Polymer solutions can fill any potential irregular cavity using minimally invasive techniques and thus have potential uses in ophthalmology. We prepared acrylamide hydrogels containing disulfide bonds by free radical polymerization in aqueous ethanol. The hydrogels were liquefied using dithiothreitol to yield water-soluble acrylamide copolymers containing pendant thiol (-SH) groups. The weight average molecular weights of the copolymers ranged from 1.43 x 10(5) to 9.22 x 10(5) daltons by GPC. Ellman's analysis and Raman spectroscopy confirmed the presence of -SH. The aqueous solutions of these purified thiol-containing copolymers were oxidized with 3,3'-dithiodipropionic acid or air to reform the hydrogels. The moduli of the reformed hydrogels ranged from 0.27 to 1.1 kPa depending on concentration and thiol content. Rapid endocapsular gelation yielded optically clear gel within the lens capsular bag. This technique now enables us to validate methods to determine the biomechanics of the lens and its role in accommodation.
The human vitreous is a gelatinous substance predominantly composed of water (97-99%). Vitreous substitutes are needed for treatment of retinal detachments by reapproximating the retina to the back of the eye, or during vitrectomies for maintenance of ocular volume. None of the current substitutes can be used long-term due to their short retention time, toxicity, or complications such as glaucoma or cataracts. In addition, all of the current compounds have a specific gravity less than water and so are not appropriate for inferior retinal detachments. The viscoelastic properties of the porcine vitreous were analyzed to develop a model for ideal substitutes. Synthetic polymers that form hydrogels in situ were researched for the development of artificial vitreous. In this study, the physical, mechanical, and optical properties of four self-gelling polyacrylamide copolymeric hydrogels were determined and compared with those of the porcine vitreous. The 2% formulation of high crosslink density, hydrophobically modified hydrogel most closely mimicked the porcine vitreous. The viscoelastic properties of hydrogels capable of being formed in situ were compared to those of the porcine vitreous to determine their efficacy as vitreous substitutes.
An autosomal dominant missense mutation in αB-crystallin (αB-R120G) causes cataracts and desmin-related myopathy, but the underlying mechanisms are unknown. Here, we report the development of an αB-R120G crystallin knock-in mouse model of these disorders. Knock-in αB-R120G mice were generated and analyzed with slit lamp imaging, gel permeation chromatography, immunofluorescence, immunoprecipitation, histology, and muscle strength assays. Wild-type, age-matched mice were used as controls for all studies. Both heterozygous and homozygous mutant mice developed myopathy. Moreover, homozygous mutant mice were significantly weaker than wild-type control littermates at 6 months of age. Cataract severity increased with age and mutant gene dosage. The total mass, precipitation, and interaction with the intermediate filament protein vimentin, as well as light scattering of αB-crystallin, also increased in mutant lenses. In skeletal muscle, αB-R120G co-aggregated with desmin, became detergent insoluble, and was ubiquitinated in heterozygous and homozygous mutant mice. These data suggest that the cataract and myopathy pathologies in αB-R120G knock-in mice share common mechanisms, including increased insolubility of αB-crystallin and co-aggregation of αB-crystallin with intermediate filament proteins. These knock-in αB-R120G mice are a valuable model of the developmental and molecular biological mechanisms that underlie the pathophysiology of human hereditary cataracts and myopathy.
The vitreous humor of the eye is a biological hydrogel principally composed of collagen fibers interspersed with hyaluronic acid. Certain pathological conditions necessitate its removal and replacement. Current substitutes, like silicone oils and perfluorocarbons, are not biomimetic and have known complications. In this study, we have developed an in situ forming two-component biomimetic hydrogel with tunable mechanical and osmotic properties. The components are gellan, an analogue of collagen, and poly(methacrylamide-co-methacrylate), an analogue of hyaluronic acid; both endowed with thiol side groups. We used response surface methodology to consider seventeen possible hydrogels to determine how each component affects the optical, mechanical, sol-gel transition temperature and swelling properties. The optical and physical properties of the hydrogels were similar to vitreous. The shear storage moduli ranged from 3 to 358 Pa at 1Hz and sol-gel transition temperatures from 35.5 to 43 °C. The hydrogel had the ability to remain swollen without degradation for four weeks in vitro. Three hydrogels were tested for biocompatibility on primary porcine retinal pigment epithelial cells, human retinal pigment epithelial cells, and fibroblast (3T3/NIH) cells, by electric cell-substrate impedance sensing system. The two-component hydrogels allowed for the tuning and optimizing of mechanical, swelling, and transition temperature to obtain three biocompatible hydrogels with properties similar to vitreous. Future studies include testing of the optimized hydrogels in animal models for use as a long-term substitute, whose preliminary results are mentioned.
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