Design of Polyurethane Composed of Only Hard Main Chain with

Aug 18, 2017 - In order to create a novel rigid polymer material for biomedical application, we designed the polymer structure of polyurethane, bearin...
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Design of Polyurethane Composed of Only Hard Main Chain with Oligo(ethylene glycol) Units as Side Chain Simultaneously Achieved High Biocompatible and Mechanical Properties Daisuke Aoki† and Hiroharu Ajiro*,†,‡,§ †

Graduate School of Materials Science and ‡Institute for Research Initiatives, Nara Institute of Science and Technology, 8916-5, Takayama-cho, Ikoma, Nara 630-0192, Japan § JST PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan S Supporting Information *

ABSTRACT: In order to create a novel rigid polymer material for biomedical application, we designed the polymer structure of polyurethane, bearing oligo(ethylene glycol) (OEG) as the side chain, which was synthesized by only hard main chain using diisocyanate and short diol monomers. We investigated the effect of the graft structure of OEG units on polymer properties using pentaethylene glycol (OEG5) or propanediol (PDO) in the main chain as the other diol monomers. Furthermore, the rigid 4,4′-methylenebis(cyclohexyl isocyanate) (HMDI) and symmetric hexamethylene diisocyanate (HDI) were selected for the isocyanate monomers. As a result, there is a significant difference in various properties, depending on both the existence and the position of OEG units in the polymer structure. For example, differential scanning calorimetry (DSC) showed that the graft structure of OEG caused a decrease in the glass transition temperature from 73 to 35 °C in the case of using HMDI as well as a disappearance of the melting point in the case of using HDI. The Fourier transform infrared (FT-IR) spectra showed that the ordered hydrogen bonding of CO stretching vibration at 1682 cm−1 was not observed in the polyurethane grafted with OEG. In the mechanical test of polyurethane composed of HMDI, the sample grafted with OEG exhibited excellent values of elastic modulus of 1.7 GPa and elongation at break of 184%, while that with OEG5 and PDO in the main chain showed 115 MPa with 370% and 739 MPa with 19%, respectively. The polyurethane grafted with OEG showed around 0.6 μg/cm2 of protein adsorption, almost the same as that with OEG5 in the main chain, while that using PDO in the main chain showed more than 3.0 μg/cm2. Therefore, the polyurethane design bearing OEG as the side chain provides excellent rigidity, toughness, and biocompatibility simultaneously.



INTRODUCTION Polymer biomaterials for health maintenance has been paid much attention due to the development of numerous pioneers’ molecular design techniques for biocompatibility. Among them, segmented polyurethanes (SPUs),1 which are one of the molecular design concepts of the polymer material, have been widely used as biomaterials because of their excellent mechanical strength and biocompatibility originating from their microphase separation structure.2,3 SPUs for medical application have been developed for various uses with the development of molecular design.4,5 Taking advantage of the properties of SPUs, various applications have been already reported, such as artificial hearts,6,7 heart valves,8 vascular grafts,9 catheters,10 and pacemakers.11 In recent decades, the development of polyurethane biomaterials focused on biodegradability has been vigorously pursued, and they are expected to find application as drug delivery systems (DDS),12,13 scaffolds,14 and injectable hydrogels.15,16 It is common that the molecular design of SPUs is composed of a © XXXX American Chemical Society

soft segment of macrodiol with low glass transition temperature (Tg) and a hard segment of isocyanate as a semicrystalline and chain extender. As well as the biocompatibility, their mechanical, thermal, and degradation properties can be controlled by monomer chemical structures. For example, it has been reported that high molecular weight in the soft segment leads to decrease the initial modulus and to increase the elongation at break.17,18 As regards to the isocyanates, it has been reported that the microphase-separated morphology and derived polymer properties of polyurethane are strongly affected by the chemical structure and symmetry of the isocyanate monomer.19,20 In particular, aromatic isocyanates such as 4,4′-diphenylmethane diisocyanate (MDI) and tolylene diisocyanate (TDI) are widely used in industry as they have excellent mechanical properties due to their high crystallinity. Received: March 24, 2017 Revised: July 20, 2017

A

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molecular chains is not ensured, even when it is necessary for ductile deformation, due to the lack of flexibility of the polymer chain segments.43 Hence, in order to facilitate the movement of molecular chains, one method for imparting toughness to rigid polymer materials is the copolymerization approach with soft molecular chains and the addition of rubber particles. In the molecular design of polyurethane, microphase separation consisting of a hard segment and a soft segment also contributes to the material design. However, at the same time, it means the loss of the essential rigidity of the urethane bond by its hydrogen bond, although the microphase separation is widely used. Despite the potential of polyurethane as a rigid biomaterial, microphase separation is required to ensure its biocompatibility. There is therefore a trade-off relationship between rigidity and biocompatibility. Thus, in order to create a novel rigid biomaterial by hydrogen bond of polyurethane, a monomer design providing rigidity and biocompatibility is required. In this study, we designed a rigid polyurethane consisting of a short diol monomer bearing OEG as the side chain in this study in order to achieve both rigidity and biocompatibility simultaneously. This structure greatly differ from the conventional graft SPUs due to highly dense and uniform graft structure and no soft segment in the main chain (Figure 1).

However, the degradation products of the aromatic polyurethane are the aromatic compounds, which has a carcinogenic influence on the living body.21,22 So, the aliphatic isocyanate is suitable for biodegradable polyurethane on their degradation products instead of aromatic isocyanates. Moreover, it has also been reported that the biodegradation rate varies by diisocyanate monomer.23 Therefore, we recognized polyurethane as a good target, making it possible to design a suitable biomaterials for the functionalization. On the other hand, it is necessary for the design of biomaterials to consider the interaction at the interface with the body. In order to enhance biocompatibility, various molecular designs of SPUs focusing on surface properties have been developed.4,5 For example, the graft structures of SPUs bearing anionic sulfonate groups,24 zwitterionic phosphorylcholine groups,25 and noncharged hydrophilic poly(ethylene glycol) (PEG)26,27 are one of the most famous molecular designs for the biocompatible improvement. Among them, it is known that PEG or oligo ethylene glycol (OEG) provides high biocompatibility onto the interface of materials. These designs exhibit a “stealth effect” that resembles the immune system in the body.28 For example, it has been reported that poly(acrylic acid) and poly(methacrylic acid) derivatives bearing OEG afforded high biocompatibility.29,30 It is noteworthy that poly(2-methoxyethyl acrylate) showed an exothermic peak in differential scanning calorimetry (DSC), which could be assigned as crystallizing the intermediate water, closely related to the suppression of nonspecific protein adsorption.31 In addition, the PEG-modified surface can also suppress protein adsorption.32 OEG and PEG have only minor differences in molecular weight, but OEG can be regarded as the superior biocompatible unit with respect to biodegradation ability. It is because that the molecular weights of OEG are less enough to be excreted from the body in urine,33 while PEG cause the possible accumulation in the body due to the inherently nondegradable property. Thus, the biodegradable material modified with OEG can be quickly removed from the body after degradation. That is OEG unit is a nice moiety for the biointerface with high biocompatibility, especially for the design of biodegradable materials. The area of the development of biodegradable polymeric materials is one of the most focused topics for the next generation of biomaterials. Their attractive property is the removal after the long-term biocompatibility and the incorporation of drugs in the materials themselves. Their potential applications include sutures,34 surgical adhesives,35 drug delivery systems (DDS),36,37 scaffolds,38 and orthopedic devices.39 To further their development in the medical field, it is important to replace conventional biomaterials that need to be removed after treatments with the biodegradable polymeric materials. One of the big challenges in the concept is their potential replacement with metal and ceramic materials, such as orthopedic devices40 and stents41 which significantly differ from biodegradable polymeric materials in mechanical properties. In this field, the mainstream research is on crystalline polymers such as poly(lactic acid) and poly(glycolic acid).39,42 However, these polymers have problems on inherent molecular design unless the additional noncovalent interactions would be available, such as hydrogen bonding and π−π stacking, resulting in the poor intermolecular forces. Furthermore, the brittle property has often recognized as a problem in the development of rigid polymeric materials as well as in the biomaterial field. This problem is caused by the fact that the mobility of

Figure 1. Schematic illstration of centipede type polyurethane (a) and conventional graft SPUs (b). The red and blue part consists of diisocyanate monomer and diol monomer, respectively.

Now, we named the centipede type polyurethane after a hard skeleton and countless feets. This structure was designed with the aim of improving biocompatibility with OEG, while keeping the main chain rigid by short diol monomers. We were also interested in the influence of polymer properties when OEG is used as a side chain, which is originally incorporated in the main chain as a conventional polyol. The OEG as the side chain can be expected not only to be biocompatible but also to act as a plasticizer directly connected to the main chain itself while maintaining rigidity. Therefore, our molecular design can be a contribution to knowledge in the development of rigid biomaterials with sufficient toughness. In order to ascertain the influence of polymer structure, we also synthesized a comparative polyurethanes with and without OEG units in the polymer main chain. For isocyanate, HMDI and hexamethylene diisocyanate (HDI) were selected because their degradation products are not carcinogenic. HMDI was expected to exhibit B

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Macromolecules Scheme 1. Synthesis of Diol-graftOEG3

Figure 2. Structures of monomers (a) and polyurethane derivatives (b). spectrometer (Shimadzu) with anisotropic samples annealed under vacuum at 70 °C overnight. Number-average molecular weights (Mn) and distribution (PDI) of polymers were estimated by a size exclusion chromatograph (SEC) equipped with an AS-2055 Plus Intelligent Sampler, PU-2080 Plus Intelligent HPLC pump, a CO-2065 Plus Intelligent Column oven, an RI-2031 Plus Intelligent RI detector (JASCO), and a commercial column (TSKgel Super3000 and GMHXL, Tosoh Corporation). The system was operated with narrow dispersed polystyrene standard (Shodex), using THF as an eluent at 40 °C. DSC was performed using a Hitachi DSC6200 under nitrogen flow. The samples were heated using a second heating cycle from −100 to 200 °C at a rate of 10 °C/min. Thermogravimetric analysis (TGA) was carried out using a Shimadzu TGA-50 from room temperature to 500 °C at a rate of 10 °C/min under nitrogen flow. Contact Angle. Time-dependent contact angles were measured by Flow Design CAM-004 contact angle measuring systems and a TOKAI HIT TPX-S applying 2 μL of ion exchange water onto spin-coated films on a glass plate at 37 °C. The spin-coated films were prepared by an Aiden SC4001 on a glass substrate at 4000 rpm for 1 min with 200 μL of 10 mg/mL polymer in methanol solution. Tensile Test. Tensile testing was performed using a Shimadzu EZSX using strip test pieces cut from films with a crosshead speed of 10 mm/min for PU-HMDI-graftOEG3 and PU-HMDI-PDO or 1 mm/ min for PU-HMDI-OEG5. The films were obtained by casting the polymer DMF solution in a Teflon mold (30 mm × 40 mm × 2 mm) (Supporting Information, Figure S17a). After the gradual evaporation of DMF solvent at 80 °C, the films were vacuumed in steps of 10 °C for 24 h from 40 to 80 °C to prevent from bubble generation. Protein Adsorption. Protein adsorption tests were carried out for dip-coated films on a glass plate using BSA, a protein assay bicinchoninate kit, and a Corona Electric MTP-310Lab. The dipcoated films were prepared by drying after dipping polymer in a dichloromethane (10 mg/mL) solution on a 12 mm round glass coverslip. First, each dip-coated film was immersed into 900 μL of BSA/PBS solution (4.5 mg/mL) for 4 h at 25 °C. After incubation, the

high rigidity owing to its two cyclohexane rings, and HDI was expected to be useful for evaluating the behavior of each diol monomer due to its structural symmetry.



EXPERIMENTAL SECTION

Materials. Triethylene glycol monomethyl ether, HMDI, HDI, trimethylolethane, p-toluenesulfonic acid monohydrate, p-toluenesulfonyl chloride, dibutyltin diacetate, and 1,3-propanediol (PDO) were purchased from Tokyo Chemical Industry Co. Ltd., Japan. Sodium hydride in paraffin liquid (60 wt %), 5 M hydrochloric acid, and the protein assay bicinchoninate kit were purchased from Nacalai Tesque, Inc. Pentaethylene glycol (OEG5), benzaldehyde, phosphate buffer solution (PBS), and bovine serum albumin (BSA) were obtained from Wako Pure Chemical Industries. Sodium dodecyl sulfate (SDS) was purchased from Sigma-Aldrich. Anhydrous tetrahydrofuran (THF) as a polymerization solvent was supplied from Kanto Chemical Co., Inc. The monomer 2-[2-{2-(2methoxyethoxy)ethoxy}ethoxymethyl]-2-methylpropan-diol (DiolgraftOEG3) was prepared according to previous reports44 (Scheme 1). Polymerization. Polymerization of polyurethane derivatives was conducted according to the literature.45,46 The typical procedure for polymerization was as follows. All diol monomers were under vacuum at 70 °C in the presence of activated molecular sieves 4A before use. Dibutyltin diacetate was dissolved in anhydrous THF with activated molecular sieves 4A. HMDI, Diol-OEG3, and the dibutyltin diacetate solution as a catalyst were added and stirred at 60 °C in a dry nitrogen atmosphere for 4 h. After the reaction, the resultant polymer was precipitated into an excess amount of hexane/diethyl ether (1/1, v/v). After the vacuum, the polymer dissolved into THF, and then the linear polymer was separated as the soluble part of the resultant polymer in THF solution. Characterization. 1H NMR spectra were recorded in CDCl3 using a JEOL JNM-ECX400 system. The Fourier transform infrared spectrometry (FT-IR) spectra were measured using an IRAffinity-1S C

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Macromolecules films were washed three times with PBS. Then, the films were immersed into 1 mL of SDS/PBS solution (10 mg/mL) for 4 h at 25 °C in order to remove the absorbed protein from samples. The mixture of 400 μL of protein assay bicinchoninate kit and 400 μL of SDS solution containing the protein from the polymer surface was incubated for 2 h at 37 °C. Then, the UV absorbance of the mixture was recorded with a Corona Electric MTP-310Lab. The amount of absorbed protein from the polymer was estimated with UV absorbance by comparing with a calibration curve of the same protein. Computation. The semiempirical molecular orbital computations were performed with a software package Fujitsu SCIGRESS. The structure optimization was employed the PM6 functional after using the molecular mechanics force field MM3. The potential surface map was described by the exhaustive search on the energy during rotation of the two connected bonds of the alcohol backbone in a dimer model using HMDI as the isocyanate monomer and Diol-graftOEG3 and PDO as the diol monomer. The dihedral angle is defined by the two geometry search labeled CH2−C−CH2−O on the alcohol backbone; the counterclockwise direction based on the cis state has a positive value.

Figure 3. 1H NMR spectra of PU-HMDI-graftOEG3 (a) and PU-HDIgraftOEG3 (b).



All of the polyurethane derivatives were successfully obtained in high yield with molecular weights about 8000−15 000. As regards to the appearance, while all samples using HMDI were colorless to white amorphous solid, PU-HDI-graftOEG3 was sticky solid and PU-HDI-OEG5 and PU-HDI-PDO were crystalline white powders regardless of molecular weight. Furthermore, T10 of polyurethane derivatives using DiolgraftOEG3 (Table 1, entries 1 and 4) was almost same as or slightly lower than that using OEG5 (Table 1, entries 2 and 5) and larger than that using PDO (Table 1, entries 3 and 6). Since both PU-HMDI-graftOEG3 and PU-HDI-graftOEG3 exhibit T10 beyond 270 °C, Diol-graftOEG3 can maintain the excellent thermal stability required for use as biomaterials that can withstand heat sterilization treatment of around 200 °C (Table 1, entries 1 and 4). Figure 4 shows DSC curves of polyurethane derivatives, which were used for determination of Tg and Tm values. All samples using HMDI showed Tg values more than 20 °C (Table 1, entries 1−3), although those using HDI were lower than around −30 °C except for PU-HDI-PDO (Table 1, entries 4 and 5). PU-HDI-OEG5 and PU-HDI-PDO which are a combination of a symmetrical isocyanate HDI and a linear diol monomer are crystalline since they exhibit Tm at 60 and 150 °C (Table 1, entries 5 and 6). In particular, PU-HDI-PDO has too high a crystallinity to define Tg clearly (Figure 4f). We assumed that the graft structure of OEG would behaves as a plasticizer because PU-HDI-graftOEG3 has no crystallinity evidenced by the disappearance of Tm (Table 1, entries 1−4). This interpretation was also supported by the low Tg of less than −30 °C on PU-HDI-graftOEG3 and PU-HDI-OEG5 (Table 1, entries 4 and 5). Normally, it is known that polyurethanes using HDI with a high content of hard segment have a Tg of around −30 °C,18 suggesting that this value depends on the flexible structure of HDI. In contrast, polyurethane derivatives using HMDI having a rigid structure showed discrete Tg (Table 1, entries 1−3). Focusing on PU-HMDI-graftOEG3 and PUHMDI-PDO using a shorter diol monomer of trimethylene structure, their Tg’s are significantly different between 35 °C (Table 1, entry 1) and 73 °C (Table 1, entry 3). The large difference of Tg between similar structures has been already reported by the different flexibility of polymer main chain.47,48 However, comparing the structure of Diol-graftOEG3 and PDO, it can be considered that Diol-graftOEG3 is harder than PDO due to the existence of a substituent as the side chain, as shown by computation later. Therefore, this result is also supported for the role of plasticity by Diol-graftOEG3.

RESULTS AND DISCUSSION For the development of a rigid and tough biocompatible material, novel polyurethane derivatives bearing homogeneous OEG as the side chain were designed and synthesized by polyaddition between synthetic trimethylene diol modified OEG as the side chain and aliphatic diisocyanate. In the diol monomer, three units of OEG were selected as having suitable hydrophilicity to make the corresponding polyurethane insoluble in water in consideration of the environment in the body. In order to consider the effect of OEG as the side chain, polyurethane derivatives using pentaethylene glycol diol monomer (OEG5) which has the same number of oxygen atoms as the diol bearing OEG and PDO which has the same main chain without OEG as the side chain were also synthesized. HMDI and HDI were chosen as the aliphatic diisocyanate monomers which were expected to yield polyurethane products with high biocompatibility and low toxicity of the degradation products. The structures of the series of monomers and polyurethane derivatives in this study are shown in Figure 2. To compare properties of polyurethane derivatives from the perspective of primary structure, the linear polymers were obtained by collecting the soluble moiety polyurethane derivatives in THF solution. All of the characterizations were performed on the linear polyurethane. Figure 3 shows the 1H NMR spectra of PU-HMDIgraftOEG3 and PU-HDI-graftOEG3, novel polyurethane derivatives bearing OEG as the side chain. Methylene protons being adjacent to the hydroxyl group of diol-graftOEG3 were shifted to the low field side to around 3.9 ppm by the formation of a urethane bond on polymerization. Likewise, protons derived from methine of HMDI and methylene of HDI were also moved to around 4.6 and 4.8 ppm (Figure 3a) and 3.1 ppm (Figure 3b). Furthermore, the methyl proton around 0.8 ppm of diol-graftOEG3 in the trimethylene backbone was slightly shifted to 0.9 ppm due to polymerization (Figure S4). The successful polyaddition of polyurethane derivatives was therefore confirmed. Both PU-HMDI-graftOEG3 and PU-HDIgraftOEG3 contain a small amount of moisture due to the hydrophilic group OEG. Polymerization results are summarized in Table 1, including the number-average of molecular weight (Mn), the glass transition temperature (Tg), the melting temperature (Tm), and the decomposition temperature of 10% weight loss (T10). D

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Macromolecules Table 1. Polymerization of Polyurethane Derivatives monomer entry 1 2 3 4 5 6

sample PU-HMDI-graftOEG3 PU-HMDI-OEG5 PU-HMDI-PDO PU-HDI-graftOEG3 PU-HDI-OEG5 PU-HDI-PDO

isocyanate HMDI HMDI HMDI HDI HDI HDI

alcohol Diol-graftOEG3 OEG5 PDO Diol-graftOEG3 OEG5 PDO

yielda (%)

Mnb (kg/mol)

>99 >99 >99e 97 >99 >99e

12.0 11.8 9.1 8.9 8.8 15.4

PDIb

Tgc (°C)

2.47 1.84 1.86 1.72 2.15 1.80

35 −31, 27 73 −32 −52 NDf

Tmc (°C)

T10d (°C)

appearance

294 294 243 275 294 267

colorless solid colorless solid colorless solid colorless sticky solid white powder white powder

f

ND NDf NDf NDf 60 150

a

Isolated as hexane/diethyl ether (1/1, v/v) insoluble part. bDetermined by SEC. cDetermined by DSC. dDetermined by TGA. T10 is the temperature which 10% of the weight was lost. eIsolated as methanol insoluble part. fNot determined.

ethane based on symmetrical isocyanates has also been reported by other groups,20 suggesting an ordered hydrogen bonding state. Specifically, in polyurethanes based on HDI and a linear diol such as OEG5 and PDO, the packing structure is promoted by their symmetry, suggesting the formation of a wide range of crystalline regions. On the other hand, PU-HDI-graftOEG3 consisting of the same symmetrical HDI shows a broad N−H stretching vibration indicating that a disordered hydrogen bonding state is formed due to packing inhibited by the graft structure (Figure 5d). Unlike N−H stretching vibration, several peak tops were observed in CO stretching vibration region. According to the literature,20,49,51−53 CO stretching vibration in polyurethane is roughly divided into free and hydrogenbonded groups at 1720−1735 and 1690−1705 cm −1 , respectively. In addition, hydrogen-bonded CO stretching vibration is classified as ordered and disordered, on the higher and lower frequency side, respectively.50,54 On the basis of these, peak top positions of CO stretching vibration of polyurethane derivatives are summarized in Table 2. In PU-

Figure 4. DSC traces of PU-HMDI-graftOEG3 (a), PU-HMDI-OEG5 (b), PU-HMDI-PDO (c), PU-HDI-graftOEG3 (d), PU-HDI-OEG5 (e), and PU-HDI-PDO (f).

FT-IR spectra of THF soluble part of polyurethane derivatives are shown in Figure 5 and Figure S9. N−H

Table 2. Peak Top Wavenumber of CO Stretching Vibration of Polyurethanes wavenumber (cm−1) hydrogen bonded

a

Figure 5. FT-IR spectra of PU-HMDI-grafOEG3 (a), PU-HMDIOEG5 (b), PU-HMDI-PDO (c), PU-HDI-graftOEG3 (d), PU-HDIOEG5 (e), and PU-HDI-PDO (f).

entry

sample

free

disordered

ordered

1 2 3 4 5 6

PU-HMDI-graftOEG3 PU-HMDI-OEG5 PU-HMDI-PDO PU-HDI-graftOEG3 PU-HDI-OEG5 PU-HDI-PDO

1715 1715 NDa 1715 NDa NDa

1697 1695 1690 1697 NDa NDa

NDa NDa NDa NDa 1682 1682

Not determined.

HMDI-graftOEG3, PU-HMDI-OEG5, and PU-HDI-graftOEG3 it is presumed that there is a non-hydrogen-bonded free carbonyl peak at 1715 cm−1 due to the fact that they all exhibit the same frequency (Table 2, entries 1, 2, and 4). Moreover, the peak of ordered hydrogen-bonded carbonyl could be confirmed at a lower wavelength side clear as peaks at 1682 cm−1 were observed in PU-HDI-OEG5 and PU-HDIPDO (Table 2, entries 5 and 6). This result is consistent with the presumption by N−H stretching vibration peak pattern at around 3300 cm−1 because the packing to create crystalline phase is promoted by the ordered hydrogen bonding between CO and N−H. Futhermore, the free CO stretching vibration was clearly confirmed in PU-HMDI-graftOEG3 and PU-HDI-graftOEG3 (Table 2, entries 1 and 4), thus suggesting

stretching vibration peaks of urethane moiety are observed at around 3300 cm−1. Similarly, around 1700 cm−1 peaks are also ascribed to CO stretching vibration derived from urethane moiety. No peak was observed at the region between 2275 and 2250 cm−1 for isocyanate, suggesting no residual isocyanate group after reaction and polyurethanes were successfully synthesized (Figure S9). Peak top positions of N−H stretching vibration at around 3320 cm−1 are the almost same in all polyurethane derivatives, which is a hydrogen bond with carbonyl.20,49−52 In addition, PU-HDI-OEG5 and PU-HDIPDO (Figures 5e and 5f) showed sharper peak patterns than the others. Such sharp N−H stretching vibration in polyurE

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account, it is suggested that hydrophobic aliphatic carbon moieties are biased to the surface by their flexible segments in the case of PU-HMDI-OEG5 (Figure 6b), PU-HDI-graftOEG3 (Figure 6c), and PU-HDI-OEG5 (Figure 6d). This therefore indicates that PU-HMDI-graftOEG3 (Figure 6a) not only does not segregate but also has uniform hydrophilic and hydrophobic moieties in processes such as film production. Since the constant hydrophilicity was revealed, we collected basic information on the surface for the biomaterial application for the PU-HMDI-graftOEG 3 . The results of protein adsorption are shown in Figure 7. The amount of albumin

the OEG as the side chain in Diol-graftOEG3 inhibites main chain packing. So, the results indicate that Diol-graftOEG3 in polyurethane made a role for promoting amorphous property. Next, we move to investigate the surface properties of the polyurethanes. Figure 6 shows the time-dependent water

Figure 6. Time-dependent contact angle of water droplet of the spin coated film of PU-HMDI-graftOEG3 (a), PU-HMDI-OEG5 (b), PUHDIgraft-OEG3 (c), and PU-HDI-OEG5 (d) by MeOH solution onto glass substrate at 37 °C (n = 10).

contact angles of films prepared by the polyurethane derivatives. Previously, we have reported the surface segregation of the block copolymers composed of the hydrophobic poly(lactic acid) and the hydrophilic polycarbonate bearing the same Diol-graftOEG3 moiety as the side chain.55 In the report, the contact of water onto the film surface caused the hydrophilic moieties were condensed over several seconds, analyzed by XPS and AFM. This phenomenon was attributed to the movement of the hydrophilic trimethylene structure grafted OEG moiety. That is, the trimethylene structure in this block copolymer could be regarded as a soft segment. In the case of polyurethane, which possesses the same composition as soft and hard segments, the segregation phenomenon on the water contact surface has often been comfirmed.56,57 This kind of segregation phenomenon is apt to occur in polymers bearing hydrophilic and hydrophobic moieties because it is accomplished by partial motion of polymer chains for surface energy minimization.55,58−60 Thus, the changes of contact angles of water droplet on the surfaces were also monitored for the selected polyurethanes in this study, bearing Diol-graftOEG3 as a function for hydrophilic condensation as shown in Figure 6. The constant value was observed in the case of PU-HMDIgraftOEG3 (Figure 6a). Therefore, no surface segregation on the PU-HMDI-graftOEG3 film indicates that the overall polymer chain moves with difficulty due to its rigidity. In addition, the order of hydrophilicity of polyurethane derivatives was ranked in order as follows: PU-HMDI-graftOEG3 (Figure 6a) > PU-HDI-OEG5 (Figure 6d) > PU-HMDI-OEG5 (Figure 6b) > PU-HDI-graftOEG3 (Figure 6c) at the starting time, but it changed to the order after about 50 s as follows: PU-HDIOEG5 (Figure 6d) > PU-HDI-graftOEG3 (Figure 6c) > PUHMDI-OEG5 (Figure 6b) > PU-HMDI-graftOEG3 (Figure 6a), which can be predicted by counting aliphatic units of their chemical structures. In particular, PU-HMDI-graftOEG3 was the most hydrophilic immediately after starting measurement (0 s) though the most hydrophobic after a certain time (60 s) (Figure 6a). It has been reported that the segregation phenomenon of hydrophobic moiety occurs due to air during processing such as coating61 and annealing.62 Taking this into

Figure 7. Albumin adsorption of PU-HMDI-graftOEG3 (a), PUHMDI-OEG5 (b), PU-HMDI-PDO (c), PU-HDI-graftOEG3 (d), PUHDI-OEG5 (e), PU-HDI-PDO (f), and glass substrate (g). *Significantly different from each other (p < 0.05). **Significantly different from each other (p < 0.005). NS means no significant difference (n = 5).

adsorption is 0.64 ± 0.52 μg/mL on PU-HMDI-graftOEG3 (Figure 7a), 0.66 ± 0.53 μg/mL on PU-HMDI-OEG5 (Figure 7b), 3.11 ± 1.20 μg/mL on PU-HMDI-PDO (Figure 7c), 1.05 ± 0.44 μg/mL on PU-HDI-graftOEG3 (Figure 7d), 1.08 ± 0.44 μg/mL on PU-HDI-OEG5 (Figure 7e), 3.65 ± 0.47 μg/mL on PU-HDI-PDO (Figure 7f), and 6.16 ± 0.91 μg/mL on glass plate (Figure 7g). There are significant differences in the amount of absorbed protein between the glass plate as a control (Figure 7g) and all films with polyurethane derivatives on them. Focusing on the structure of diol monomers, polyurethane derivatives using Diol-graftOEG3 and OEG5 clearly decrease the adsorption amount for PU-HMDI-PDO and PU-HDI-PDO using a shorter diol, PDO. Comparing the structure of PDO and Diol-graftOEG3, the graft structure of OEG clearly contributes to restraint of the protein adsorption amount as with the vinyl polymer bearing OEG reported by the other groups.28−32 Moreover, it indicates that the chemical structure of OEG prevents the protein adsorption, since there was no difference in the protein adsorption amount between those using Diol-graftOEG3 and OEG5. According to the literature,35 it is reported that PU-HMDI-OEG5 analogues have excellent biocompatibility, suggesting that PU-HMDI-graftOEG3 also has the structure capable of successfully suppressing protein adsorption because it shows almost the same amount of adsorbed protein. Therefore, the novel molecular design of polyurethane bearing OEG as the side chain probably functions as the structure for suppressing protein adsorption, which can replace conventional polyurethane using OEG in the main chain. F

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Macromolecules

almost the same main chain (Figure 8c), there is a distinct difference in elongation at break but only a slight difference in Young’s modulus. Moreover, the graft structure of OEG contributes not only to toughness but also to a slight improvement of rigidity. It is presumed that the rigidity of the molecular chain is increased by the effect of introducing OEG into the side chain; thereby the conformation of the polymer chain is already close to the elongation chain at the initial deformation at the initial stage. Generally, in rigid chains such as PU-HMDI-PDO in this study, toughness is sacrificed due to their lower entanglement of molecular chains; however, PU-HMDI-graftOEG3 has both rigidity and toughness. This result looked strange if PU-HMDI-graftOEG3 would be considered a stiff molecular chain more than PU-HMDIPDO. According to FT-IR results, PU-HMDI-graftOEG3 showed fewer hydrogen bonds between CO and N−H than PU-HMDI-PDO, suggesting that the different microstructure occur given their mechanical properties. Namely, it indicates that Diol-graftOEG3 units play an important role in efficient dispersion of stress while maintaining rigidity by the side chain OEG unit. As the similar effect for improving toughness of a rigid polymer, it is known the external plasticization on polymer blend or the internal plasticization on copolymerization. However, the graft structure of OEG differs from that because it affects not only toughness but also rigidity, although the plasticization mentioned above acts on only toughness. Therefore, in PU-HMDI-graftOEG3, the molecular design for graft structure of OEG in a rigid molecular chain successfully realized rigidity and toughness. According to the literature,66 it has been reported that the tensile modulus at initial stage is related to continuity between the extended alltrans sequences in polyethylene as a simple model. Thus, it is assumed that PU-HMDI-graftOEG3 has different conformation properties and attendant microstructure than PU-HMDI-PDO. For the assessment of the properties of Diol-graftOEG3 as a segment in the polyurethane, Figure 9 shows the computation result of the potential surface of dihedral angle change by the semiempirical molecular orbital method PM6. The dimer model using Diol-graftOEG3 shows an asymmetrical and steep potential surface despite its symmetrical structure (Figure 9a). The valley bottom of low energy corresponding to a conformer with a high existence probability is biased around some dihedral angle. This biased shape of the potential surface indicates that the motion of the alcohol unit is restricted by the OEG unit and methyl group. On the other hand, those using PDO have multiple valleys of similar energy within 1 kcal/mol, indicating that the stable structure is diverse; thus, it has a flexible structure (Figure 9b). This result supports the contention that the Diol-OEG3 unit functions as a harder segment than the PDO unit. It is consistent with the result that PU-HMDIgraftOEG3 has the mechanical property of higher rigidity than PU-HMDI-PDO because it is in the state closer to the extended chain at the initial stage.

Figure 8 shows stress−strain curves of polyurethane derivatives. The stress−strain behavior of PU-HMDI-OEG5

Figure 8. Stress−strain curves for PU-HMDI-graftOEG3 (a), PUHMDI-OEG5 (b), and PU-HMDI-PDO (c).

(Figure 8b) where the stress value keeps increasing even after the elastic region is akin to a typical segmented polyurethane.17 It is due to the formation of oriented polymer chains according to elongation derived from the soft segment of OEG5.63 On the other hand, the stress−strain curve of PU-HMDIgraftOEG3 shows a high modulus and plastic deformation attending yield as a local maximum (Figure 8a). A similar shaped curve is also observed in PU-HMDI-PDO having the same main chain unit as Diol-graftOEG3 without OEG moiety as the side chain (Figure 8c). This type of stress−strain behavior in polyurethanes has been occasionally reported in the high hard segment content.64 According to the literature,65 “the yielding behavior is found in crystalline polymers and it is described that the external force applied through these intercluster links decomposes the lamellar clusters into their fragments (cluster units) at the yield point”. In other words, it is caused by the existence of a strong aggregated structure such as a lamellar cluster. Thereby, the plastic deformation indicates that their shorter diol monomer, resulting in a high content of hard segment, behaves as a whole hard segment rather than a soft segment. The mechanical properties of polyurethane derivatives are summarized in Table 3. Table 3. Mechanical Properties of Polyurethane Derivatives entry

sample

1

PU-HMDIgraftOEG3 PU-HMDIOEG5 PU-HMDIPDO

2 3

tensile modulus (MPa)

strain at break (%)

stress at break (MPa)

stress at yield (MPa)

1722 ± 149

184 ± 22

46 ± 5

53 ± 4

115 ± 40

370 ± 32

14 ± 1

7±1

739 ± 7

19 ± 5

25 ± 2

38 ± 0



PU-HMDI-graftOEG3 has a Young’s modulus of 1722 ± 149 MPa, elongation at break of 184 ± 22%, and a tensile strength of 46 ± 5 MPa, thus possessing both rigidity and toughness with excellent mechanical properties (Table 3, entry 1). Both of PU-HMDI-graftOEG3 (Figure 8a) and PU-HMDI-PDO (Figure 8c) are composed of the shorter diol units, resulting in the rigid mechanical properties because of their high content of hard segments. It is significantly different from the typical polyurethanes using polyols, such as PU-HMDI-OEG5 (Figure 8b). Additionally, compared with PU-HMDI-PDO which has

CONCLUSION In conclusion, a novel polyurethane bearing OEG as the side chain was designed and synthesized yielding a rigid polyurethane biomaterial. FT-IR spectra and DSC curves suggested that the graft structure of OEG inhibits packing of molecular chains and behaves like a plasticizer. Moreover, in the timedependent contact angle measurement, the large movement of the molecular chain of PU-HMDI-graftOEG3 is probably restricted because it alone did not exhibit surface segregation. G

DOI: 10.1021/acs.macromol.7b00629 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

Figure 9. Potential energy surfaces of a symmetrical dimer model of PU-HMDI-graftOEG3 (a) and PU-HMDI-PDO (b).



This unique graft structure of polyurethane significantly affected the mechanical properties; PU-HMDI-graftOEG3 showed excellent rigidity and toughness due to the rigid main chain and the effect of side chain OEG. In addition, the grafted OEG also had a successful impact on suppressing protein adsorption. Therefore, the novel polyurethane in this study succeeded in having rigidity, toughness, and biocompatibility. This research provides important knowledge for the design of rigid polyurethane biomaterials that have potential as biodegradable materials instead of metal owing to their hydrogen bond. The microstructure of polyurethane bearing OEG as the side chain and the effect of the main chain structure and OEG structure are currently under investigation.



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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.7b00629.



REFERENCES

Experimental details; Figures S1−S23 and Tables S1−S4 (PDF)

AUTHOR INFORMATION

Corresponding Author

*(H.A.) E-mail [email protected]. ORCID

Hiroharu Ajiro: 0000-0003-4091-6956 Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS This work is supported by JST PRESTO “Molecular technology” under the direction of Prof. Takashi Kato. We also thank Prof. Hironari Kamikubo for performing small-angle X-ray scattering analysis. H

DOI: 10.1021/acs.macromol.7b00629 Macromolecules XXXX, XXX, XXX−XXX

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J

DOI: 10.1021/acs.macromol.7b00629 Macromolecules XXXX, XXX, XXX−XXX