Hydrogels of Modified Ethylenediaminetetraacetic Dianhydride Gelatin Conjugated with Poly(ethylene glycol) Dialdehyde as a Drug-Release Matrix G. V. N. Rathna School of Pharmacy, University of Wisconsin at Madison, Madison, Wisconsin 53706 Received 19 February 2002; accepted 30 May 2003 ABSTRACT: Hydrogels have been recognized as versatile biomaterials in biomedical applications. This article de- scribes the synthesis and characterization of a poly(ethylene glycol) (PEG) dialdehyde derivative, the modification of gelatin with ethylenediaminetetraacetic dianhydride (ED- TAD), and the conjugation of PEG dialdehyde for enhanced hydrophilicity, biocompatibility, and flexibility. Hydrogels of gelatin conjugated with various percentages of PEG dial- dehyde (10 –30%), 35% EDTAD-modified gelatin, and 12% PEG dialdehyde conjugated with 31% EDTAD-modified gel- atin with or without 1% chlorhexidine were prepared. For all the synthesized gel formulations, the swelling kinetics and drug release in pH 7.4 and pH 4.5 buffers at 37°C were studied. Gels of PEG-conjugated gelatin, 35% EDTAD-mod- ified gelatin, and 12% PEG conjugated with 31% EDTAD- modified gelatin, with or without 1% chlorhexidine, showed significantly improved swelling ratios in comparison with gelatin. The drug release was unaffected by an increase in the percentage of PEG conjugation with gelatin. Complete drug release was recorded within 48 h in the pH 4.5 buffer, whereas in the pH 7.4 buffer, the drug release was accom- plished within 128 h. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 1059 –1067, 2004 Key words: hydrogels; biodegradable; swelling INTRODUCTION Hydrogels are versatile biomaterials. Acrylic-based hy- drogels have a very good water uptake capacity, but most acrylic polymers are nondegradable and are very toxic because of unreacted toxic monomers; 1–10 there- fore, synthetic polymers have limited applications as biomaterials. Although polyurethanes provide good me- chanical strength and biocompatiblity, 11–17 the pro- longed use of polyurethanes can lead to inflammation because of interactions of the material with proteins that lead to an adverse host reaction. Hence, biomaterial re- searchers have focused on biodegradable, biocompat- ible, natural-polymer-based hydrogels such as gelatin, collagen, amylase, cellulose, chitosan, hylauronic acid, fish, soy, agarose, and alginate. 18 –27 However, natural-polymer-based hydrogels are less hydrophilic and provide low mechanical strength; un- like synthetic polymers, natural polymers are unique, having various functional groups. Therefore, by mod- ifying the functional groups, we can tailor the prop- erties as we desire. We propose developing a protein- based hydrogel with improved swelling and mechan- ical properties with drug-release capability. For our studies, we have chosen gelatin, a denatured protein derived from collagen, because of its unique gelling properties, abundance, solubility, biocompatibility, and biodegradability and because of the functional groups that are present on the gelatin backbone, which can be chemically modified for increased hy- drophilicity and biocompatibility along with im- proved physicochemical properties. Lysyl residues of gelatin have been modified with ethylenediaminetet- raacetic dianhydride (EDTAD) to incorporate carbox- ylic groups in order to increase the hydrophilicity and conjugated with poly(ethylene glycol) (PEG) dialde- hyde to increase the flexibility and biocompatibility. EXPERIMENTAL Materials and methods Type A porcine skin gelatin (Bloom 300) and trinitro- benzenesulfonic acid (TNBS; 20% chlorhexidine diglu- conate) were obtained from Sigma Chemical Co. (St. Louis, MO). PEG (2000 Da), sodium cynoborohydride, EDTAD, and acetic anhydride were purchased from Aldrich Chemical Co. (Milwaukee, WI). All other re- agents were analytical-grade. Modification of gelatin with EDTAD The EDTAD-modified gelatin was synthesized as pre- viously reported. 18,28 A 1% gelatin solution in 100 mL Correspondence to: G. V. N. Rathna, Department of Chem- ical Engineering, National Tsing Hua University, Hsinchu, Taiwan 30043, Republic of China (gundloorir@hotmail.com). Journal of Applied Polymer Science, Vol. 91, 1059 –1067 (2004) © 2003 Wiley Periodicals, Inc.