Macromolecules healed upon exposure to UV light.14 Herein, we present an alternative and complementary material system containing photolabile, photoadaptable groups. Speciﬁcally, the material was designed to overcome the challenges of light attenuation and low quantum yield, permitting the degradation of hydrogels up to 2 mm thick within 120 s of exposure to relatively low light intensities and long wavelength ultraviolet light (10 mW/cm2 and 365 nm, respectively). This degradation was achieved by exploiting the disruption of disulﬁde bonds by reaction with photogenerated carbon- and phosphorus-centered radicals and subsequent disulﬁde rearrangement by cascading transfer of sulfur radicals. Disulﬁde bonds, typically formed by the oxidation of thiols, have been shown previously to be susceptible to radical cleavage by carboxylate and hydroxyl radicals, a mechanism of radical protein denaturation, resulting in thiyl radical products.15 Ob- serving relaxation in disulﬁde and tetrasulﬁde polymers contain- ing elemental sulfur, Tobolsky et al. hypothesized in 1963 that disulﬁde exchange could be initiated by radicals generated from the thermal cleavage of the S8 sulfur ring.16 Moreover, addition of certain disulﬁdes to radical chain growth polymerizations has been shown to impart some living polymerization attributes via fragmentation reactions,17 and radical exchange reactions with disulﬁdes have been employed in the synthesis of tertiary (thioca- rbonyl) sulfanyl compounds.18 In this article, hydrogels are formed by the oxidation of thiol- functionalized 4-armed poly(ethylene glycol) macromolecules in solution. This disulﬁde cross-linked hydrogel was swollen in a solution of a lithium acylphosphinate (LAP) photoinitiator,19 recently demonstrated to possess a higher eﬃciency and quan- tum yield than alternative water-soluble cleavage-type radical photoinitiators.20 Upon exposure to light at a wavelength of 365 nm, the radicals formed from the scission of the photoinitiator attack and cleave the disulﬁdes, liberating thiyl radicals which then undergo fragmentation and exchange with other disulﬁdes. When the concentration of radicals generated by the initiator is on the order of the concentration of sulfur atoms in the network, the network can be completely degraded into soluble PEG segments. If, however, the number of radicals generated is much less than the number of sulfur atoms in the gel (accomplished by limiting the initial photoinitiator concentration), the network will instead adapt to an applied strain to minimize the free energy of the system.21 23 Under such conditions, self-healing is possible as disulﬁde exchange at the interface of two prefabricated gels in contact will chemically anneal to form a single gel of combined dimensions. This simple approach to photodegradable, photoadaptable hydrogels portends the study of cellular response to mechanically and topographically dynamic substrates as the photoreactions are performed under cytocompatible conditions. One might also envision encapsulation methods by the annealing of preformed solid substrates as an alternative to the typical encapsulation by gelation of liquid solutions. Moreover, the principles and chem- istry described herein are not limited to hydrogel materials but may prove beneﬁcial when performing photoinitiated radical reactions in the presence of disulﬁde-containing materials and the development of photoadaptable polymers more generally. ’ MATERIALS AND METHODS Synthesis of Monomer and Initiator. Thiol-terminated four- armed poly(ethylene glycol) PEG4SH was prepared in a manner similar ARTICLE to Goessl et al.,6 but with some significant modifications. Five grams of hydroxy-terminated, four-armed PEG (MW 10 000) (Jenkem) was dissolved in 70 mL of toluene in a round-bottomed flask and refluxed at 80 C. Sodium hydride (Sigma-Aldrich), 1.5 mol equiv with respect to hydroxyls, was added to the solution. Allyl bromide (Sigma-Aldrich), 1.5 mol equiv relative to hydroxyls, was diluted with 10 mL of toluene and added dropwise to the solution via an addition funnel. The reaction was refluxed overnight at 80 C. Any unreacted sodium hydride was neutralized with the addition of 1 mL of methanol, whereupon sodium salts were removed via ﬁltration, and the PEG was recovered from solution by precipitation in cold diethyl ether. The PEG tetraallyl ether was dried in vacuo and then redissolved in 50 mL of methanol in a 100 mL round-bottom ﬂask, to which was added 0.10 g of the radical photoinitiator 2,2-dimethoxy-1,2-dipheny- lethan-1-one (trade name Irgacure 651, BASF). Thiol acetic acid (Sigma-Aldrich), 1.5 equiv relative to the allyl groups, was added, and the solution was stirred vigorously under exposure to 10 mW/cm2 365 nm UV light for 20 min. PEG thioacetate was recovered from solution by precipitation and dried as before. Dried PEG thioacetate was dissolved in 20 mL of deionized water (diH2O), whereupon 20 mL of 2 M NaOH was added and the solution was stirred for 5 min, and 11 mL of 4 N HCl solution was added to acidify the solution and discourage disulﬁde formation. The aqueous solution was extracted with equivalent volumes of chloroform twice, combined fractions were concentrated by rotary evaporation, and product was recovered by precipitation in cold diethyl ether. Substitution was determined to be ∼90% by both Ellman’s analysis and proton NMR. The initiator LAP was synthesized as described previously.20 Gel Formation. Polymerization of the PEG4SH was performed in diH2O. To a 10 wt % solution of PEG-4SH was added 30% hydrogen peroxide (Sigma-Aldrich) to a final concentration of 1% and sodium iodide (Sigma-Aldrich) to a concentration of 1 mM. The solution was then injected between glass slides separated with silicon rubber gaskets to form circular disks. After at least 3 h, 40 μL gels (height = 1 mm, diameter = 7 mm) were removed from molds and put in 1 mL of diH2O each. After an hour at room temperature, gels were removed to fresh diH2O and placed at 4 C for subsequent experiments. Hydrogels were placed in 1 mL of aqueous LAP solution for 60 min prior to light exposure. Mechanical and Chemical Characterization. In situ dynamic photorheometry was performed on an Ares TA 4400 rheometer with photoexposure attachments as described previously.5,20 Samples were measured at 20% strain and 20 Hz frequency with parallel-plate geometry. For strained exposures, the rheometer was employed to provide the normal force. Collimated light was supplied by an EXFO Omnicure 1000 at 365 nm and 10 mW/cm2 for all experiments on and off the rheometer. Topographical features of hydrogel were imaged with a Leica MZIII stereomicroscope and the dimensions quantitatively examined by proﬁlometry (Stylus Proﬁler, Dektak 6M, force = 1 mg and radius = 12.5 mm). 1H NMR and 31P NMR were performed on a Bruker AV-III 300 MHz NMR spectrometer in D2O. All spectra were analyzed with Mestre- Nova 6.1. ’ RESULTS AND DISCUSSION An idealized schematic of the oxidation of the PEG-4SH, performed with 1 mM NaI and 1% H2O2, to form networks is shown in Figure 1. Following polymerization and removal of the oxidants, degradation behavior of the cross-linked gels in the presence of varying concentrations of the photoinitiator was examined (Figure 2). In situ dynamic photorheometry suggests that, upon light exposure and initiator cleavage, both radical 2445 dx.doi.org/10.1021/ma200202w |Macromolecules 2011, 44, 2444–2450