Evaluation of redox-responsive disulfide cross-linked poly(hydroxyethyl methacrylate) hydrogels Muhammad Ejaz a , Haini Yu b , Yong Yan a , Diane A. Blake b , Ramesh S. Ayyala c , Scott M. Grayson a, * a Department of Chemistry, Tulane University, New Orleans, LA 70118, United States b Department of Biochemistry, Tulane University, School of Medicine, New Orleans, LA 70112, United States c Department of Ophthalmology, Tulane University, School of Medicine, New Orleans, LA 70112, United States article info Article history: Received 3 June 2011 Received in revised form 7 September 2011 Accepted 9 September 2011 Available online 21 September 2011 Keywords: Poly(hydroxyethyl methacrylate) hydrogel Stimulus responsive Disulfide cross-linker abstract Poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels were prepared with a disulfide containing cross- linker bis(2-methacryloxyethyl) disulfide (DSDMA) that exhibited enhanced release in the presence of glutathione (GSH), a biologically available reducing agent. Varying concentrations of the DSDMA cross- linker were incorporated into the prepolymer before the radical polymerization, enabling the cross- link density to be easily tuned. Dye release studies were performed using rhodamine B and rhoda- mine 6G dyes, and the UV response of the dyes released into the supernatant measured with the addition of GSH. Using ether-based cross-linkers as a control, the disulfide cross-linkers exhibited a substantial increase in release rates, confirming the responsive nature of the hydrogels to biological reducing agents. The polymers were also tested in a cell culture system for their ability to release the anti- fibroproliferative agent, mitomycin C (MMC). Polymers cross-linked with DSDMA delivered MMC over a slightly longer time period than control polymers prepared with a conventional ether cross-linker. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction In the recent years, a number of novel polymer-based delivery systems have been developed for the entrapment of proteins, drugs, genes or antigens in devices such as micelles, vesicles, or within hydrogel matrices [1]. Polymer based drug systems have attracted much attention in the fields of polymer chemistry, pharmaceutics and biomedical science because of the potential for both targeted delivery and controlled release of the drug payload [2]. While soluble polymer-drug conjugates can exhibit mobility in vivo to achieve selective targeting, insoluble hydrogels can offer the complimentary property of immobility once they are implanted or injected into the desired site of treatment. Hydrogels are three-dimensional cross- linked hydrophilic polymer networks stabilized through physical or chemical cross-links, and can be designed to absorb up to many thousands of times their dry weight in water, enabling them to mimic the physical characteristics of soft tissues. Their chemical composi- tion and three dimensional structure can be easily modified to tune their swelling, mechanical properties, biocompatibility, and encap- sulation of drugs [3,4]. The insoluble and often robust character of the hydrogels provides them with mechanical stability, yet the permeability of hydrogel systems to small molecules and solvents also maintains a dynamic behavior typical of liquid phases [5]. Because they can be designed to exhibit exceptional biocompati- bility, (e.g. reduced inflammatory responses, thrombosis and tissue damage,) hydrogels have been studied extensively for biomedical applications [2,6] including drug delivery [7e13] and tissue engi- neering [14,15]. Hydrogels also offer significant opportunities for in vivo targeted applications due to the ability to control their size and shape, the ability to tune their porosity and their ability to incorpo- rate biorelated molecules such as DNA, proteins and drugs. Hydrogels are also easy to functionalize for multivalent bioconjugation [16e18]. Recently stimuli-responsive smart hydrogels have been devel- oped with a variety of triggers including enzymes [19], pH [20], temperature [21] light [22], electric field [23], magnetic field [24] and selective chemical triggers (for example metal ions or glucose) [25] with versatile applications that include controlled drug and gene delivery systems [6,26] chemical and biological separations [27,28] as well as sensors and actuators [29,30]. Pol- y(hydroxyethyl methacrylate) (PHEMA) is one of the most widely used hydrogels for various biomedical applications such as drug delivery systems [31,32], tissue engineering, and contact lenses [33,34] because of its biocompatibility [32]. PHEMA hydrogels consist of a framework of PHEMA chains with intermediate water- filled voids that act as pores for the passage of the solute [35]. The high density of hydroxyl groups within PHEMA hydrogels results in * Corresponding author. Tel.: þ1 504 862 8135; fax: þ1 504 865 5596. E-mail address: sgrayson@tulane.edu (S.M. Grayson). Contents lists available at SciVerse ScienceDirect Polymer journal homepage: www.elsevier.com/locate/polymer 0032-3861/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.polymer.2011.09.018 Polymer 52 (2011) 5262e5270