# Biomaterials for Ophthalmic Applications
## 2 Biomaterials in Ophthalmology
### Vitreous Substitutes
Fragmentation and changes in viscoelastic properties and resiliency after injection through a small-gauge needle have also been found in some types of hydrogels. Smart hydrogels are a relatively new class of stimuli-sensitive hydrogels. They possess the common properties of conventional hydrogels, and they can respond to a variety of signals, including PH, temperature, light, pressure, electric fields, and chemicals [12; 86; 89; 90]. These interactions lead to better gelation, drug diffusion, and gel expansion. However, there is still insufficient information about its toxicity or inflammatory action. These materials are still in the experimental phase, as certain complications are still not well understood. Generally, smart hydrogels appear promising, but research on their use is still at an early experimental stage, and their effects on long-term toxicity are unknown [5]. Recent research in vitreous substitutes mostly include cross-linked hydrogels; these materials show an enhanced retention time in the eye and are capable of acting as a tamponade agent. New developments in existing hydrogel-based vitreous substitutes have been reported. A study conducted by [PERSON] et al. reported PVA hydrogels synthesis through cross-linking with non-toxic trisodium trimetaphosphate (STMP), resulting in rheological properties similar to the natural vitreous body. These properties were preserved after injection and in vitro cytotoxicity presented good results. In vivo studies to prove the long-term compatibility of this promising material have yet to be conducted [92]. [PERSON] et al. copolymerized acrylamide with bisacryloylcystamine, obtaining good mechanical properties similar to the natural vitreous humor with in vivo animal testing showing good biocompatibility. However, long-term testing is still needed [93]. [PERSON] et al. proposed a different cross-linking approach using two reactive PEG derivatives and tested it on rabbits. The obtained hydrogel was stable during the time of the in vivo rabbit study (9 months), the mechanical and optical properties were very similar to the natural vitreous body and no adverse reactions were found [94]. Natural polymers for vitreous replacement have also been investigated with hyaluronic acid (HA) the most promising material. [PERSON] et al. compared two different HA hydrogels regarding their suitability as a vitreous substitute with different cross-linking methods (adipic dihydrazide (ADH) as well as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and the photopolymerization of glycidyl methacrylate groups. During in vitro cell culture experiments, ADH/EDC cross-linked hydrogels induced mild cytotoxicity, whereas photopolymerized HA gels presented no toxicity. During 6 weeks of in vivo testing, the photopolymerized gels showed appropriate biocompatibility [95]. However, another study found no toxic effects with similar ADH cross-linked HA hydrogels not only in vitro but also in vivo [96]. Although significant improvements have been achieved over the past years, there are currently no artificial vitreous substitutes that reach the properties of the natural vitreous body available. Even in situ cross-linkable hydrogels, which are generally favored due to the absence of shear thinning, do not meet all of the requirements to act as long-term vitreous substitutes [89]. Another possibility is the use of tissue engineering and gene therapy to artificially synthesize the vitreous via the proliferation of hylocytes. This research has been aided by the use of a reverse transcriptase polymerase chain reaction to analyze and compare the expression profiles of several genes involved in the synthesis of the vitreous [86; 97]. Table 3 summarizes the main classes of ophthalmic applications involving biomaterials and related studies.