NMR Imaging of the Diffusion of Water at 310 K into Semi-IPNs of PEM

For example, Peppas and co-workers1-3 have extensively investigated the copolymers ... In the study, the mechanism for the diffusion process will be i...
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Biomacromolecules 2004, 5, 1405-1411

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NMR Imaging of the Diffusion of Water at 310 K into Semi-IPNs of PEM and Poly(HEMA-co-THFMA) with and without Chlorhexidine Diacetate Mohammad A. Chowdhury,† David J. T. Hill,*,† Andrew K. Whittaker,‡ Michael Braden,§ and Mangala P. Patel§ Polymer Materials and Radiation Group, Department of Chemistry, The University of Queensland, Brisbane, QLD 4072 Australia, Centre for Magnetic Resonance, The University of Queensland, Brisbane, QLD 4072 Australia, and Department of Biomedical Materials in Relation to Dentistry, Queen Mary and Westfield College, Mile End Road, London E1 4NS, United Kingdom Received January 8, 2004; Revised Manuscript Received March 31, 2004

Magnetic resonance imaging has been used to monitor the diffusion of water at 310 K into a series of semi-IPNs of poly(ethyl methacrylate), PEM, and copolymers of 2-hydroxyethyl methacrylate, HEMA, and tetrahydrofurfuryl methacrylate, THFMA. The diffusion was found to be well described by a Fickian kinetic model in the early stages of the water sorption process, and the diffusion coefficients were found to be slightly smaller than those for the copolymers of HEMA and THFMA, P(HEMA-co-THFMA), containing the same mole fraction of HEMA in the matrix. A second stage sorption process was identified in the later stage of water sorption by the PEM/PTHFMA semi-IPN and for the systems containing a P(HEMA-coTHFMA) component with a mole fraction HEMA of 0.6 or less. This was characterized by the presence of water near the surface of the cylinders with a longer NMR T2 relaxation time, which would be characteristic of mobile water, such as water present in large pores or surface fissures. The presence of the drug chlorhexidine in the polymer matrixes at a concentration of 5.625 wt % was found not to modify the properties significantly, but the diffusion coefficients for the water sorption were systematically smaller when the drug was present. Introduction The controlled release of drugs at therapeutic dose levels via the use of polymeric delivery vehicles is now a well established technique in pharmacy. The delivery vehicles are often either polymers which will erode under physiological conditions or polymers which will swell in body fluids and release the drug by slow diffusion from the resulting hydrogel. The most common family of polymers which make up the latter category is that based on poly(2-hydroxyethyl methacrylate), PHEMA. The PHEMA matrix properties can be modified to control their swelling, water diffusion, and drug release behavior. For example, Peppas and coworkers1-3 have extensively investigated the copolymers of HEMA and methyl methacrylate, MMA, for this purpose, whereas Patel and co-workers have similarly investigated the properties of the copolymers of HEMA with tetrahydrofurfuryl methacrylate, THFMA, and other similar systems.4-12 Hill and co-workers have also investigated the properties of hydrogels based on P(HEMA-co-THFMA)13-20 and some other related systems.21-24 Mass uptake and magnetic resonance imaging, MRI, of cylindrical samples have been used to determine the mechanism of the diffusion of water into these copolymers over a range of temperatures, which * To whom correspondence should be addressed. E-mail: hill@ chemistry.uq.edu.au. † Department of Chemistry, The University of Queensland. ‡ Centre for Magnetic Resonance, The University of Queensland. § Queen Mary and Westfield College.

has been shown to be Fickian, and to determine the diffusion constants. However, during the swelling process, the MRI studies showed that cracks develop at the interface between the swelling, rubbery outer region and the glassy core and that these cracks are “repaired” behind the diffusion front when the glass transition temperature, Tg, of the waterplacticized matrix drops below the measurement temperature. In addition, NMR T2 relaxation time measurements have been used to probe the states of the water in equilibrium hydrogels,15 and pulse field gradient nuclear magnetic resonance, PFG NMR, has been used to measure the selfdiffusion coefficients of the sorbed water.16 Besides their studies of the P(HEMA-co-THFMA) systems, Braden and co-workers have also studied semiinterpenetrating networks, semi-IPNs, of these copolymers with poly(ethyl methracylate),11,12,25-27 as well as some other semi-IPN systems,28,29 for use as drug delivery vehicles and soft lining materials for dentistry. Patel et al.,12 Swai,27 and Riggs et al.30 have carried out studies of the diffusion of water into the PEM/P(HEMA-co-THFMA) IPNs, including systems containing chlorhexidine. They have also examined the kinetics for the release of chlorhexidine. Swai27 has fitted the water mass uptake data to a Fickian kinetic model and has calculated the diffusion coefficients for this process at 310 K. Many workers,31-36 including ourselves,13,14 have previously demonstrated the use MRI to observe the ingress of penetrants into solid systems and to provide two- or three-

10.1021/bm040003u CCC: $27.50 © 2004 American Chemical Society Published on Web 05/05/2004

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dimensional, time-dependent images of the density of these highly mobile components in a material. Since MRI provides direct information on the nature of the penetrant diffusion front during sorption, it provides direct information on the penetrant diffusion mechanism. Therefore, to complement the work of previous researchers, we have now carried out a study of the water sorption process for the PEM/P(HEMAco-THFMA) IPNs by direct examination of the diffusion front in real time using MRI. In the study, the mechanism for the diffusion process will be identified unequivocally from the nature of the water concentration profiles of the diffusion front, and the diffusion coefficients for the water will be obtained in the early stages of the sorption process by curve-fitting the profiles. In addition, the effect of added chlorhexidine on the water soption process will be probed, and the role of stress induced cracking of the glassy core of the matrix will be examined. These features of the diffusion process cannot be obtained directly from a mass uptake study. Experimental Section Materials. Poly(ethyl methacrylate) powder (PEM) containing 0.6% w/w residual benzoyl peroxide, BPO, was obtained as a white powder from Bonar Polymers Ltd. The monomers, HEMA and THFMA, were obtained from Sigma Aldrich and Rohm Chemie GmbH, respectively. Dimethylp-toluidine (DMPT) and chlorhexidine diacetate (CDA) were supplied by Sigma Aldrich Chemicals, U.K. To remove the stabilizers, the HEMA and THFMA were passed through an anhydrous alumina column and then further purified by distillation. The colorless middle fractions, with boiling points of 76-78 °C (6.6-6.7 × 102 Pa) for HEMA and 64-66 °C (6.7 × 102 Pa) for THFMA, were collected for use. The purified monomers were stored in dark brown containers at 4 °C and used within 1 week of distillation. Sample Preparation. The PEM powder was added to the monomers or monomer mixtures in the ratio of 10 g of powder to the required amounts of the monomer or monomer mixture. Either 1.0 wt % or 2.5 wt % of the catalyst, DMPT, was added to the monomer prior to mixing with the PEM. For studies of systems containing CDA, the PEM powder was mixed with 9 wt % CDA, and the mixture was milled for 10-12 h in a ball mill to ensure a uniform distribution of the drug through the PEM sample. The PEM was thoroughly mixed with the monomers at low temperature in a dry ice bath. The monomers swell the PEM powder to form a viscous mixture with a dough-like consistency. The viscous mixture was then poured into cylindrical Teflon moulds (diameter. 4.5 mm). The Teflon mould was placed in a modified pressure cooker, and the pressure inside was raised to 2 bar by addition of nitrogen in order to dissipate any bubbles in the sample. The mould was then left for approximately 1 h under pressure. The pressure was then released, and the sample was allowed to complete the polymerization process under nitrogen at room temperature and atmospheric pressure. After the cylinder of polymer was removed from the mould, it was checked for complete conversion over the

Chowdhury et al.

Figure 1. MRI of the water protons in a PEM/PHEMA cylinder after water sorption at 310 K for 4.3 h. The cylinder was prepared using 1 wt % DMPT.

length by FT-NIR spectroscopy as described previously.17 No evidence was found for the presence of any unreacted double bonds, which have a NIR absorbance at 6170 cm-1. MRI Studies. The polymer cylinders fitted neatly into the NMR resonator used for the imaging studies. The samples were placed in distilled water at 310 K and were removed periodically, their surfaces were dried with a soft paper tissue, and they were placed in the NMR resonator. To detect the ingress of the water into the polymer and to identify the nature of the diffusion front, proton images of the samples were obtained using an AMX 300 NMR spectrometer. T2-weighted NMR images consisting of 128 × 128 × 8 voxels were obtained across the central region of the cylinders, as described previously.13,14 The images were obtained at 295 K using a 3D spin-echo method with the following parameters: read gradient strength 0.303 T m-1; excitation pulse 90° of duration 14.0 s; refocusing pulse 180° of 28.0 s; echo time 3.531 ms; recovery time 3 s. All the images have an in-plane resolution of 78 × 78 m and a slice thickness of 5.00 mm in a field of view of 1 × 1 × 4 cm. Two averages were co-added to increase the signal-to-noise ratio. The MRI images were analyzed using the NIH image37 program to extract the water-concentration profile across the cylinders. Results and Discussions PEM/PHEMA. Figure 1 shows a typical T2-weighted 2D slice from the 3D-MRI image of the water protons in a cylinder of the PEM/PHEMA, prepared using 1 wt % DMPT and without added drugs. It was obtained after a water sorption time of 4.3 h at 310 K. The radial dependence of the water concentration in the system is obtained from a section across the diameter of the image. A typical section taken from the image in Figure 1 is shown in Figure 2A, where the profile has been normalized using the concentration of water at the surface of the cylinder, which is constant. The profile is concave to the radial distance through the cylinder, as expected for a Fickian diffusion mechanism, so confirming the report of Swai27 based on a mass uptake study.

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Figure 3. Profiles of the relative concentration of water on sorption at 310 K into a PEM/PHEMA cylinder. (a) 6.58, (b) 22.2, (c) 48.63, and (d) 192.62 h. The cylinder was prepared using 2.5 wt % DMPT.

Figure 2. Relative concentration of water (C/C0) profiles across the cylinder after water sorption at 310 K. (A) for the image in Figure 1; (B) a comparison of the profile in (A) with that for a PHEMA cylinder after water sorption for 4.0 h.

The water concentration profile for sorption into a PHEMA cylinder, prepared as described previously18 by thermal initiation using benzoyl peroxide as the initiator, is shown in Figure 2B after a sorption time of 4 h at 310 K, a slightly shorter sorption time than that for the PEM/PHEMA cylinder is also shown in the figure. There are two distinct differences between the two profiles in Figure 2B. First, the inner features in the profile for PHEMA are not visible in the profile for the PEM/PHEMA semi-IPN. The inner features observed for PHEMA have been reported previously by Ghi et al.14 to be due to the presence of water in stress-generated cracks formed at the interface between the swelling rubbery outer annulus and the remaining central glassy core. The presence of mobile water in the cracks, which has a longer T2 relaxation time than the more tightly bound water in the rubbery region, distorts the concentration profile in the interface region. Thus, the presence of the PEM reduces the level of stress at the interface by modifying the Tg of the PHEMA in the semi-IPN. The second difference between the two profiles in Figure 2B is in the extent of water diffusion; the water has penetrated somewhat further into PHEMA than into PEM/PHEMA, even though the sorption time for PEM/PHEMA was slightly longer. Thus, the presence of the nonpolar PEM component of the IPN causes a lowering of the diffusion coefficient over that for water diffusing into PHEMA. A similar conclusion has been reached by Swai27 from mass uptake measurements. In Figure 3, a series of concentration profiles is shown for sorption of water at 310 K into a PEM/PHEMA cylinder prepared using 2.5 wt % DMPT. Here the time evolution of the diffusion front is shown. The water concentration profile shown in curve b in the figure is convex to the radial distance through the cylinder. This suggests that, although no inner

features such as those shown for the PHEMA cylinder in Figure 2B are observed in the swelling of PEM/PHEMA, a limited extent of interface cracking does indeed occur, particularly as the swelling stress on the glassy core increases at longer sorption times, as the volume of the swollen outer annulus increases and little of the glassy core remains. (This may not be the only explanation for the convex shape of curve b, although it appears to be the most likely reason.) As shown in Figure 3 curve c, once the glassy core has disappeared, the profile returns to being concave to the radial distance axis, as has been found previously by Ghi et al.14 for PHEMA. Finally, at a longer sorption time, the system reaches equilibrium, and the profile is flat across the cylinder as shown in Figure 3 curve d. PEM/PTHFMA. The time evolution of the water diffusion front for sorption into a cylinder of PEM/PTHFMA at 310 K is shown in Figure 4. In Figure 4A, two profiles typical of those obtained in the early stages of the diffusion are shown, whereas three profiles typical of those obtained in the later stages are shown in Figure 4B. Riggs et al.9,30 have reported that the mass uptake of water during diffusion into PEM/PTHFMA semi-IPNs films occurs in two stages (films 1 mm thick prepared using the same initiation process as that used herein). The first stage was characterized by an enhanced rate of water uptake over a period of approximately 15 h which was followed by a slower, almost constant rate of uptake over a very long period of time (several months). A similar conclusion can be drawn from the water concentration profiles shown in Figure 4. Riggs et al.9,30 have explained the second stage behavior by a reorganization of the furfuryl rings in the PTHFMA chains and clustering of them with water. In Figure 4A, the two profiles are concave toward the radial distance axis, as expected for a Fickian diffusion mechanism, and are similar to the profiles reported by Ghi et al.14 for cylinders of PTHFMA prepared by thermal initiation. There is no evidence in the profiles for the formation of cracks at the interface between the rubbery and

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Figure 5. Profiles of the relative concentration of water on sorption at 310 K. PEM/PTHFMA cylinder after 5.13 h, s; PEM/PHEMA cylinder after 4.3 h, - - - .

Figure 4. Profiles of the relative concentration of water on sorption at 310 K into a PEM/PTHFMA cylinder. (A) (a) 5.13 and (b) 20.87 h. (B) (a) 41.9, (b) 84.35, and (c) 1659.02 h. The cylinder was prepared using 2.5 wt % DMPT.

glassy regions during the diffusion of the water into the cylinder. This could be a result of the lower mass uptakes of the PEM/PTHFMA system compared to that for PEM/ PHEMA, or of the greater ductility of PTHFMA which allows any stress generated in the glassy core to be dissipated by creep. By contrast with the profiles in Figure 4A, the profiles shown in Figure 4B are clearly different in shape. The major difference in the profiles is the presence of sharp peaks at the outer edge of the cylinders and a decrease in the relative water concentrations in the inner areas of the profiles as the sorption time increases. Since Riggs et al.9,30 have shown that the mass uptake continues to increase in the PEM/ PTHFMA systems as the sorption time increases, the latter observation indicates that either the water concentration is increasing near the edges of the cylinders relative to the center or the intensities of the T2 weighted MRI images at the outer edge are distorted (increased) relative to the central regions. MRI images of the water protons obtained at different echo times indicated that the water protons in the outer regions have a longer T2 relaxation time than those in the central regions. We therefore conclude that some of the water sorbed near the edge of the cylinder must be more like “bulk water” and reside in larger pores. However, it is unfortunately not possible to determine from the images whether this water is associated with clusters of furfuryl rings, as suggested by Riggs et al.,30 or whether it resides in larger pores or fissures formed at the surface of the cylinder which grow in size with time. The concave nature of the profiles in Figure 4B in the inner regions of the cylinders indicates that water continues to diffuse into the cylinders over a very long time period.

In Figure 5, the water concentration profiles obtained in the early stages of diffusion into cylinders of PEM/PHEMA and PEM/PTHFMA are compared for similar sorption times at 310 K. The signal-to-noise in the profile for PEM/ PTHFMA is much lower than that for PEM/PHEMA because the extent of water uptake is much lower in the former system. In addition, though the sorption time for PEM/ PHEMA is slightly shorter than for PEM/THFMA, the water diffusion front has penetrated further into the matrix. This reflects a higher diffusion constant for water in the more polar PEM/PHEMA. PEM/P(HEMA-co-THFMA). A series of water concentration profiles for sorption at 310 K into cylinders of the semi-IPNs with three different P(HEMA-co-THFMA) copolymers are shown in Figure 6. The profiles for the three systems reflect the effects of copolymer composition and the features of the PEM/PHEMA and PEM/PTHFMA systems discussed above. However, unlike the profiles for PEM/PHEMA, the profiles for PEM/P(HEMA-co-THFMA) with the copolymer containing 80 mol % HEMA are all concave toward the radial distance axis, indicating a complete absence of crack formation in the glassy core. This is presumably associated with a lowering of the PHEMA Tg by incorporation of the THFMA into the copolymers. On the other hand, even the PEM/P(HEMA-co-THFMA) with the copolymer containing 43 mol % THFMA showed evidence for the presence of a second stage sorption process at longer times, similar to that observed for PEM/PTHFMA. Effect of DMPT Concentration. Riggs et al.30 have reported that the concentration of the DMPT catalyst has little effect on the mass uptake behavior of PEM/THFMA. The water sorption profiles in the early stages of sorption were obtained for PEM/PHEMA, PEM/PTHFMA, and PEM/ P(HEMA-co-THFMA) cylinders prepared using 1 wt % and 2.5 wt % DMPT. The profiles showed that the DMPT concentration had no significant effect on the diffusion process, confirming the findings of Riggs et al. for all of the semi-IPN systems

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Diffusion of Water at 310 K into Semi-IPNs

Figure 7. Typical curve fit to the water sorption profile for PEM/ P(HEMA-co-THFMA) with copolymer mole fraction HEMA ) 0.8 after 23.95 h to determine the water diffusion coefficients at 310 K. (A) The dependence of the sum of the squared residuals, n, on the value of D; (B) The fit of the curve generated by the value of D at the minimum in (A), the best value of D, to the experimental profile. Fitted curve, - - - .

Figure 6. Profiles of the relative concentration of water on sorption at 310 K into PEM/P(HEMA-co-THFMA) cylinders with different mole fractions of HEMA in the copolymers. (A) P(HEMA-co-THFMA) FHEMA ) 0.80 (a) 2.50, (b) 7.18, (c) 23.95, (d) 49.27, and (e) 1815.33 h. (B) P(HEMA-co-THFMA) FHEMA ) 0.57 (a) 4.63, (b) 10.78, (c) 24.17, (d) 72.60, (e) 649.35, and (f) 1540 h. (C) P(HEMA-co-THFMA) FHEMA ) 0.30 (a) 26.93, (b) 32.80, (c) 82.18, and (d) 1512.62 h.

Diffusion Coefficient Measurements. For Fickian diffusion of a penetrant into a polymer matrix, the penetrant concentration profile across a cylinder is given by eq 1 below.38 Ghi et al.13,14 used this relationship to fit the underlying water concentration profile for sorption into cylinders of P(HEMA-co-THFMA) in the absence of added drugs Cr,t C0,∞

)1-

2

∞

1 J0(rRn)

∑ an)1R

n J1(aRn)

exp(-DRn2t)

(1)

where t is the time for which penetrant diffusion has occurred, D is the diffusion coefficient, Cr,t is the concentration of the penetrant at radial distance r at time t, C0 is the constant surface concentration, a is the radius of the cylinder, Rn is the positive root of J(aRn) ) 0, J0(x) is a Bessel function of the first kind of order zero, and J1(x) is a Bessel function of the first order. The diffusion coefficient can be obtained from a curve-fit to the time-dependent, MRI water concentration profiles

using eq 1. Ghi et al.14 used a summation over 150 roots of the Bessel function in calculating values of the diffusion coefficients for P(HEMA-co-THFMA). A similar curve fitting procedure was adopted in the current work and the results of a typical curve-fit are demonstrated in Figure 7. Figure 7A shows the dependence of the sum of the squared residuals for the fits on the value of the diffusion coefficient. The best value of D to represent the profile data is that at the minimum in the curve in the figure. The fit of the best value of D to the experimental data is shown in Figure 7B. The standard error in the diffusion coefficient can be estimated from the curve in Figure 7A. Based on the curvefits, the error in the diffusion coefficients were estimated to be approximately 10 percent. The dependence of the calculated diffusion coefficients on the composition of the PEM/P(HEMA-co-THFMA) is shown in Figure 8, along with values found by Ghi et al.14 for P(HEMA-co-THFMA) from mass uptake measurements. In this figure, in estimating FHEMA, allowance has been made for the presence of EM as well as THFMA and HEMA in the matrix. Thus, the diffusion coefficients are plotted as a function of the mole fraction of HEMA present in the system (calculated from the masses of PEM, HEMA, and THFMA present in the matrix). The water diffusion coefficients for the PEM/P(HEMA-co-THFMA) systems are comparable with and follow a similar trend to those for P(HEMA-coTHFMA). The presence of the relatively nonpolar PEM component in the semi-IPN results in a lower value of the diffusion coefficients which suggests that the water molecules experience higher tortuosity in penetrating the matrix than they do in the pure copolymers containing an equivalent

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Figure 8. Dependence of measured diffusion coefficients at 310 K on the mole fraction of HEMA in the matrix. P(HEMA-co-THFMA), O; PEM/P(HEMA-co-THFMA), 0; P(HEMA-co-THFMA) with 5.625 wt % CDA, ].

amount of HEMA. The increase in the value of D at low HEMA contents has been previously attributed to the ductility of the THFMA component in the copolymers,17 which may allow the matrix to creep slightly under the swelling stress, but this may not be the only explanation for the observed increase. Systems Containing CDA. The evolutions of the water concentration profiles for the semi-IPNs loaded with 5.625 wt % of CDA were delineated in real time at 310 K. A comparison is drawn in Figure 9 between some typical profiles obtained at similar sorption times for PEM/PHEMA, PEM/PTHFMA, and PEM/P(HEMA-co-THFMA) containing 57 mol % HEMA in the copolymer with and without a loading of CDA. All three examples in Figure 9 show the early stages of the diffusion process prior to the disappearance of the glassy core. The profiles indicate that the water diffusion front for the systems containing CDA are consistent with what would be expected for a Fickian diffusion mechanism. A comparison of the profiles for diffusion with and without CDA present shows that the diffusion fronts have progressed further into the cylinders when no drug is present, even though the diffusion times for these systems were slightly shorter in all three cases. This observation is consistent with that of Riggs et al.30 for mass uptake studies in the early stages of water sorption at 310 K for PEM/THFMA with and without CDA present. The MRI water concentration profiles obtained in the early stages of water sorption in the presence of CDA were fitted to eq 1 for the three copolymer systems shown in Figure 9. The values obtained are shown in Figure 8, which demonstrates that the diffusion coefficients for water for these systems in the presence of CDA are slightly lower than the values for the corresponding systems without the drug present. This may indicate that the CDA restricts the penetration of the water via some of the pathways available when no drug is present. This would be consistent with the

Figure 9. Profiles of the relative concentration of water on sorption at 310 K into cylinders with (‚‚‚) and without (s) added CDA (5.625 wt %). (A) PEM/PHEMA, (B) PEM/P(HEMA-co-THFMA) copolymer FHEMA ) 0.57, and (C) PEM/PTHFMA. The cylinders were prepared using 2.5 wt % DMPT.

formation of water droplets around the particles of CDA and their subsequent growth due to the osmotic pressure generated. Thomas and Muniandy39 have demonstrated a reduction of the diffusion coefficient of water in elastomers consequent on the presence of water-soluble inclusions. Conclusions NMR imaging of the water diffusion front has confirmed that the Fickian diffusion mechanism provides an adequate representation of the diffusion water at 310 K into the cylinders composed of PEM/P(HEMA-co-THFMA) semiIPNs. The PEM/PHEMA displayed some evidence for crack formation at the interface between the rubbery region and the glassy core just prior to the disappearance of the core, when the swelling stress would be greatest, but the level of cracking was much less than that observed for PHEMA alone. By contrast, the PEM/THFMA and PEM/P(HEMAco-THFMA) with copolymer mole fractions of HEMA less than 0.6 displayed a second stage sorption process which was characterized by the appearance of water with a longer

Diffusion of Water at 310 K into Semi-IPNs

NMR T2 relaxation time near the surface of the cylinders, which would be characteristic of the presence of more mobile water. This water could be resident in larger pores or fissures formed at or near the surface of the cylinders. The diffusion coefficients calculated from the water concentration profiles were comparable, but systematically smaller than those for P(HEMA-co-THFMA) containing a similar mole fraction of HEMA. The presence of CDA did not modify the behavior of the systems greatly, except that the diffusion coefficients for water were found to be slightly smaller in the presence of the drug. Acknowledgment. The authors which to acknowledge the financial support for this work from the Australian Research Council. M.A.C also acknowledges the receipt of the Arlo Harris travel award from the University of Queensland to allow some of this work to be carried out at QM&W College. References and Notes (1) Franson, N. M.; Peppas, N. A. J. Appl. Polym. Sci. 1983, 28, 12991310. (2) Davidson, G. W. R., III.; Peppas, N. A. J. Controlled Release 1986, 3, 243-258. (3) Brazel, C. S.; Peppas, N. A. Polymer 1999, 40, 3383-3398. (4) Patel, M. P.; Braden, M.; Davy, K.W. M. Biomaterials 1987, 8, 5356. (5) Patel, M. P.; Braden, M. Biomaterials 1989, 10, 277-280. (6) Patel, M. P.; Braden, M. Biomaterials 1991, 12, 645-648. (7) Patel, M. P.; Braden, M. Biomaterials 1991, 12, 649-652. (8) Patel, M. P.; Pearson, G. J.; Braden, M.; Mirza, M. A. Biomaterials 1998, 19, 1911-1917. (9) Riggs, P. D.; Braden, M.; Tilbrook, D. A.; Swai, H.; Clarke, R. L.; Patel, M. P. Biomaterials 1999, 20, 435-441. (10) Downes, S.; Braden, M.; Archer, R.; Patel, M. P.; Davy, K. W. M.; Swai, H. Modifications of Polymers for Controlled Hydrophobicity. In Surface Properties of Biomaterials; West, R., Batts, G., Eds; Butterworth-Heinmann: London, U.K., 1994; pp 11-23. (11) Patel, M. P.; Pavlovic, P.; Hughes, F. J.; King, G. N.; Cruchley, A.; Braden, M. Biomaterials 2001, 2081-2086. (12) Patel, M. P.; Cruchley, A.; Coleman, A. T.; Swai, H.; Braden, M.; Williams, D. M. Biomaterials 2001, 22, 2319-2324. (13) Ghi, P. Y.; Hill, D. J. T.; Maillet D.; Whittaker, A. K. Polymer 1997, 38, 3985-3989.

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