass transition temperature of PHEA hydrogel reported in the literature is low, and varies from -10 to 7 °C; therefore, PHEA is in the rubbery state at room temperature, demonstrating elastic behavior [50–52]. Tg values for PHEMA reported in the literature range from 85 to 105 °C [53–55]. The Tg of PIA cannot be measured because degradation commences first, accompanied by broad endothermic peaks in the DSC thermogram [56]. The Tg values for the copolymer samples are presented in Table 2 [P(HEMA/IA/ PEGDMA)] and Table 3 [P(HEA/IA/PEGDMA)]. For all copolymer networks a single Tg value was clearly observed, showing a clear dependence on the copolymer composition. The Tg values for copolymers are higher than those for pure PHEMA and PHEA, due to the presence of IA residues. As it can be expected, P(HEMA/IA/PEGDMA) have higher Tg values than P(HEA/IA/PEGDMA) copolymers. However, the content and molecular weight of PEGDMA component have also a marked influence on copolymer Tg values; lower Tgs are obtained for copolymers with higher PEGDMA content and for higher PEGDMA molecular weight. These differences in Tg values for samples of varying PEGDMA content and molecular weight can be explained also by dual, crosslinking and copolymer, effect of PEGDMA chains introduced in HEMA/IA and HEA/IA copolymers. The crosslinking effect will act to increase Tg, due to the decreased free volume of the system, which restricts the molecular motion of the polymer chains and increases the temperature at which larger-scale molecular motions can occur. The copolymer effect will act in the opposite direction. Copolymer Tg values decrease, reflecting the increase in chain flexibility of low Tg PEG segments that are not bound-up close to a network junction. The longer (875PEGDMA) units increase more the free volume of the system, and thus decrease the temperature at which molecular motion can Table 2 Tg values for P(HEMA/IA/PEGDMA) hydrogels Sample

Tg/oC

Sample

Tg/oC

P(HEMA/IA/550PEGDMA-5)

129.1

P(HEMA/IA/875PEGDMA-5)

118.3

P(HEMA/IA/550PEGDMA-10)

120.4

P(HEMA/IA/875PEGDMA-10)

109.5

P(HEMA/IA/550PEGDMA-15)

113.8

P(HEMA/IA/875PEGDMA-15)

103.5

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Polym. Bull. Table 3 Tg values for P(HEA/IA/PEGDMA) hydrogels Sample

Tg/oC

Sample

Tg/oC

P(HEA/IA/550PEGDMA-5)

36.9

P(HEA/IA/875PEGDMA-5)

29.6

P(HEA/IA/550PEGDMA-10)

35.8

P(HEA/IA/875PEGDMA-10)

29.1

P(HEA/IA/550PEGDMA-15)

32.0

P(HEA/IA/875PEGDMA-15)

28.1

occur and lowering Tg. Thus, the reduction in Tg due to the incorporation of low Tg PEG segments increases with the molecular weight of this segment (Tables 2, 3).

Conclusion The present study investigates the influence of (meth)acrylic comonomer and PEGDMA chain length (550 and 875) and content on the hemocompatibility, swelling properties and Tg values of P(HEA/IA/PEGDMA) hydrogels. In vitro assay of the hemolytic activity of all prepared hydrogels showed beneficial hemocompatible behavior. Hydrogels containing HEA component show a slightly higher hemocompatibility then those with PHEMA. Swelling studies showed pH-sensitive behavior with a sharp transition in the physiological pH range, due to the presence of IA. Hence, the obtained copolymers can be classified as ‘‘smart’’ materials. Although the copolymers show temperature-dependent swelling, they are not temperature sensitive because there is no discontinuous change of the degree of swelling with temperature. The acrylate component in P(HEA/IA/PEGDMA) hydrogels (HEA) is more hydrophilic than the methacrylate (HEMA) one; therefore, the swelling of hydrogels containing HEA component, as well as the pH sensitivity, was more pronounced for the samples containing HEA units. Furthermore, the swelling degrees of P(HEA/IA/PEGDMA) hydrogels showed higher dependence on the PEGDMA content and molecular weight. All copolymer networks had a single Tg value, which were also dependent on the monomer type (HEMA/HEA) and PEGDMA content and molecular weight. Flexible PEGDMA chains inside the network have dual, crosslinking and copolymer, effect on swelling behavior and Tg values, which makes possible the fine tuning of these properties. The obtained results indicate that P(HEA/IA/PEGDMA) hydrogels show good potential for biomedical applications as wound dressing materials. Acknowledgments This work has been supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grants No. 172026 and 172062).

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