Synthesis and Characterization of Novel Blood-Compatible Soluble

Biomacromolecules 2005, 6, 1713-1721

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Synthesis and Characterization of Novel Blood-Compatible Soluble Chemically Cross-Linked Polyurethanes with Excellent Mechanical Performance for Biomedical Applications Zunfeng Liu,‡ Xiang Wu,† Xiaoying Yang,§ Dongping Liu,‡ Chen Jun,† Ruimin Sun,† Xueping Liu,† and Fangxing Li*,†,‡ State Key Lab of Functional Polymer Materials for Adsorption and Separation, Tianjin 300071, P.R.C, and Department of Chemistry, Nankai University, Tianjin 300071, P.R.C, Pharmaceutical College, Tianjin Medical University, Tianjin 300070 P.R.C. Received December 31, 2004; Revised Manuscript Received January 31, 2005

A controlled cross-linking polymerization system was designed, and soluble chemically cross-linked polyurethane was synthesized using laurylamine, n-octylamine, n-pentylamine, and ethylenediamine chain extenders. The mechanical analysis showed that the polyurethane materials synthesized in this paper have very excellent mechanical properties with a breaking elongation of 1914% and a tensile strength of 4303 N/cm2. Such good mechanical properties must enable it to have good longevity when used as biomaterials. The polyurethane materials with n-pentylamine and n-octylamine chain extenders show reduced platelet adhesion than that with an ethylenediamine chain extender after sustaining 200 000 times of load cycles, indicating that polyurethanes introduced with an alkyl side chain onto the hard segments keep good antithrombogenic properties after sustaining load cycles. This might be because the hard segments are shielded by the alkyl side chain when the micro-phase-separation structure is destroyed in the repeated deformation of the polyurethane materials. The present investigation reveals that the influence of introducing long alkyl side chains into the backbone of the polyurethane macromolecule has been shown to reduce platelet deposition and to enhance in vitro albumin adsorption. However, in this paper, it has been observed that the polyurethane material introduced with a proper-length alkyl side chain onto the hard segment has the best antithrombogenic properties after the fatigue test. 1. Introduction Polyurethanes (PUs) have been used for various biomedical applications, viz., cardiovascular devices, in comparison to the other elastomers due to appreciable physical and mechanical properties and biocompatibility.1,2 During the past few decades, PUs have been widely used for biomedical applications such as vascular prostheses, endotracheal tubes, pacemaker lead wire insulation, catheters, and artificial hearts due to their excellent mechanical properties and comparatively good tissue and blood compatibility.1,2 For most cardiovascular products, in which polyurethanes are incorporated as a structural or coating material, it is essential that the material should be not only stable for a prolonged period but also blood-compatible if inserted into the blood stream. It has been reported that PUs show a high affinity for albumin adsorption and low platelet reactivity, and introducing an alkyl side chain or incorporating phospholipids or phosphatidylcholine analogues into the polyurethane backbone has been shown to improve its blood compatibility.3-22 * To whom correspondence should be addressed. E-mail: lifangxing@ nankai.edu.cn. † State Key Lab of Functional Polymer Materials for Adsorption and Separation. ‡ Nankai University. § Tianjin Medical University.

However, the mechanical strength of the films prepared from these polyurethanes is almost too weak to prepare real films or tubes. To improve the mechanical strength and biodurability of this material for practical biomedical application, some contributions have focused on the physically cross-linked polyurethane elastomers for long-term applications.23-26 The urea groups in a polyurethane are potential sites for intermolecular hydrogen bonding leading to a physically cross-linked structure and are responsible for the high flex life. However, soluble polyurethane with a chemically crosslinked structure has never been reported. This study deals with the synthesis of soluble chemically cross-linked polyurethane from PTMG, MDI, and diamine or monoamine and the characterization of its mechanical properties and blood compatibility in vitro. The main reactions with a diamine chain extender are shown in Scheme 1. The oligomer capped with -NCO with an isocyanate index of 200% was formed in reaction I. Reaction II is the chain extension step. In this step, reducing the amount of the chain extender leads to the formation of NCO-terminated prepolymers. The rest of the remaining -NCO groups can react with the H atoms of -NHCOO- and -N(CONH)2 groups to give allophanate and biuret groups, respectively, resulting in the cross-linking of the prepolymer.27,30-32 (H atoms in allophanate and biuret groups can also react with

10.1021/bm049173x CCC: $30.25 © 2005 American Chemical Society Published on Web 03/30/2005

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Biomacromolecules, Vol. 6, No. 3, 2005

Scheme 1. Reactions in the Polymerization Comprising of a Diamine Chain Extender

-NCO groups.) Reaction site A in reaction III occurs inside a macromolecule, called an intramolecular reaction, which consumes reactive groups and forms cyclic structure but does not increase the molecular weight. Reaction site B in reaction III occurs between two macromolecules, called an intermolecular reaction, which produces the branched and crosslinked structure. They are a pair of competitive reactions. When a great amount of the functional groups are consumed by the intramolecular reaction and the reactive functional groups on the coil’s surface is below the critical level to permit further intermolecular reaction, the cross-linking process can be controlled and soluble polyurethane (intramolecularly cross-linked macromolecules (ICMs)) with huge size will be synthesized.28-31 Reactions with a monoamine chain extender are shown in Scheme 2.32 The mechanical evaluation shows that soluble chemically cross-linked PUs exhibit very good mechanical properties, especially breaking elongation, which might originated from the network structure and the very large molecular weight.31 The platelet adhesive test results show that the PU materials added an alkyl side chain to the hard segment using a monoamine chain extender, which keeps good antithrombogenic properties when the micro-phase-structure of PU materials was destroyed after the fatigue test, which might be because the exposed hard segments can be shielded by the alkyl side chains to minimize the surface free energy. The PU materials introduced with a proper length of alkyl side chain exhibit the best antithrombogenic properties. 2. Experimental Section 2.1. Materials. PTMG (Mn 1568) was prepared in our laboratory.34 4,4′-Methylenediphenyl diisocyanate (MDI),

Liu et al. Scheme 2. Reactions in the Polymerization Comprising of a Monoamine Chain Extender

laurylamine (LA), n-octylamine (OA), n-pentylamine (PA), ethylenediamine (EA), tetrahydrofuran (THF), and dimethyl formamide (DMF: plant of Chemical reagent, Tianjin, PRC) were purified by low-pressure distillation prior to use. 2.2. Polymerization. In a four-neck flask equipped with a stir bar, reflux condenser, and N2 on command, MDI was added and melted at 60 °C. Then PTMG was slowly added dropwise and maintained at 60 °C for 1 h. The reaction mixture was then cooled to room temperature, and then DMF and the chain extender (LA, PA, OA, and EA for the four samples, respectively) was added. The reaction was then allowed to stir at room temperature for 0.5 h, after which time it was warmed to 60 °C and stirred for an additional 1 h. Then it was warmed to 80 for 2 h and then warmed to 90 °C for an additional 2 h. The mixture was then poured into a mold to remove the solvent. After evaporation of the solvent, the sample was dried to a constant weight at 70 °C under vacuum. 2.3. Measurement of Mechanical Properties. The mechanical properties of the samples were measured on a universal testing machine (KN M500-10 test metric, U.K.) according to GB528-76 with a tensile speed of 300 mm/ min at 23 ( 0.2 °C to obtain the tensile strength (σb) and the breaking elongation (b). 2.4. Hemocompatibility Studies. The blood-material interaction is a measure of hemocompatibility of polyurethanes. The blood compatibility of present polyurethanes is investigated by measuring the reduction of platelets in blood after exposure of the polymers to human blood. Blood was drawn from healthy donors by venipuncture through a 21 gauge needle into a syringe containing the anticoagulant

Biomacromolecules, Vol. 6, No. 3, 2005 1715

Synthesis and Characterization of Polyurethanes

sodium citrate (1 volume of 3.8% sodium citrate to 9 volumes of blood) and mixed gently. One milliliter of blood was incubated with each polymer material in a multiwell tissue culture plate for 30-50 min at 37 °C with occasional shaking. Uniform square samples with a total surface area of 220 mm2 (10 mm sidelength and 0.5 mm thickness) were used. The experiment was conducted in triplicate. Blood taken in the tissue culture plate (without material) was used as the control. The platelet adhesion index (PAI) was calculated according to eq a η)

n0 - n × 100% n0

(a)

where η is PAI, n0 is the platelet count in the control, and n is the platelet count after blood-material contact. 2.5. Fatigue Test. The fatigue tests were performed on a homemade fatigue test machine in the air at 37 °C at a frequency of about 4 Hz. The strain rate estimated would be 7 s-1, and the dynamic strain reached 40%. All of the force variation is repeated a total of 200 000 times. 2.6. Molecule Size. A photon correlation spectrometer (PCS) was used to determine the macromolecular size at 25 °C, with a BI-900-AT correlator, a BI-200-SM photometer, and an Innova 304 argon laser. λ was 514.5 nm, the power was 1 W (Coherent Co., USA), and the practical power was under 200 mW. The solvent was DMF. The dust in the solution was removed by ultracentrifugation.33 3. Results and Discussion 3.1. Nomination and the Basic Parameters of the Samples. 3.1.1. Nomination of the Samples. In this paper, the sample is denominated “1568X-r”, where 1568 is the number-averaged molecular weight of PTMG, X is the abbreviation of the chain extender, the value r is the molar ratio of the amine H atoms of the chain extender to the NCO groups in the oligmer formed in reaction I. 3.1.2. Isocyanate Index and AVerage Molecular Weight of the Oligmer. The polymerization system in this paper is a two step reaction. First, MDI reacts with PTMG to give an isocyanate-terminated oligmer. Second, in the chain extension step, the oligmer reacts with chain extender to give an isocyanate-terminated prepolymer. If there are excess -NCO groups, branching reactions will occur and crosslink points will be formed. During the first step (reaction I), because the ratio of MDI to PTMG is 2:1, the isocyanate index (NCO-OH ratio) of the isocyanate-terminated oligmer is 200%, and consequently, the molecular weight of the oligmer is 2068. 3.1.3. Isocyanate Index and AVerage Molecular Weight of the Prepolymer and the Functionality of the Reactants in Reaction II. During the chain extension step (reaction II), the isocyanate index of the prepolymer is the molar ratio of -NCO groups on the end of oligmer to the amine H in the chain extender, for example, the isocyanate indexes of prepolymer of samples 1568EA-r, 1568LA-r, 1568OA-r, 1568PA-r, are 1/r. The functionality of the reactants should be calculated based on the -NCO groups in the oligmer

because all of the -NCO groups can be consumed in the following reactions. In a polymerization system with a diamine chain extender, such as 1568EA-r in this paper, the functionality of the reactants can be calculated by eq b hf )

2×2×1 r 1+ 2

(b)

The hf numbers of the each sample with different diamine chain extenders are listed in Table 1. The average molecular weight of the prepolymer can be calculated as

(

Mp ) 2

)

4136 + rMe 1+r 1 1 + r r Me ) 2068 + , 1-r1+r 1-r1+r 2 1-r (r > 0) (c)

where Mp is the average molecular weight of the prepolymer, Me is the molecular weight of the diamine chain extender, and the number 2068 is the molecular weight of the oligmer. In a polymerization system with a monoamine chain extender, such as 1568LA-r, 1568OA-r, and 1568PA-r, the functionality of the reactants can be calculated by eq d hf )

2×2×1 1+r

(d)

The average molecular weight of the prepolymer can be calculated as Mp )

2068 + rMe 1+r r 1+r 1 2068 + Me ) , 1-r1+r 1-r1+r 1-r (r g0) (f)

where Me is the molecular weight of the monoamine chain extender. 3.1.4. Degree of Cross-Linking of the Samples. Traditionally, the average molecular weight between two cross-links (Mc) is used to evaluate the degree of cross-linking. Because the PU samples in this work are soluble, it is difficult to determine the Mc using the Flory-Rehner equation. Therefore, we calculate it in theory. First, assuming that a perfect network (chains existing between two cross-links do not form network defects such as dangling chain ends or loops) was formed, we can get φµ ) 2N

(g)

where φ is the cross-link functionality, µ is the amount of cross-link points, and N is the amount of chains between two cross-link points. Then N)

φµ 2

(h)

For the polymerization system with a monoamine chain extender, such as 1568MA-r, the degree of polymerization of (X h n) the prepolymer can be calculated by eq i X hn )

1+r 1-r

(i)

Assuming that the amount of isocyanate-terminated oligmer

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Table 1. Basic Parameters of PU Samples in This Paper

sample

D.C. (Mc)

NCO index of the oligmer (%)

molecular weight of the oligmer

NCO index of the prepolymer (%)

MP

functionality of the reactants in reaction II

1568-EA-1 1568-EA-0.85 1568-EA-0.7 1568-EA-0.6 1568-EA-0.5 1568-EA-0.4 1568-EA-0.25 1568-EA-0.12 1568-EA-0 1568-LA-0.5 1568-OA-0.5 1568-PA-0.5

2098 1610.4 1305.6 1158.9 1041.5 945.5 830.2 750.6 689.3 1440.3 1421.7 1402

200 200 200 200 200 200 200 200 200 200 200 200

2068 2068 2068 2068 2068 2068 2068 2068 2068 2068 2068 2068

100 117.6 142.9 166.7 200 250 400 833.3 ∞ 200 200 200

∞ 27913.3 13926.7 10430 8332 6933.3 5534.7 4708.2 2068 4336 4280 4238

2.67 2.81 2.96 3.08 3.2 3.33 3.56 3.77 4 2.67 2.67 2.67

is n mol, the amount of MA will be nr mol, and then the amount of the prepolymer can be calculated by eq j np )

n + nr X hn

(j)

where np is the molar amount of the prepolymer. The -NCO groups on the end of the prepolymers can react with the H atoms to produce cross-link points with a crosslink functionality of 3. Then we can get the molar amount of cross-link points µ ) 2np

(k)

From eqs g-k, we can get N ) 3n(1 - r)

(l)

Then we can get the average molecular weight between two cross-links Mc )

Then N ) (3 - 2r)n

m N

(m)

m ) 2068n + Mern

(n)

where Mc is the average molecular weight between two crosslinks and m is the weight of the network. From eqs l-n, we can get Mc )

Figure 1. Effect of the amount of chain extender on the tensile strength and the breaking elongation of PU materials with an EA chain extender.

2068 + Mer 3(1 - r)

(o)

For the polymerization system with a diamine chain extender, i.e., 1568EA-r in this paper, assuming that the amount of isocyanate-terminated oligmer is n mol, then the amount of EA is rn/2 mol. Because one of the excess -NCO groups can produce one cross-linking point with a cross-linking functionality of 3, the excess of -NCO groups can produce 2(n - nr) ) 2n(1 - r) mol of cross-link points. Because one EA molecule can produce one cross-link point with a cross-link functionality of 4, the amount of cross-link points provided by EA molecules is 2nr/4 ) rn/2 mol. Consequently, eq g becomes the following formulation: nr ) 2N 2

3[2n(1 - r)] + 4

(p)

(q)

Then we can get the average molecular weight between two cross-links m Mc ) ) N

2068n + Me (3 - 2r)n

rn 2

)

4136 + Mer 2(3 - 2r)

(r)

where Me is the molecular weight of the diamine chain extender. The basic parameters are listed in Table 1. 3.2. Influence of the Amount of the Chain Extender on the Mechanical Performance of PU Materials. The mechanical performance was measured on the samples 1568EA-0, 1568EA-0.12, 1568EA-0.25, 1568EA-0.4, 1568EA-0.5, 1568EA-0.6, 1568EA-0.7, 1568EA-0.85, and 1568EA-1. The tensile strength and breaking elongation were plotted versus the molar ratio of amine H atoms to -NCO groups, shown in Figure 1. Figure 1 shows the mechanical performance of PU materials with different amounts of chain extender. All of the PU materials show a very excellent mechanical performance, especially the breaking elongation. It is very surprising and interesting that the sample with a ratio of amine H/NCO ) 0.4 exhibits a maximum breaking elongation value


Synthesis and Characterization of Polyurethanes Table 2. Molecular Size of Sample 1568-EA Series samples

molecular size (nm)

D.C. (Mc)

conc. (g/mL)

1568-EA-1 1568-EA-0.7 1568-EA-0.5 1568-EA-0.25 1568-EA-0

173 243 217 187 282

2098 1305.6 1041.5 830.2 689.3

10-6 10-6 10-6 10-6 10-6

Table 3. Mechanical Performance of PU Materials samples 1568-LA-0.5 1568-PA-0.5 1568-OA-0.5 1568-EA-0.5 a

ave.a S.D.b ave. S.D. ave. S.D. ave. S.D.

breaking elongation (%)

tensile strength (N/cm2)

578.77 52.17 931.33 77.58 1074.4 134.3 1858.5 156.2

728.8 85.8 994.7 121.5 1138.0 98.2 3787.5 152.8

The average number of 5 films. b The standard deviation of 5 films.

Figure 3. Influence of the kind of the chain extender on the PAI. The platelet count in the control is 101 × 109 L-1. The samples 1568DA-0.5, 1568-OA-0.5, 1568-AA-0.5, and 1568-EA-0.5 were soaked for 20, 30, and 40 min. Table 4. Influence of the Fatigue Test on PAIa chain extender

EA

PA

OA

the increment of PAI after the fatigue test

29.2%

12.8%

17.9%

a

The PAI were measured after each sample soaked in whole blood for 30 min.

Figure 2. Influence of the amount of the chain extender on PAI. The platelet count in the control is 197 × 109 L-1. The samples 1568EA-0.25, 1568-EA-0.5, 1568-EA-0.86, and 1568-EA-1 were soaked for 20, 30, and 40 min.

of 1914%. Such a good mechanical performance cannot be achieved using other synthesis methods. As is well-known, an increase of material tensile strength results usually in the decrease of its breaking elongation for most polymers or polymer composites.35 However, the tensile strength and the breaking elongation of soluble chemically cross-linked polyurethanes increase simultaneously in this research. The tensile strength of the PU sample with a ratio of amine H/NCO ) 0.6 has a value of 4303N/cm2. Breaking elongation and tensile strength reach the minimum value (1720% and 2500 N/cm2) when amine H/NCO ) 0, whereas this mechanical performance is still very high compared with other PU samples. When used for biomedical applications, they are expected to have a much longer life span. With an increase in the ratio of amine H/NCO, the tensile strength (σb) and the breaking elongation (b) of PU materials increase first and then decrease, which can be oriented from the huge size (shown in Table 2) and network structure of ICM. ICM synthesized in this paper has high deformation ability because of its huge size. The bigger the molecular size, the higher the deformation ability. Therefore, the PU materials show good breaking elongation, e.g., b reaches 1914%. It can be seen that the breaking elongation of the

sample with the highest degree of cross-linking is not the best among the samples. This might be because, as the degree of cross-linking increases, ICM coils become much more compact and rigid which makes it more difficult for deformation compared with the one with a moderate and low degree of cross-linking. Furthermore, the spherulite crystal can be produced in the sample with a high degree of crosslinking, resulting in a decrease in its breaking elongation because of the high density of the hard segments.31,38 The sample with a moderate degree of cross-linking also has the best tensile strength, indicating that the physical interaction between the ICMs is the strongest compared with other samples, which agrees well with the conclusion in the Literature 28. 3.3. Influence of the Kind of Chain Extender on the Mechanical Performance of PU Materials. To investigate the influence of the kind of chain extender on the mechanical performance of PU materials, LA, OA, PA, and EA were used as the chain extenders. Because the mechanical performance is very good when the molar ratio of -OH/ NCO equals to 0.5, we synthesized four samples 1568-LA0.5, 1568-OA-0.5, 1568-PA-0.5, and 1568-EA-0.5 and measured their mechanical performance. The experimental results are listed in Table 3. The mechanical performance of the sample 1568-EA-0.5 is better than the other three samples, and that of the PU material with a monoamine chain extender decreases with increasing the amount of C atoms in the chain extender. This might be because the addition of the alkyl side chain to the hard segments will lower the mechanical intensity of the crystal points, and the greater the amount of C atoms in the chain extender, the lower the mechanical intensity will be.

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Figure 4. Schematic representation of the influence of the addition of alkyl side chain on the blood-material interaction. (Graph 4-1) The schematic representation of the blood-material interaction for the polyurethane sample which is not introduced with an alkyl side chain. On the sample surface the hard-segment-rich phases are coverd by the soft-segment-rich phases to result in a good the phase separation, and the sample has a good blood-compatibility. (Graph 4-2) The schematic representation of the blood-material interaction for the polyurethane sample introduced with a short alkyl side chain added onto the hard segment of the polyurethane macromolecule. The phase separation structure on the surface of the sample was slightly hampered by the alkyl side chain, and a few blood platelets are prior to deposit on the exposed hard segments. The rotation of the single C-C bond of the alkyl side chain bond hampers the aggregation and deposition of the blood platelet. (Graph 4-3) The schematic representation of the blood-material interaction for the polyurethane sample introduced with a long alkyl side chain added onto the hard segment of the polyurethane macromolecule. The phase separation structure on the surface of the sample was a little more hampered by the alkyl side chain than that in graph 4-2, and the blood platelets are much prior to deposit on the exposed hard segments. The rotation of the single C-C bond of the long alkyl side chain is a little slower and less hampers the aggregation and deposition of the blood platelet. Therefore, shielding effect of the long alkyl side chain on the hard segment is less than that of the short alkyl side chain.

3.4. In Vitro Study on the Blood Compatibility. Platelet adhesion and aggregation by synthetic materials limit their

use for blood contact applications.35 The blood compatibility of the new polyurethanes was evaluated by counting the

Synthesis and Characterization of Polyurethanes


Figure 5. Representation of effect of alkyl side chain on the blood-material interaction for the polyurethane sample after the fatigue test. (Graph 5-1) The micro-phase-separation structure on the surface of the material is destroyed after the fatigue test and lead to an exposure of the hard domains, but the alkyl side chain added into the chain backbone of the polyurethane shields exposed hard segments and hampers the deposition of the blood platelets. Furthermore, the rotation of single C-C bond also hampers the aggregation on the exposed area of hard domains. (Graph 5-2) The micro-phase-separation structure on the surface of the material is destroyed after the fatigue test and lead to an exposure of the hard domains, and blood platelets deposit and aggregate on the exposed area of the hard domains.

platelet count in the blood remaining after the exposure to the material. The data for the number and the reduction of platelets in the blood exposed to the present polymers are given in Figures 2 and 3 and Table 4. 3.4.1. Influence of the Amount of the Chain Extender on the PAI. The platelet adhesion test (PAdT) was performed on the samples 1568-EA-0.25, 1568-EA-0.5, 1568-EA-0.8, and 1568-EA-1. The experimental results are listed in Figure 2. Quite interestingly, the test for the present polyurethanes showed a remarkably lower number of consumed platelets in comparison with the control (without test material). This is attributed to the presence of a micro-phase-separated hard domain. Vinoy Thomas et al. dealt with the effect of physical cross-linking polyurethanes on the in vitro blood-material interaction.23 Their studies illustrate that a higher physical cross-link density results in a lower consumption of platelets. However, an inverse trend was observed in the case of the present polyurethanes. The PUs with the higher degree of cross-linking have a relatively higher consumption of

platelets. The degree of platelets consumed in 1568-EA-0.25 is comparatively higher than that in the other three samples and PAI decreases with the increase of the amount of the chain extender. Therefore, it is understood that the higher the degree of cross-linking in the present candidate polyurethanes, the higher the consumption of platelets and vice versa. This might be because the antithrombogenic properties of PU materials depend mainly on the micro-phase-separation structure.36,37 PU can hydrogen bond very well and thus can be very crystalline.38-40 The rigid sections from different chains clump together and align to form hard phases that are linked together by the rubbery soft sections. During the micro-phase-separation of PU materials, the thermodynamic driving force for minimizing the total free energy of the system results in preferential surface segregation of the lower surface energy constituent (soft-segment block) of the polymer and improves the antithrombogenic properties.25,26 The more the amount of the chain extender, the less reactions III and IV will occur, the easier the crystalline will form in

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the ICM, the greater the micro-phase-separation will be, and the better the antithrombogenic properties will be. 3.4.2. Influence of the Kind of Chain Extender on PAI. To investigate the influence of the kind of chain extender on PAI, The PAdT was performed on the samples 1568LA-0.5, 1568-OA-0.5, 1568-PA-0.5, and 1568-EA-0.5. The experimental results are listed in Figure 3. The platelet consumption in the presence of 1568EA-0.5 is minimal, and for the other three samples with a monoamine chain extender, the PAI increases with an increase in the amount of the C atoms in the chain extender. This might be because the alkyl side chains of the monoamine based polyurethanes will tend to stick out of the material surface, hamper the overlay of the soft segments on the hard segments, lead to the exposure of the hard segments, and then increase the PAI thanks to the immiscibility of the alkyl group and the soft segment (PTMG). The longer the alkyl side chain, the greater the exposure of the hard segments will be, as shown in Figure 4. Graph 4-1 shows the blood-material interaction for the polyurethane sample not introduced with an alkyl side chain. Graph 4-2 shows the blood-material interaction for the polyurethane sample introduced with a short alkyl side chain. Graph 4-3 shows the blood-material interaction for the polyurethane sample introduced with a long alkyl side chain. The phase separation of the sample 1568-EA-0.25 is greater than the other three samples because it is not introduced with an alkyl side chain. The alkyl side chain hampers the overlay of the soft segment on the hard segment thanks to the thermodynamic incompatibility of the alkyl group and PTMG and exposes parts of the rigid hard-segment-rich microphases, resulting in a little deterioration of the antithrombogenic properties. Experimental results show that the addition of a big alkyl side group will lead to a relatively higher PAI. This might be because a longer alkyl side chain results in a much greater exposure of the hard-segment-rich microphases. Furthermore, the rotation of a single C-C bond will hamper the platelet adhesion and deposition by the PU materials. The quicker the rotation is, the more difficult the platelets deposit on the surface of PU materials. The rotation of the single C-C bond of the alkyl side chain will be certainly reduced with an increase in its length; therefore, the PU materials with a short alkyl side chain has a relatively low PAI. 3.4.3. Influence of the Fatigue Test on PAI. Because biodurability in highly flexing biomechanical environments is one of the mandatory requirements of biomedical devices, the influence of fatigue test on the blood compatibility was investigated in this paper. The PAdTs were performed on the samples 1568-OA-0.5, 1568-PA-0.5, and 1568-EA-0.5, and the increments of the PAI after the fatigue test are shown in Table 4. The polyurethanes based on an EA chain extender exhibit the best blood compatibility before the fatigue test, whereas a reverse trend has been observed after the fatigue test. This different trend observed for the platelet consumption after the fatigue test is attributed to the surface phase-mixed morphology. The micro-phase-separation structure will be destroyed after the sustaining load cycles. For the samples with a monoamine chain extender, the alkyl side chain added

Liu et al.

onto the hard segment of polyurethane can shield the hard segments when the micro-phase-separation structure was destroyed, as shown in graph 5-1, whereas the sample with a diamine chain extender cannot, as shown in graph 5-2. Furthermore, the rotation of the C-C single bond of the alkyl side chain also plays a role in hampering the depositing of the blood platelet. Therefore, the sample with a monoamine chain extender shows better antithrombogenic properties after the fatigue test. From Table 4, it can also be seen that the antithrombogenic properties of the samples with a PA chain extender is better than that with an OA chain extender, indicating that the addition of the alkyl side chain with proper length will produce best shielding effect after the fatigue test. 4. Conclusion Soluble chemically cross-linked PUs have been synthesized in this paper. The preliminary results show that this kind of material may be regarded as a promising candidate for biomedical applications for its favorable blood compatibilities and excellent mechanical performances. Moreover, polyurethanes introduced with an alkyl side chain onto the hard segments keep good antithrombogenic properties after repeated load cycles. This might be because the alkyl side chains introduced onto the hard segments of PU can provide a shielding effect on the exposed hard segments and then keep good antithrombogenic properties of PU materials. The experimental results also show that this shielding effect depends greatly on the length of the alkyl side chains. References and Notes (1) Lelah, M. D.; Cooper, S. L. Polyurethanes in Medicine; CRC Press: Boca Raton, FL, 1986. (2) Planck, H., Syre, I., Dauner M., Egbers, G., Eds.; Polyurethane in Biomedical Engineering II, Progress in Biomedical Engineering; Elsevier Science: Amsterdam, 1987. (3) Li, Y.-J.; Matthews, K. H.; Chen, T.-M.; Wang, Y.-F.; Kodama, M.; Nakaya, T. Chem. Mater. 1996, 8, 1441-1450. (4) Li, Y.-J.; Shibata, Y.; Nakaya, T. Macromol., Rapid Commun. 1995, 16, 253-258. (5) Li, Y.-J.; Bahulekar, R.; Chen, T.-M.; Wang, Y.-F.; Kodama, M.; Nakaya, T. Macromol. Chem. Phys. 1996, 197, 2827-2835. (6) Yamada, M.; Li, Y.-J.; Nakaya, T. J. Macromol. Sci., Pure Appl. Chem. 1995, A32, 1235-1242. (7) Yamada, M.; Li, Y.-J.; Nakaya, T. Macromol., Rapid Commun. 1995, 16, 25-30. (8) Li, Y.-J.; Nakamura, N.; Chen, T.-M.; Wang, Y.-F.; Kitamura, M.; Nakaya, T. Macromol., Rapid Commun. 1996, 17, 737-744. (9) Korematsu, A.; Li, Y.-J.; Nakaya, T. Polym. Bull. 1997, 38, 133140. (10) Li, Y.-J.; Tomita, T.; Tanda, K.; Nakaya, T.; Chem. Mater. 1998, 10, 1596-1603. (11) Li, Y.-J.; Hanada, T.; Nakaya, T.; Chem. Mater. 1999, 11, 763770. (12) Tomita, T.; Li, Y.-J.; Nakaya, T.; Chem. Mater. 1999, 11, 21552162. (13) Li, Y.-J.; Nakamura, N.; Wang, Y.-F.; Kodama, M.; Nakaya, T.; Chem. Mater. 1997, 9, 1570-1577. (14) Grasel, T. G.; Pierce, J. A.; Cooper, S. L. J. Biomed. Mater. Res. 1987, 21, 815-842. (15) Pitt, W. G.; Grasel, T. G.; Cooper, S. L. Biomaterials 1988, 9, 3646. (16) Munro, M. S.; Eberhart, R. C.; Maki, N. J.; Brink, B. E.; Fry, W. J. ASAIO J. 1983, 6, 65-75. (17) Marconi, W.; Martinelli, A.; Piozzi, A.; Zane, D. Macromol. Chem. Phys. 1994, 195, 875-888. (18) Rahman, R.; Ratner, B. D. J. Polym. Sci., Part A: Polym. Chem. 1989, 27, 2673.

Synthesis and Characterization of Polyurethanes (19) Eberhart, R. C.; Munro, M. S.; Williams, G. B.; Kulcarni, P. V.; Shannon, W. A.; Brink, B. E.; Fly, W. J. Artif. Organs 1987, 11, 375-382. (20) Strizinar, I.; Sefton, M. J. Biomed. Mater. Res. 1992, 26, 577-592. (21) Marconi, W.; Galloppa, A.; Martinelli, A.; Piozzi, A. Biomaterials 1995, 16, 449-456. (22) Coury, A. J.; Cobian, K. E.; Cohalan, P. T.; Jevne, A. H. AdV. Urethane Sci. Technol. 1984, 9, 130-168. (23) Thomas, V.; Kumari, T. V.; Jayabalan, M. Biomacromolecules 2001, 2, 588-596. (24) Takahara, A.; Tashita, J. I.; Kajiyama, T.; Takayangi, M.; MacKnight, W. J. Polymer. 1985, 26, 978-986. (25) Jayabalan, M.; Lizymol, P. P. Vinoy Thomas Macomolecules-New Frontiers; Srinivasan, K. S. V., Ed.; Allied Publishers: New Delhi, India, 1998; pp 617-620. (26) Jayabalan, M.; Lizymol, P. P. Vinoy Thomas Polym. Int. 2000, 49, 88-92. (27) Solomon, D. H., Ed.; Step-growth polymerizations; Marcel Dekker: New York, 1972; Chapter 3. (28) Li, F.; Zuo, J.; Song, D. H.; Li, Y. T.; Ding, L. H.; An, Y. L.; Wei, P.; Ma, J. B.; He, B. L. Eur. Polym. J. 2001, 37, 193-199. (29) Li, F.; Liu, Z. F.; Qian, H. T, Rui, J. M.; Chen S. N.; Jiang, P.; An, Y. L.; Mi, H. F. Macromolecules 2004, 37, 764-768. (30) Li, F.; Liu, Z.; Liu, X.; Yang, X.; Chen, S.; An, Y. Zuo, J.; He, B. Macromolecules 2005, 38, 69-76.

Biomacromolecules, Vol. 6, No. 3, 2005 1721 (31) Li, F.; Zuo, J.; Dong, L. M.; Wang, H. J.; Luo, J. Z. et al. Eur. Polym. J. 1998, 34, 59-66. (32) Li, F.; Ju, Z.; Dong, L.; Zhou, Q.; Han, W.; Luo, Polym. Mater. Sci. Eng. 1999, 15, 55-58. (33) Zuo, J. In Principles and Applications of Laser Light Scattering in Polymer Science; Han, J. X., Ed.; Press of Science and Technology: Henan, 1994; p 65. (34) Li, F. X.; Wang, H. J.; Li, C. G.; Ma, K. Q. J. Polym. Sci. A. Polym. Chem. 1994, 52, 1939-1947. (35) Dai, X.; Xu, J.; Guo, X.; Lu, Y.; Shen, D.; Zhao, N.; Luo, X.; Zhang, X. Macromolecules 2004, 37, 5615-5623. (36) Garrett, J. T.; Siedlecki, C. A.; Runt, J. Macromolecules 2001, 34, 7066-7070. (37) Hearn, M. J.; Ratner, B. D.; Briggs, D. Macromolecules 1988, 21, 2950-2959. (38) Marand, E.; Hu, Q.; Gibson, H. W.; Veytsman, B. Macromolecules 1996, 29, 2555-2562. (39) Teo, L.-S.; Chen, C.-Y.; Kuo, J.-F. Macromolecules 1997, 30, 17931799. (40) Pollack, S. K.; Smyth, G.; Papadimitrakopoulos, F.; Stenhouse, P. J.; Hsu, S. L.; MacKnight. W. J. Macromolecules 1992, 25, 2381-2390.

BM049173X

Synthesis and Characterization of Novel Blood-Compatible Soluble

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