hydrogels assembled by inclusion complexation of poly(ethylene glycol) with alpha-cyclodextrin

ASIA-PACIFIC JOURNAL OF CHEMICAL ENGINEERINGAsia-Pac. J. Chem. Eng. 2009; 4: 544–550Published online 15 June 2009 in Wiley InterScience(www.interscience.wiley.com) DOI:10.1002/apj.280

Special Theme Research Article

Hydrogels assembled by inclusion complexation ofpoly(ethylene glycol) with alpha-cyclodextrin

Jie Wang, Li Li,* Yunying Zhu, Peng Liu and Xuhong Guo

State Key Laboratory of Chemical Engineering, East China University of Science and Technology, Shanghai 200237, China

Received 31 October 2008; Revised 22 January 2009; Accepted 22 January 2009

ABSTRACT: Polymeric hydrogels were prepared based on the inclusive complexation between α-cyclodextrin (α-CD)and poly(ethylene glycol) (PEG). Because the rheological property of a thermodynamic stable hydrogel should begap-independent, it is found in this work that the uniformed hydrogel can be distinguished from gel-like aggregationby changing the plate gap during the rheological measurement. By this rheological method it is determined that suitablestorage duration is necessary for the preparation of uniform hydrogels. However, the sonication technique after mixingCD and PEG solutions or increasing PEG concentration can shorten the time to form stable hydrogels. Moreover,the molecular weight of PEG should be high enough (≥8000 g/mol) for sol-gel transition. The higher the molecularweight of PEG is, the longer storage time is needed to obtain a uniform hydrogel. From the observation by differentialscanning calorimetry (DSC) and X-ray diffraction (XRD) of prepared hydrogels, we concluded that the driving forceof networks should be attributed to the crystallization of complexed α-CDs in the α-CD/PEG pseudo-polyrotaxanes. 2009 Curtin University of Technology and John Wiley & Sons, Ltd.

KEYWORDS: α-cyclodextrin; poly(ethylene glycol); inclusive complexation; hydrogel

INTRODUCTION

Polymeric hydrogels can be classified into two typesbased on their cross-linking ways: the chemical bondingand the physical binding.[1] The chemical bonding isirreversible and always uses toxic cross-linkers, whichmay cause limitation to their biomedical applications.[2]

Physical gelation is achieved by noncovalent cohesiveinteractions, such as hydrophobic interaction, stereo-complexation, electrostatic interaction and inclusiveassociation, and no cross-linking agent is needed.[3]

Recently, the reversible polymeric hydrogels formedby physical binding have been extensively investigatedbecause they are ideal candidates for biomaterials due totheir controllable structure, high water content, tissue-like flexibility, and biocompatibility.[4–8]

Using the inclusive or host–guest association ofcyclodextrin (CD) to construct biocompatible poly-meric hydrogels has been explored.[7–11] CDs are cyclicoligosaccharides consisting of six (α-CD), seven (β-CD), or eight (γ -CD) glucose units prepared by enzy-matic degradation of starch. They have a shallowtruncated cone shape and hydrophobic cavities whichare nonpolar relative to their outer surface.[12] The

*Correspondence to: Li Li, State Key Laboratory of ChemicalEngineering, East China University of Science and Technology,Shanghai 200237, China. E-mail: [email protected]

most important property of CD is the ability to forminclusion complexes with a great variety of guestmolecules.[13] Since the first report on the formationof complexes between cyclodextrins and polymers,[14]

several polymeric hydrogels formed by the inclusioncomplexes of cyclodextrins and linear polymers havebeen reported.[15–20]. Aqueous solutions of α, β, orγ -CD can selectively form stable complexes with suit-able linear polymers. The complexes are supramolecularadducts produced by the threading of the chain into theempty cavity of the CDs[21–26] and the starting chemi-cal architectures for other interesting structures such asmolecular trains[27] and molecular tubes.[28]

CDs are very selective to form inclusive complexeswith linear polymers due to the size match.[29–32]

Among them, α-CD is often used to form necklace-like inclusive complexes or pseudo-polyrotaxanes withpoly(ethylene glycol) (PEG), which can penetrate intothe inner cavity of α-CD. Due to the crystallizationof threaded α-CDs, the cross-linking among PEG/α-CD inclusion complexes can form networks.[33–36] Liet al .[6] reported hydrogels based on the inclusion com-plexes between high molecular weight PEG and α-CD.A sol–gel transition was observed during the forma-tion of inclusion complexes between α-CD and PEGin aqueous solutions when the molecular weights ofPEG were higher than 2000.[6] The results are encour-aging, but the formation of gel-like system in sol–gel

2009 Curtin University of Technology and John Wiley & Sons, Ltd.

Asia-Pacific Journal of Chemical Engineering HYDROGELS ASSEMBLED BY INCLUSION COMPLEXATION OF PEG WITH α-CD 545

transition makes it difficult to distinguish the thermo-dynamic stable hydrogel from a gel-like aggregation.

In this article, we mainly use rheological method toobserve the sol–gel transition induced by the assem-bly of inclusive complexes between PEG and α-CD.We demonstrated that rheology was a powerful toolto distinguish the polymeric hydrogel structure froma gel-like aggregation. Especially, we systematicallyinvestigated the effect of PEG molecular weight, thestorage time, and the assistant of sonication. The ther-mal properties and crystalline structure of the hydrogelsformed between α-CD and high molecular weight PEGwere characterized by differential scanning calorimetry(DSC) and X-ray diffraction (XRD).

EXPERIMENTAL

Materials

The α-CD was obtained from Wacker Biochem. Corp.(MI, USA). The poly(ethylene glycol) with molecularweight of 600 000, 20 000, 8000, 5000, 2000, and600 g/mol were purchased from Sigma–Aldrich.

Hydrogel preparation

The aqueous solution of α-CD was added carefullyto an aqueous solution of PEG. In the mixture, themolar ratio of ethylene glycol units to α-CD was2 : 1. The mixed solution was then stirred for 5 minor ultrasonically treated (Kunshan Hechuang UltrasonicInstruments CO., LTD, KH-250B, 40 kHz) for 5 min

at room temperature, followed by stand at the roomtemperature.

Characterization

DSC measurements were carried out using EXTARSII-6000 DSC system (Seiko Instruments Inc.). Eachsample was encapsulated in a metal pan (5 mm indiameter) and heated from 0 to 200 ◦C at a heating rateof 10 ◦C/min in a nitrogen flow.

XRD patterns were performed using a diffractome-ter (type 4037, Rigaku) with graded d-space ellipticalside-by-side multilayer optics, monochromatic Cu Kαradiation (940 kV, 30 mA, λ = 1.542 A), and an imag-ing plate (R-Axis IV) in a flat camera. The sampleswere sealed in quartz capillary tubes (1.5 mm diame-ter; 0.01 mm wall thickness) and positioned on a hotstage (Mettle FP82HT). The powders were exposed toradiation for 10 min with a camera length of 150 mm.

The steady and dynamic rheological measurementswere performed on a Physica MCR 101 (Anton PaarGmbH) rheometer with 25 mm parallel plate geome-try. The temperature was controlled to 25 ± 0.1 ◦C by aPeltier plate. Effect of the gap between the plate and thestage of the rheometer was investigated. As an exam-ple, the rheological properties of gel-like systems withPEG molecular weight of 8000 g/mol (PEG8000) and600 000 g/mol (PEG600000) prepared without sonica-tion after 3 days are shown in Figs. 1 and 2, respec-tively. For the gel-like system with PEG8000, the vis-cosities (Fig. 1a) as well as the storage modulus (G ′)and viscous modulus (G ′′) (Fig. 1b) reduced by morethan two orders of magnitude upon increasing the gapfrom 1 mm to 2 mm, while the viscosities (Fig. 2a),

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Figure 1. Static (a) and dynamic (b) rheological properties of gel-like systemformed by α-CD and PEG with a molecular weight of 8000 g/mol.

2009 Curtin University of Technology and John Wiley & Sons, Ltd. Asia-Pac. J. Chem. Eng. 2009; 4: 544–550DOI: 10.1002/apj

546 J. WANG ET AL. Asia-Pacific Journal of Chemical Engineering

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Figure 2. Static (a) and dynamic (b) rheological properties of hydrogel formed by α-CDand PEG with a molecular weight of 600 000 g/mol.

G ′ and G ′′ (Fig. 2b) did not change within the errorlimit of rheological measurement for the hydrogels withPEG600000. This phenomenon reveals the fact thatthe structure of mixture system with PEG8000 is nota uniform gel but a gel-like aggregation. The gap-dependence is a powerful criterion to judge whethera gel-like system is thermodynamic stable. The rhe-ological property of real hydrogels should be gap-independent like the system with PEG600000.

RESULTS AND DISCUSSION

Hydrogel formation

As shown in Fig. 3, the small mouth of α-CD cavityis 4.7 A in diameter while the sectional size of PEGis 3.1 A in diameter. Therefore, PEG should be ableto thread into α-CD and form inclusion complex.Since the height of α-CD cavity (7.9 A) is only catwo times of the contour length of two PEG units(Fig. 3), more α-CDs could thread into PEG molecularchain and form necklace-like inclusion complexes orpseudo-polyrotaxanes. Because α-CDs can crystallize inaqueous solution, the cross-linking among PEG/α-CDinclusive complexes leads to the formation of networks(Fig. 4).

Effect of PEG molecular weight on gelformation

The photographs of the aqueous solutions of PEG/α-CD were shown in Figs. 5 and 6. The components of

the mixed solutions were listed in Table 1. When thetransparent aqueous solutions of α-CD and PEG (Fig. 5)were mixed, white aggregates or gels formed due to thecrystallization of α-CDs threaded into PEG chains.[2,3]

With increase in the molecular weight of PEG, themixed solutions changed from phase separation statewith white precipitates to gel-like (Fig. 6).

Phase separation was observed for mixtures withlow molecular weight PEG such as 600 or 2000 g/mol(Fig. 6). In the case of PEG molecular weights of5000 g/mol, a gel-like structure was formed. However,the structure was unstable, and phase separation hap-pened gradually during the storage time. Through rheo-logical proof, it is determined that only hydrogels with

Figure 3. Schematic structures of α-CD and poly(ethyleneglycol). This figure is available in colour online atwww.apjChemEng.com.



Figure 4. Schematic illustration of the proposedstructure of hydrogels assembled by inclusioncomplexation of PEG and α-CD. This figure is avail-able in colour online at www.apjChemEng.com.

Figure 5. Aqueous solutions of α-CD andpoly(ethylene glycol) with various molecularweights before mixing. Samples from left to rightare: α-CD, PEG with molecular weight of 600 000,20 000, 8000, 5000, 2000, and 600 g/mol, respec-tively. This figure is available in colour online atwww.apjChemEng.com.

Figure 6. Mixtures of α-CD and poly(ethyleneglycol) with various molecular weights. PEGmolecular weights in the mixture from left toright are 600 000, 20 000, 8000, 5000, 2000, and600 g/mol, respectively. This figure is available incolour online at www.apjChemEng.com.

Table 1. Components of PEG/α-CD inclusioncomplexes.

PEG,Mw(g/mol)

PEG(wt%)

α-CD(wt%)

EG(unit): α-CD(molarratio) Appearance

600 1.0 10.7 2 : 1 Phase separation2 000 0.9 10.2 2 : 1 Phase separation5 000 1.2 10.0 2 : 1 Gel8 000 1.0 10.2 2 : 1 Gel20 000 0.9 10.1 2 : 1 Gel60 000 0.9 9.4 2 : 1 Gel

high molecular weight of PEG (≥8000 g/mol) are ther-modynamically stable.

Effect of storage time

After the aqueous solutions of α-CD and PEG weremixed, the sol–gel transition happened after 30 min

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]

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Figure 7. Effect of time on (a) the viscosity and (b) the storage modulus (G′) of the gel-likeinclusive complexion system formed by 10% α-CD and 5% PEG8000.



due to the formation of inclusion complexes betweenα-CD and PEG. However, the viscosity (Fig. 7a) andstorage modulus (G ′) (Fig. 7b) increased with thestorage time until formation of a stable structure.This phenomenon reflects the structural change of theinvestigated gel-like system. For the α-CD + PEG8000system, 3 days are needed to reach the equilibriumstructure. Without change in rheological propertiesstorage at room temperature can be observed after3 days.

Effect of sonication

As shown in Fig. 8a, the storage modulus (G ′) andloss modulus (G ′′) of gel-like system formed by mix-ing 10% α-CD and 5% PEG20000 aqueous solutionsafter 3 days without sonication reduced by nearly oneorder of magnitude upon increasing the gap from 1to 2 mm. However, treated by ultrasonic for 5 minafter mixing the two aqueous solutions followed by30-min storage at room temperature, the gel-like sys-tem showed no more gap-dependence (Fig. 8b). Forcomparison, we prolonged the storage time for the gap-dependent mixture in Fig. 8a from 3 to 30 days, andthe system became gap-independent (Fig. 8c). There-fore, the mixture of α-CD and PEG20000 can forma uniform hydrogel after suitable storage time whichis necessary to reach the thermodynamic equilibriumstructure. However, ultrasonic treatment after mixingCD and PEG solutions can shorten the time to reachequilibrium structure.

Thermal properties and crystalline structure ofgel

The thermal properties of the hydrogel formed bymixing α-CD and PEG600000 (α-CD/PEG600000 gel)were investigated by DSC and compared with pureaqueous PEG600000 solution. As shown in Fig. 9, asharp endothermic peak was found at 77 ◦C for the α-CD/PEG gels, while no peak could be observed for PEGor α-CD solution around this temperature. The peakshould be attributed to the crystallization of the α-CDscomplexes with PEG, which is the driving force to formcross-linking structure in the hydrogels.

The XRD powder patterns were used to characterizethe crystalline structure. Figure 10 showed a compar-ison of the XRD patterns of α-CD, PEGs with dif-ferent molecular weights (8000, 20 000, and 600 000),and freeze–dried α-CD/PEG gel-like samples with var-ious PEG molecular weights. The XRD pattern ofα-CD shows a number of sharp reflection peaks at2θ = 10◦ –22◦. No peaks can be determined in thisarea for PEGs with different molecular weights, while

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Figure 8. The elastic modulus G′ and theviscous modulus G′′ of hydrogels formed bymixing 10% α-CD and 5% PEG20000 as afunction of frequency. (a) Without ultrasonicafter 3 days; (b) With ultrasonic for 5 min fol-lowed by 30 min storage; (c) Without ultrasonicafter 30 days.

two strong diffraction peaks at 2θ = 19.1◦ and 23.2◦can be found and their strengths decrease with increas-ing the molecular weight (b, c, and d in Fig. 10). Thepeaks around 11◦ and 20◦ for all the α-CD/PEG gel-like samples belong to the hexagonal lattice of α-CDin channel-type crystal structures[37,38] and their heightsdecrease with increasing the molecular weights of PEG(e, f, and g in Fig. 10).



0 50 100 150 200

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Figure 9. Differential scanning calorimetryspectra for (a) α-CD/PEG600000 gel and (b)PEG600000.

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(f)

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Figure 10. X-ray diffraction patterns for (a) α-CD, (b) PEG8000, (c) PEG20000, (d) PEG600000,(e) α-CD/PEG8000 gel, (f) α-CD/PEG20000 gel,and (g) α-CD/PEG600000 gel.

CONCLUSION

Polymeric hydrogels can be formed by inclusive com-plexation of α-cyclodextrin and poly(ethylene glycol)with suitable molecular weight. The characterization ofthe hydrogels by DSC and XRD powder patterns con-firmed the formation of channel-type crystal structure bythreading α-CDs into PEG chains. The driven force ofcross-linkage in hydrogels should be the crystallizationof the α-CD/PEG pseudo-polyrotaxanes. Rheology was

found to be a powerful tool to distinguish hydrogel fromgel-like aggregation by changing the gap between plateand stage of rheometer during the measurement. Thesol–gel transition can be observed by changing molec-ular weight of PEG. To form a uniform gel structure,molecular weight of PEG should be equal or higher than8000 g/mol. Moreover, suitable storage time is neededto reach a thermodynamic equilibrium gel structurewhile ultrasonic treatment can accelerate the processto equilibrium structure.

Acknowledgements

We gratefully acknowledge NSFC Grant 20774030,Shanghai Shuguang Plan Project 06SG35, ShanghaiPujiang Talent Project 08PJ14036, and 07PJ14022 forsupport of this work.

REFERENCES

[1] G. Fleury, G. Schlatter, C. Brochon, C. Travelet, A. Lapp,P. Lindner, G. Hadziioannou. Macromolecules, 2007; 40,535–543.

[2] S.J. De Jong, S.C. De Smedt, M.W.C. Wahls, J. Demeester,J.J. Kettenes-van den Bosch, W.E. Hennink. Macromolecules,2000; 33, 3680–3686.

[3] Y.H. Bae, K.M. Huh, Y. Kim, K.H. Park. J. ControlledRelease, 2000; 63, 3–13.

[4] H.J. Schneider, F. Hacket, V. Rudiger. Chem. Rev., 1998; 98,1755–1785.

[5] A. Harada. Adv. Polym. Sci., 1997; 133, 141–191.[6] J. Li, A. Harada, M. Kamachi. Polym. J., 1994; 26,

1019–1026.[7] X.H. Guo, A.A. Abdala, B.L. May, S.F. Lincoln, S.A. Khan,

R.K. Prud’homme. Macromolecules, 2005; 38, 3037–3040.[8] X.H. Guo, A.A. Abdala, B.L. May, S.F. Lincoln, S.A. Khan,

R.K. Prud’homme. Polymer, 2006; 47, 2976–2983.[9] G. Wenz, B.H. Han, A. Muller. Chem. Rev., 2006; 106,

782–817.[10] K.A. Udachin, L.D. Wilson, J.A. Ripmeester. J. Am. Chem.

Soc., 2000; 122, 12375–12376.[11] A. Harada, J. Li, M. Kamachi. Nature, 1992; 356, 325–327.[12] J. Szejtli. Chem. Rev., 1998; 98, 1743–1753.[13] H. Ikeda. Chem. Rev., 1998; 98, 1755–1785.[14] A. Harada, M. Kamachi. Macromolecules, 1990; 23,

2821–2823.[15] T. Ikeda, T. Ooya, N. Yui. Polym. J., 1999; 31, 658–663.[16] H. Fujita, T. Ooya, N. Yui. Macromolecules, 1999; 32,

2534–2541.[17] H. Fujita, T. Ooya, N. Yui. Polym. J., 1999; 31, 1099–1104.[18] Y. Okumura, K. Ito. Adv. Mater., 2001; 13, 485–487.[19] T. Karino, Y. Okumura, K. Ito, M. Shibayama. Macro-

molecules, 2004; 37, 6177–6182.[20] T. Shimomura, T. Akai, K. Ito. J. Chem. Phys., 2002; 116,

1753–1756.[21] T. Akai, T. Shimomura, K. Ito. Synth. Met., 2003; 135,

777–778.[22] M. Tamura, A. Ueno. Bull. Chem. Soc. Jpn., 2000; 73,

147–154.[23] M. Tamura, D. Gao, A. Ueno. Chem. – Eur. J., 2001; 7,

1390–1397.[24] N. Yui, T. Ooya, T. Kumeno. Bioconjugate Chem., 1998; 9,

118–125.[25] T. Ooya, K. Arizono, N. Yui. Polym. Adv. Technol., 2000; 11,

642–651.[26] T. Ooya, N. Yui. J. Comtrolled Release, 2002; 80, 219–228.



[27] P. Lo Nostro, J.R. Lopes, B.W. Ninham, P. Baglioni. J. Phys.Chem. B, 2002; 106, 2166–2171.

[28] A. Harada, J. Li, M. Kamachi. Nature, 1993; 364, 516–518.[29] T. Kataoka, T. Kidowaki, C. Zhao, H. Minamikawa, T.

Shimizu, K. Ito. J. Phys. Chem. B, 2006; 110, 24377–24383.[30] C.A. Dreiss, T. Cosgrove, F.N. Newby, E. Sabadini. Lang-

muir, 2004; 20, 9124–9129.[31] Y. Isobe, A. Sudo, T. Endo. Macromolecules, 2006; 39,

7783–7785.[32] R. Hernandez, M. Rusa, C.C. Rusa, D. Lopez, C. Mijangos,

A.E. Tonelli. Macromolecules, 2004; 37, 9620–9625.[33] A. Harada, J. Li, M. Kamachi. Macromolecules, 1993; 26,

5698–5703.

[34] T. Ikeda, T. Ooya, N. Yui. Macromol. Rapid Commun., 2000;21, 1257–1262.

[35] K.M. Huh, T. Ooya, W.K. Lee, S. Sasaki, I.C. Kwon, S.Y.Jeong, N. Yui. Macromolecules, 2001; 34, 8657–8662.

[36] J. Araki, C. Zhao, K. Ito. Macromolecules, 2005; 38,7524–7527.

[37] T. Kataoka, M. Kidowaki, C. Zhao, H. Minamikawa, T.Shimizu, K. Ito. J. Phys. Chem. B, 2006; 110, 24377–24383.

[38] M. Kidowaki, T. Nakajima, J. Araki, A. Inomata, H. Ishibashi,K. Ito. Macromolecules, 2007; 40, 6859–6862.


hydrogels assembled by inclusion complexation of poly(ethylene glycol) with alpha-cyclodextrin

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