Journal of Polymer Research 9: 23–29, 2002.© 2002 Kluwer Academic Publishers. Printed in the Netherlands.

23

Preparation and Gel Properties ofPoly[hydroxyethylmethacrylate-co-poly(ethylene glycol) methacrylate]Copolymeric Hydrogels by Photopolymerization

Wen-Fu Lee∗ and Wei-Jiuan LinDepartment of Chemical Engineering, Tatung University, Taipei, Taiwan, ROC (∗Author for correspondence;Tel.: +886-2-25925252 ext.3451; Fax: +886-2-25861939; E-mail: wflee@ttu.edu.tw)

Received 19 October 2001; accepted in revised form 15 January 2002

Key words: drug release, interaction, partition coefficient, poly(HEMA-co-PEGMA) copolymeric hydrogel

Abstract

Copolymeric hydrogels based on 2-hydroxyethyl methacrylate (HEMA) and poly(ethylene glycol) methacrylate (PEGMA)and isopropanol as a diluent were prepared by photopolymerization. The swelling kinetics, mechanical properties, drugrelease behaviors, and the interaction between various drugs and the present copolymeric gels were investigated in this study.The results showed that the addition of PEGMA could effectively increase the equilibrium water content and the diffusioncoefficient and penetration velocity of water though the gels. Although Young’s modulus increased with the increase ofPEGMA content, the resulting gels had smaller elongation and more brittle characteristics. The drug release behavior wasstrongly dependent on the interaction between the present copolymeric gels and drugs such as caffeine, crystal violet (CV),phenol red, and vitamin B12.

Introduction

Hydrogels are three-dimensional hydrophilic polymers thatswell but do not dissolve when brought into contact withwater or physiological liquid. They are of special interestin biological environments because of their appropriate wa-ter contents and biocompatibility [1]. Hydrogels are widelyused in medical implants, diagnostics, biosensors, biore-actors and bioseparators, where they are used primarily asmatrices for drug delivery systems [1–6].

2-Hydroxyethylmethacrylate (HEMA) has been widelyused as biomaterials because of the good biocompatibil-ity of its crosslinked polymer. The main applications forpoly(HEMA) hydrogels are contact lenses and intraocularlenses [7–12], surface modification for biomaterials [13–15],along with other uses [16–20].

The most common method used for improving the hy-drophilicity of materials is grafting. Hydrophilic monomersor polymers are often grafted onto lower hydrophilic materi-als to enhance their affinity to water, so that they can be moresuitable for biomaterial applications. Ionic monomers andmonomers containing PEO are the most used compoundsfor hydrophilicity modifications. For example, A. S. Hoff-man and his group have proposed hydrophobically-modifiedbioadhesive polyelectrolyte hydrogels prepared by graft-ing oligomers of methyl methacrylate to the backbone ofpoly(acrylic acid) hydrogels to evaluate drug delivery ef-ficiency [6]. Methacrylic acid, N-vinylpyrrolidone, andmonomers containing PEO have been used to increase theequilibrium water contents of hydrogel contact lenses [7–12].

Among hydrophilic compounds, compounds containingPEO have been most widely used not only for their goodhydrophilicity but also for their strength, processability, lowfouling potential, stability in temperature and pH, and mini-mum cell adhesion and protein absorption [21, 22]. Recently,the PEO modification of polymer surfaces or polymer chainshas attracted huge attention in biomaterial modification andprotein delivery systems because PEO has the ability tosuppress the interaction of the polymeric materials withbiological cells, lipids, proteins, fats, and enzymes [23–31]. PEO also exhibits a reversible thermodynamic behaviorwhen dissolved in water; this characteristic makes it possiblefor hydrogels containing PEO to be applied in thermore-versible drug delivery systems [21, 32, 33]. Furthermore,PEO containing materials have been reported to have beenused as transdermal membranes [34, 35] because of theirgood biocompatibility and gas permeability, gas separatingmembranes [36, 37], sensors and electrodes [38–41], etc.

The main purpose of this study was to prepare a seriesof poly[hydroxyethylmethacrylate-co-poly(ethylene glycol)methacrylate] copolymeric hydrogels by photopolymeriza-tion and to evaluate the swelling behavior and drug releasebehavior. In addition, the mechanical properties and in-teraction between drugs and the present gels were alsoinvestigated.

ExperimentalMaterials

2-Hydroxyethylmethacrylate (HEMA) was purchased fromWako Pure Chemical Co. LTD. Poly(ethylene glycol)

24 W.-F. Lee and W.-J. Lin

methacrylate (PEGMA, Mn = 360) and ethyleneglycoldimethacrylate (EGDMA) as a crosslinker were purchasedrespectively from Aldrich Co. and TCI Co. Diethoxyace-tophenone (DEAP) as a photoinitiator was purchased fromFluka Chemical Co. All the compounds and solvents wereused as received. HEMA was purified by vacuum distillationat 68 ◦C/7 mmHg before use.

Instruments

Photopolymerization was carried out under exposing toa full-wavelength UV lamp; the distance between thelamp and the sample chamber was 20 cm. A UV/Visiblespectrophotometer (Jasco V-530) was used for quantitativeanalysis. The mechanical tests were carried out using aLLOYD-LRX instrument.

Preparation of Hydrogels

Various ratios of HEMA and PEGMA were weighed andwell mixed in a 20 mL sample bottle. To this solution,1 mol% of EGDMA and 1 mol% of DEAP were added, and30 wt% of isopropanol based on monomer weight, as a dilu-ent, was then poured into and mixed the solution well. Themixture was then injected into the space between two glassplates with a 1 mm silicone rubber as a spacer. Polymer-ization was carried out by exposing the monomer solutionto a UV light for 2 h. After gelation was completed, thecopolymer membrane was immersed in water for softening,and then cut into disk of 1 cm in diameter. The disks wereimmersed in ethanol for one day to wash out the photoinitia-tor, unreacted monomer, and isopropanol, and then put intoethanol solutions in the order of 80 vol%, 60 vol%, 40 vol%,and 20 vol% ethanol-water solution, respectively, for oneday. The disks were finally put into water to wash away theresidual ethanol, and dried in a 50 ◦C vacuum oven for oneday. The feed compositions and yields for the synthesizedgels are listed in Table 1.

Measurement of the Various Properties of the SynthesizedGels

Light Transmittance of the Synthesized CopolymericMembranesThe copolymeric membranes were immersed in 25 ◦C deion-ized water for swelling equilibrium, and then cut into rec-tangular membranes 3 × 1 cm in size. The membranes were

Table 1. The feed compositions of the synthesized gels

Sample Feed composition (mol %) Equilibrium Yield (%)

code HEMA PEGMA water content

(%)

HEMA 100 0 36.14 99.75

P10 90 10 43.67 97.54

P20 80 20 48.95 95.48

P30 70 30 52.34 93.27

adhered onto the surface of quartz cube cell, and the trans-mittance was measured under wavelengths from 800 nm to400 nm with air as standard. Every membrane was measuredfor 5 scans.

Swelling Kinetics Measurement for the Synthesized GelsTwo pre-weighed dried disks were immersed in 10 mL ofdeionized water at 25 ◦C, and the swollen gels were weighedat various time intervals. The water content of the gels wascalculated as follows.

Water Content (Wc)

= weight of wet gel − weight of dry gel

weight of wet gel× 100%.

Equilibrium Water Contents at Various Temperatures forthe Synthesized GelsTwo pre-weighed dried disks were immersed in 10 mL ofdeionized water, and the temperature was kept at 25 ◦C forone day. After swell equilibrium was reached, the equi-librium water content was calculated. Then the gels wereimmersed in 10 mL of deionized water again, and the watertemperature was kept at 35 ◦C, 45 ◦C, 55 ◦C, or 65 ◦C forone day. The equilibrium water content for the gels at everytemperature was calculated.

Mechanical PropertiesThe copolymeric membranes were directly immersed in50 vol% ethanol for one day after photopolymerization wascompleted; the membranes were then swelled in water forone day and cut into ASTM dumbbell membranes with atotal length of 80 mm and a gauge length of 16 mm. Thestress-strain curves of the membranes were recorded with anextension speed of 10 mm/sec. Five tests were repeated foreach gel composition.

Drug Release BehaviorTwo pre-weighed dried disks were immersed into 10 mLof drug solution, which was of known concentration, forone day at 25 ◦C to load the drug into the gels. After thedrug loading equilibrium was reached, the gels were movedinto 10 mL of release media (water, PBS, or saline) andchanged into another 10 mL of fresh release media after aperiod of time until the release of the drug was completed.The concentration of released drug was measured by UVspectrophotometer for caffeine at 272 nm, Vitamin B12 at360 nm, and CV at 588 nm.

Determination of Partition CoefficientTwo gel disks were swollen in deionized water for one day,and then immersed in 10 mL of 50 ppm drug solution untilthe diffusion of the drug was completed. The volumes ofgels were determined by using a micrometer, and the finalconcentration of the drug solution was measured by usinga UV spectrophotometer for CV at 588 nm, neutral red at523 nm, Vitamin B12 at 360 nm, and phenol red at 430 nm.The partition coefficient (Kd) is defined as follows [44],

Kd = Cm

Cs= Vs(Ci − Co)

VmCo,

Preparation and Gel Properties 25

where Cm is the concentration of drug inside the membrane,Cs is the concentration of drug in the solution, Ci is the initialconcentration of drug in the solution, Co is the concentrationof drug at equilibrium, Vs is the volume of drug solution, andVm is the volume of membrane at equilibrium of swelling.

Results and Discussion

Synthesis of Copolymeric Membranes

HEMA/PEGMA copolymeric membranes were successfullyobtained from photopolymerization; all the yields of variouscompositions were above 90%. The gels were transpar-ent after being well washed and dried. Contraction of thecopolymeric membranes during copolymerization, and themembrane fractured when the content of PEGMA was raisedto 40 mol%, which might be due to the large contractionforce of the copolymer chains during gel formation, so thatthe complete gel could not be obtained. The higher thePEGMA content, the more serious the fracture of the gel.

Effect of PEGMA on the Swelling Behavior of Gels

The swelling kinetic profiles at 25 ◦C in water for the syn-thesized gels containing 10 mol%, 20 mol%, and 30 mol%of PEGMA are shown in Figure 1. The following equa-tion is used to calculate the diffusion coefficient, D, forWt/W∞ � 0.8, [45–47]

Wt

W∞=

(4

π0.5

)(D × t

L2

)0.5

,

where Wt is the weight of gel after swelling for time t, W∞is the weight of gel at swelling equilibrium, L is the thick-ness of dry gel, and D is the diffusion coefficient of wateragainst gels. Furthermore, the penetration velocity (v) ofsolvent (water) in each gel, which was described by Peppaset al., is determined as follow [48, 49],

v = 1

2ρwA· dw

dt,

where dw/dt is the slope of the weight gain versus timecurve, ρw is the density of water, A is the area of oneface of the disk, and factor 2 accounts for the fact thatpenetration takes place through both sides of the disk.The results shown in Table 2 indicate that the equilibriumwater content could be effectively elevated by increasingthe PEGMA content in the gel, and comes to an orderof P30 > P20 > P10 > HEMA. The oxyethylene side chainson PEGMA offer the crosslinked polymer chains more H-bonding sites with water and therefore the equilibrium watercontent of the gels increases as the PEGMA content in-creases. The diffusion coefficient of water through the gels,D, and the penetration velocity of water into the gels, v, bothshow a tendency of P30 > P20 > P10 > HEMA. This is be-cause PEGMA possesses better hydrophilic properties thanHEMA for its longer oxyethylene side chain, which enhancethe affinity of crosslinked copolymeric chains toward water.

Figure 1. The swelling kinetic profiles in 25 ◦C water for the synthesizedgels containing various contents of PEGMA.

Table 2. The characteristics of the synthesized hydrogels

Sample Feed composition (mol %) v∗103 D∗106

code HEMA PEGMA (cm/min) (cm2/sec)

HEMA 100 0 0.39 1.327

P10 90 10 0.64 1.539

P20 80 20 0.78 2.138

P30 70 30 1.10 3.801

Effect of Temperature on Equilibrium Water Contents of theGels

The equilibrium water content of the gels containing variouscontents of PEGMA was examined at various temperatures.The results shown in Figure 2 indicate that the equilib-rium water content of each gel decreases as the temperatureincreases. The entropy of the water increases while the tem-perature of the water rises, and it becomes more difficultfor the water to bind stably on the PEGMA side chains ofthe copolymeric gels, resulting in a lower water affinity ofthe gels at higher temperatures. The above-mentioned ef-fect was insignificant for poly(HEMA) gels alone, but itbecame more obvious when more PEGMA was added intothe poly(HEMA) gels.

Effect of PEGMA on the Mechanical Properties of the Gels

The stress–strain curves of the present copolymeric mem-branes are shown in Figure 3. Young’s modulus, the fracturestrength, and the elongation for each gel are listed in Table 3.The results shown in Figure 3 and Table 3 indicate that allthe synthesized gels exhibit a hard but brittle characteristic.The results also show that the addition of PEGMA raises theYoung’s modulus of gels and largely lowers the elongationof membranes, which might be due to the H-binding and thepartial crystallinity of the PEG chains during extension.

Drug Release Behavior of the Gels

The drug release profiles of caffeine, crystal violet, and Vita-min B12 in various media for the synthesized gels are shown

26 W.-F. Lee and W.-J. Lin

Figure 2. The equilibrium water contents at different temperatures for thesynthesized hydrogels containing various contents of PEGMA.

Figure 3. The stress–strain curves for the synthesized hydrogels containingvarious contents of PEGMA.

in Figures 4 to 7 respectively. The drug loading concentra-tions are 3000 ppm for caffeine, 100 ppm for Vitamin B12,and 50 ppm for crystal violet. Figure 4 shows the caffeinerelease profiles for the gels containing various contents ofPEGMA; except for the initial release rate increasing with anincrease of the content of PEGMA, the accumulated releaseamount did not exhibit any relationship to the composition ofthe gels. This phenomenon might be caused by the extremely

Table 3. The mechanical properties of the synthesized hydrogels contain-ing various contents of PEGMA

Sample Young’s modulus Elongation Fracture strength

code (MPa) (% of gauge length) (MPa)

HEMA 4.451 63.75 0.27

P10 7.908 28.81 0.22

P20 6.518 23.65 0.15

P30 7.455 11.36 0.08

weak interaction between caffeine and the gels. Hence, caf-feine molecules were only adsorbed on the surface of thegel and could not easily penetrate the gel, which resultedin an irrelevant amount of accumulated release to the gelcomposition (see Figure 4). As for the initial caffeine releaserate, the variance is mainly caused by the equilibrium watercontent of the gels; those gels having a larger equilibriumwater content have more sites for the accommodation of wa-ter, and caffeine molecules can diffuse more easily in thegel network because of the availability of more water as adiffusion medium, resulting in an initial caffeine release ratein the order of P30 > P20 > P10 > HEMA (see Table 4).

Because the amount of Vitamin B12 released could notbe precisely determined when water was taken as the releasemedium, the release of the Vitamin B12 in the synthesizedgels was carried out in PBS (phosphate buffer saline). Therelease profiles of Vitamin B12 in PBS for various gels areshown in Figure 5. In comparison with Figure 4, the re-sults show that Vitamin B12 release takes more time thancaffeine release to finish drug release; they also show thatthe accumulated release amount is related to the equilibriumwater content of gels, i.e. P30 > P20 > P10 > HEMA. Thediffusion medium for Vitamin B12 is also water, and diffu-sion of the Vitamin B12 molecules is facilitated when thegel contains more water in the copolymeric network; thisoccurrence results in an initial Vitamin B12 release rate in theorder of P30 > P20 > P10 > HEMA, which is in the sameorder as the caffeine release rate (see Table 4). Comparingthe initial release rates of caffeine and Vitamin B12 for eachgel, as shown in Table 4, the results indicate that the releaserate of caffeine is larger than that of Vitamin B12.This mightbe due to the smaller size of the caffeine molecules, allow-ing them to diffuse more easily to the outside of the gels.On the other hand, the interaction between the Vitamin B12molecules and the copolymeric chains might be larger thanthat between the caffeine and the copolymeric chains, so thatVitamin B12 could penetrate the gels under loading and theaccumulated release amounts of Vitamin B12 for each gelmay be related to the equilibrium water contents.

The CV release profiles in deionized water for the presentgels are shown in Figure 6. The accumulated release ratios ofCV in deionized water for all gels are lower than 20%. Thisresult might be due to the large interaction force betweenthe CV molecules and copolymeric chains, which might bein the form of a complex, since only CV molecules existingin the free water phase of a gel could diffuse to the outsidesolution. An increase in the accumulated release ratio withan increase in the PEGMA content is observed in the orderof P30 > P20 > P10 > HEMA; this phenomenon is causedby the greater amount of free water in the gel network, whichcould carry more CV molecules in the gel when loading thedrug into the gel.

The CV release profiles in saline (0.9 wt% NaCl aque-ous solution) for the various gels are shown in Figure 7.Comparing Figures 7 and 6, the results show that the CVcould release slowly for a long period of time with an almostconstant release rate; this result might be due to the complex-ation between the CV molecules and copolymeric chains

Preparation and Gel Properties 27

Figure 4. The caffeine release profiles in 37 ◦C water for the synthesizedhydrogels containing various contents of PEGMA.

Figure 5. The Vitamin B12 release profiles in 32 ◦C PBS for the synthe-sized hydrogels containing various contents of PEGMA.

Figure 6. The CV release profiles in 37 ◦C water for the synthesizedhydrogels containing various contents of PEGMA.

Figure 7. The CV release profiles in 37 ◦C saline for the synthesizedhydrogels containing various contents of PEGMA.

Table 4. The initial drug release rates for the synthesized hydrogels

Sample Caffeine release Vitamin B12 release

code rate in water rate in PBS

(ppm/min g of polymer) (ppm/min g of polymer)

HEMA 4.522 0.567

P10 5.655 0.799

P20 5.629 0.950

P30 5.738 1.029

being exchanged when Na+ or Cl− ions exist in the releasemedium. This ion-exchange effect would slowly release CVions from copolymeric gels to the solution.

The Interaction between Drugs and Gels

The Interaction between Drugs and Gels in DeionizedWaterTo confirm the drug release results mentioned above, thepartition coefficients (Kd) of various drugs in the gels wereexamined; the larger the Kd value is, the stronger the inter-action of the drug to the gel is. The Kd values of variouscationic and anionic drugs in the synthesized gels are listedin Tables 5 and 6. For nonionic drugs, such as caffeineand theophylline, the interaction between the drugs andgels was too small for the UV spectrophotometer to de-tect the concentration variations, i.e. Kd � 0. This resultconforms to the results for caffeine drug release, whichhas been described above: because of the similar interac-tion between caffeine and gels with various compositions,the accumulated release amounts of all gels are almost thesame.

Table 5 shows that cationic drugs have a strong affinityto the synthesized gels, and the affinity increases with theincrease of PEGMA content. Oxygen atoms on the PEOchains possess lone-pair electrons, and these lone-pair elec-trons might complex with cationic drugs to form complexesbetween PEO chains and CV molecules, so that Kd increaseswith the PEGMA content. The Kds of anionic drugs for var-ious gels are listed in Table 6. The Kds of anionic drugs,compared with cationic drugs, are much smaller; the reason

28 W.-F. Lee and W.-J. Lin

Table 5. The partition coefficients of cationic drugs in different media for the synthesizedhydrogels containing various contents of PEGMA

Sample Crystal violet Neutral red

code H2O 0.9 wt% NaCl 1.8 wt% NaCl H2O 0.9 wt% NaCl

HEMA 51.40 958.2 909.5 13.26 56.55

P10 54.57 1395 1096 12.12 43.84

P20 63.16 1191 1060 10.94 34.61

P30 78.29 908.4 974.3 10.51 39.88

Table 6. The partition coefficients of anionic drugs in different media forthe synthesized hydrogels containing various contents of PEGMA

Sample Vitamin B12 Phenol red

code H2O 0.9 wt% NaCl H2O 0.9 wt% NaCl

HEMA 1.854 2.363 1.100 8.111

P10 2.113 2.406 1.586 9.677

P20 2.093 2.324 1.480 10.78

P30 2.118 1.019 1.456 11.77

for this is probably due to the existence of an electrostaticforce between the anionic drugs and PEO chains. The Kd ofphenol red in each gel is smaller than that of Vitamin B12;this might be due to the smaller electrostatic force betweenthe PEO chains and phenol red, which has a larger electrondensity than Vitamin B12 molecules.

The Interaction between Drugs and Gels in NaCl AqueousSolution

The Kd values of various cationic and anionic drugs in NaClaqueous solution for the synthesized gels are listed in Ta-bles 5 and 6. The Kds for each gel in NaCl solutions arelarger than those in deionized water for crystal violet andneutral red, both are cationic drugs, as shown in Table 5.In the presence of Na+ and Cl− ions, the complexation for-mation between crystal violet ions and copolymeric chainsmight be completely different from that in deionized water,so that Kds alter sharply and the Kds in NaCl solution areall very close no matter what the composition is. Similarphenomena are observed in neutral red, but the change ofKds for neutral red in NaCl solution is not as sharp as thatfor crystal violet. For anionic drugs, the same effects arealso observed. The main factor causing the alternation ofKds should be the same, that is, the complicated complex-ation of drug ions, salt ions, and copolymeric chains. Thealternation of Kds for Vitamin B12 is not as obvious as forothers; perhaps because the low charge density of the largeVitamin B12 ion makes it more difficult to complex with saltions, thus inhibiting the alternation of Kd in NaCl aqueoussolution.

The Transmittance of Gel Membranes

The transmittance of gels from 400 nm to 800 nm is shownin Figure 8. The transmittance of gels is over 81% and theycould be applied as transparent materials.

Figure 8. The transmittance of visible UV light for hydrogels containingvarious contents of PEGMA.

Conclusions

HEMA/PEGMA copolymeric gels were successfully syn-thesized from photo-polymerization with DEAP as a pho-toinitiator. All the gels were transparent, and their equilib-rium water content was relatively low because of the highmonomer concentration.

Our results indicate that the equilibrium water contentincreases as the content of PEGMA increases, and the dif-fusion coefficient and water penetration velocity both alsoincrease due to the improvement of the hydrophilicity of thegels. The equilibrium water content for each gel decreasesas the temperature rises, and the dehydration effect becomesmore obvious when PEGMA content increases.

The addition of PEGMA enhances Young’s modulus butlowers the broken strength and elongation of gel membranes.These results might be due to the partial crystallization ofPEO chains during extension, which causes the imperfectionof amorphousness and a tendency to break when a force isapplied.

The low interaction between gels and caffeine results in arelationship between accumulated drug release amount andgel composition, that is irrelevant; as for the Vitamin B12release, a proportional relationship between accumulated re-lease amount and equilibrium water content was observed.The initial release rate of Vitamin B12 is slower than thatof caffeine due to its larger molecular size. The accumulatedrelease ratio of CV is low because there is an extremely large

Preparation and Gel Properties 29

interaction force between CV and the gels, and only the CVmolecules existing in free water can be released from thegel. In saline solution, however, the CV release time can beprolonged; this could be due to the fact that the Na+ or Cl−ions disrupt the binding between CV and the PEO chainsand allow CV ions to be released slowly. This characteristiccould be applied in sustained release for cationic drugs.

In deionized water, cationic drugs complex with PEOchains which are possessed by PEGMA so that the Kd in-creases with the increase of PEGMA content; anionic drugsmight also complex with gels, but the complexation is notas obvious as that of cationic drugs. In saline solution, thedrug ions, copolymeric chains, and salt ions might complexin a form completely different from that in deionized water,which might result in the sharp alternation of Kds.

Acknowledgement

Financial support of this research by Tatung University,Taipei, Taiwan, ROC, under Grant B89-1413-01 is gratefullyacknowledged.

References

1. N. A. Peppas (ed.), Hydrogels in Medicine and Pharmacy, CRC Press,Boca Raton, FL, 1987, p. 109.

2. A. S. Hoffman, A. Afrassiabi and L. C. Dong, J. Control. Release, 4,213 (1986).

3. L. Brannon-Peppas and N. A. Peppas, J. Control. Release, 8, 267(1989).

4. B. Gander, R. Gurny, E. Doelker and N. A. Peppas, J. Control.Release, 5, 271 (1988).

5. N. A. Peppas and J. Klier, J. Control. Release, 16, 203 (1991).6. T. Inoue, G. Chen, K. Nakamae and A. S. Hoffman, J. Control.

Release, 49, 167 (1997).7. F. F. Molock and J. D. Ford, US Pat 5938795, 1999.8. D. G. Vanderlaan, US Pat 5356751, 1993.9. S.-H. Chang and M.-Z. Chang, US Pat 5712327, 1998.

10. J. R. Kunzler, US Pat 5914355, 1999.11. P. H. Benz and J. A. Ors, US Pat 5891932, 1999.12. D. G. Vanderlaan, US Pat 5311223, 1994.13. H. Mirzadeh, A. A. Katbab and R. P. Burford, Radiat. Phys. Chem.,

46, 859 (1995).14. S. Downes, M. Patel, L. Disilvio, H. Swai, K. Davy and M. Braden,

Biomaterials, 16, 1417 (1995).15. K. S. Jin, S. N. Hee, M. L. Young, H. Hoon and C. N. Young, J.

Membr. Sci., 190, 215 (2001).16. A. Denizli, G. Ozkan and M. Ucar, Sep. Purif. Technol., 24, 255

(2001).17. N. A. Peppas and L. Brannon-Peppas, J. Control. Release, 40, 245

(1996).

18. Anonymous, Br. Pat 1205769, 1970.19. K. Inui, H. Okumura, T. Miyata and T. Uragami, J. Membr. Sci., 132,

193 (1997).20. C. S. Brazel and N. A. Peppas, Polymer, 40, 3383 (1999).21. J. L. Stringer and N. A. Peppas, J. Control. Release, 42, 195 (1996).22. E. W. Merrill, K. A. Dennison and C. Sung, Biomaterials, 14, 1117

(1993).23. K. Makino, M. Umetsu, Y. Goto, A. Nakayama, T. Suhara, J. Tsujii,

A. Kikuxhi, H. Ohshima, Y. Sakurai and T. Okano, Colloids Surf. B:Biointerf., 13, 287 (1999).

24. N. A. Alcantar, E. S. Aydil and J. N. Israel, J. Biomed. Mater. Res.,51, 343 (2000).

25. J. M. Harris (ed.), Poly(ehtylene glycol) Chemistry, Biotechnical andBiomedical Applications, Plenum Press, New York, 1992.

26. J. D. Andrade, V. Hlady and S. I. Jeon, Adv. Chem. Ser., 248, 51(1996).

27. J. H. Lee, H. B. Lee and J. D. Andrade, Prog. Poly. Sci., 20, 1043(1995).

28. C.-G. Golander, J. N. Herron, K. Lim, P. Claesson, P. Stenius andJ. D. Andrade, Poly(ehtylene glycol) Chemistry, Biotechnical andBiomedical Applications, Plenum Press, New York, 1992, p. 221.

29. K. Holmberg, K. Berstrom and M. B. Stark, Poly(ehtylene glycol)Chemistry, Biotechnical and Biomedical Applications, Plenum Press,New York, 1992, p. 303.

30. C. R. Jenny and J. M. Anderson, J. Biomed. Mater. Res., 44, 206(1999).

31. E. Kulik and Y. Ikada, J. Biomed. Mater. Res., 30, 295 (1996).32. T. Govender, T. Riley, T. Ehtezazi, M. C. Garnett, S. Stolnik, L. Illum

and S. S. Davis, Int. J. Pharm., 199, 95 (2000).33. T. Aoyagi, K. Sugi, Y. Sakurai, T. Okano and K. Kataoka, Colloids

Surf. B: Biointerf., 16, 237 (1999).34. P. Mura, M. T. Faucci, G. Bramanti and P. Corti, Eur. J. Pharm. Sci.,

9, 365 (2000).35. C. Valenta, M. Wanka and J. Heidlas, J. Control. Release, 63, 165

(2000).36. Y. Hirayama, Y. Kase, N. Tanihara, Y. Sumiyama, Y. Kusuki and K.

Haraya, J. Membr. Sci., 160, 87 (1999).37. Y. Hirayama, N. Tanihara, Y. Kusuki, Y. Kase, K. Haraya and K.

Okamoto, J. Membr. Sci., 163, 373 (1999).38. G. D. Marco, M. Lanza and M. Pieruccini, Solid State Ion., 89, 117

(1996).39. L. Qi, Y. Lin and F. Wang, Eur. Polym. J., 35, 789 (1999).40. A. Pennisi, F. Simone, G. Barletta, G. D. Marco and M. Lanza,

Electrochim. Acta, 44, 3237 (1999).41. K. Podual, F. J. Doyle and N. A. Peppas, Polymer, 41, 1975 (2000).42. T. Matsushita and K. Hirai, US Pat 4340090, 1982.43. J. L. Valimont, US Pat 4263350, 1981.44. C. L. Bell and N. A. Peppas, J. Control. Release, 39, 201 (1996).45. J. M. Crank, The Mathematics of Diffusion, Clarendon, Oxford, 1975.46. R. W. Korsmeyer, E. V. Meerwall and N. A. Peppas, J. Polym. Sci.,

Polym. Phys. Ed., 24, 409 (1986).47. B. G. Kabra, S. H. Gehrke, S. T. Hwang and W. A. Ritschel, J. Appl.

Polym. Sci., 42, 2409 (1991).48. N. A. Peppas and N. M. Franson, J. Polym. Sci., Polym. Phys. Ed., 21,

983 (1983).49. C. W. Davidson and N. A. Peppas, J. Control. Release, 3, 259 (1986).