Shaped Films of Ionotropic Hydrogels Fabricated Using Templates of Patterned Paper

This article describes the use of paper—patterned either by hand or with a color laser printer—to fabricate films of ionotropic hydrogels structured into regular shapes with lateral dimensions from 2mm to several centimeters, and with thicknesses from 0.2 to 1.3mm. Water-soluble polymers such as alginic acid (AA) and carboxymethyl cellulose (CMC) form hydrogel films with defined shapes when solutions of these polymers are brought into contact with patterned templates of paper wetted with aqueous solutions of multivalent cations. The hydrogel films have sufficient mechanical strength to be handled with tweezers, and they retain their shapes when stored in water for weeks. When multivalent cations of high magnetic susceptibility (x) cross-link the polymers (as in holmiumor gadolinium-cross-linked AA, Ho3þ–AA and Gd3þ–AA), the films can be manipulated using rare-earth bar magnets. This procedure provides a new method for the fabrication of hydrogel films into structures that cannot be achieved (easily, or at all) using other methods. It renders possible the production of topographically and topologically complex three-dimensional shapes (e.g., interlocking rings and Mobius strips), and overcomes the difficulty presented in adding solutions of crosslinking ions to millimeter-sized layers of uncured polymer without deforming the shapes of the resulting hydrogel films. For certain patterns, our procedure provides a manufacturing method, since the patterned paper templates can be reused. Ionotropic hydrogels are hydrated gel matrices that form when metal ions cross-link water-soluble linear polymers. Polymers that form hydrogels in the presence ofmultivalent cations include AA, CMC, i-carrageenan (CG), poly(galacturonic acid) (PG), and poly[bis(4-carboxyphenoxy)-phosphazene]. Ionotropic hydrogels shaped in three dimensions with controlled compositions are an important class of biomaterials, with applications in the fields of controlled (drug) delivery, cellular immobilization, and biomimicry. Ionotropic hydrogels can serve as delivery devices for drugs and proteins when the polymers are biocompatible and degrade slowly relative to conventional sustained/slow-release systems. Ionotropic hydrogels (especially Ca2þ–AA) have been investigated as cellular scaffolds, but usually as spherical beads because other 3D structures are more difficult to fabricate. Lim and Sun demonstrated that alginate gels are suitable materials for cell encapsulation, although cells will usually not attach directly to unmodified alginate. Ionotropic hydrogels modified to present ligands for cell receptors have been used to mimic extracellular matrices (ECMs) that provide structural support to cells in tissue. Biomimetic materials are synthetic materials that have physical properties and biological functions similar to materials found in nature. Hydrogels have attracted interest as biomimetic materials due to their pliability, extent of hydration, low toxicity, and biocompatibility. For instance, Aizenberg and coworkers used hydrogels to mimic the microlens arrays of brittle stars (Ophiocoma wendii). Hydrogels can also be used to study creatures that creep, crawl, inch, and slither. Mahadevan et al. agitated cylindrical rods of hydrogels to simulate the muscular contractions of a snail. Yeghiazarian et al. heated rods of thermosensitive hydrogels confined to glass capillaries to mimic the movement of earthworms. Other uses for ionotropic hydrogels include as binding agents in food products, as sorbents for toxic metals, and as wound dressings. AA cross-linked with radioactive Ho3þ has been used in anti-tumor therapy that can be monitored by MRI. On sub-micrometer scales, Lahav et al. used microfluidic channels to pattern thin films of poly(acrylic acid) (PAA) crosslinked by metallic ions (e.g., Pb2þ, Ba2þ, Zn2þ, Pd2þ, Cu2þ, La3þ, Ho3þ).[14] Winkleman et al. used photolithography to create patterns of thin films of PAA cross-linked bymetal ions to assist in theproductionof low-kdielectricmaterials.Whileourgroupand others have fabricated sub-micrometer-thick layers of metal cross-linked polymers such as PAA, films of ionotropic hydrogels with millimeter thicknesses are more challenging to construct, because of the difficulty of introducing the multivalent cations across the entire surface of the film without disturbing the uniformity of the uncured layer of polymer. Techniques used to construct ionotropic gels on this scale include that of Chang et al., who produced synthetic facial implants in the shapes of chins, cheeks, and nasal septa out of hydrogels by injecting mixtures of chondrocytes, alginate, and CaSO4 into Silastic molds. [16] Cohen et al. developed a robotic system to fabricate arbitrary 3D hydrogel structuresby sequentially printing2D layers ofCa2þ–AApatterned with 1.2mmwide and 0.8mm tall threads of a solution of alginate for which cross-linking with CaSO4 was initiated prior to deposition. Liu and coworkers fabricated microscale spheres, rods, plugs, disks, and threads of alginate hydrogels using a flow-focusingmicrofluidic device. In their process, droplets of a solution of sodium alginate collided with droplets of a solution of CaCl2 inside microchannels and formed hydrogels. Solutions of sodium alginate gelled into membranes when cast onto porous media—including paper—wetted with solutions of multivalent cations. Cheng and coworkers controlled the porosity of these