Novel Vitreous Substitutes: The Next Frontier in Vitreoretinal Surgery

André Schulz; Kai Januschowski; Peter Szurman


Curr Opin Ophthalmol. 2021;32(3):288-293. 

In This Article

Physically Crosslinked Hydrogels

Physically crosslinked hydrogels can be formed using physical or supramolecular interactions such as hydrogen bonding, hydrophobic association or electrostatic (ionic) interaction. The gelation of physical crosslinked hydrogels is generally induced by relatively mild stimuli such as temperature changes, slight pH changes, shear stress or the presence of ionic moieties. As a result, toxic monomers and crosslinking agents can mostly be excluded. The majority of physically crosslinked systems are designed to be thermoresponsive with an in-situ gelation at body temperature of 37°C.

Recently, Yu et al.[21] reported in-situ physically crosslinked hydrogels based on polyvinyl alcohol and chitosan, crosslinked in the presence of calcium chloride via hydrogen bonds when heated to body temperature. One percent polyvinyl alcohol/chitosan hydrogels possessed a water content (98.7%), refractive index (1.33) and light transmittance (93%) comparable to native vitreous. However, this similarity decreased with increasing polymer content. In terms of mechanical properties, 3% gels were needed to simulate the stiffness of the human vitreous body. Biocompatibility of the gels was demonstrated in vitro in ARPE-9 cells and in vivo in rabbits. To simultaneously address the therapy of PVR, 5-FU microspheres were added to the thermogelling system resulting in a decreased recurrence rate in a PVR rabbit model. However, slit-lamp images showed the injected graft to be whitish and cloudy, which may cause visual impairment. In addition, 5-FU has a certain retinal toxicity, leading to a limitation as a therapeutic agent against PVR.[36] Furthermore, the established system was limited by transient high intraocular pressure and complicated cataract occurred in some rabbit eyes.

A material system that gels by cooling to body temperature was recently described by Laradji et al..[37] On the basis of thiolated gellan and poly (methacrylamide-co-methacrylate-co-bis (methacryloyl)cystamine), thermoresponsive gelation occurred after injection as a 45°C warm solution as a result of a random coil-to-double-helix transition of gellan and additional crosslinking via disulfide bonds. The in-situ formed gels have suitable optical and mechanical properties with an acceptable swelling behaviour of 18–27%. In rabbits, no signs of toxicity, no cataract formation and normal fluctuations in intraocular pressure were observed. However, the reduced metabolic activity of fibroblasts after gel addition was striking and should be investigated more deeply to verify the biocompatibility of the system. Likewise, it should be clarified whether the injection of a 45°C warm solution potentially damages ocular tissues in the long term.

The thermogelling in-situ physically crosslinked hydrogel system based on poly (ethylene glycol, poly (propylene glycol) and poly (ε-caprolactone) has been extensively evaluated preclinically[20,38–40] and has the potential to enter the clinical phase soon. After injection of the cooled solution, gelation occurs with increasing temperature due to dehydration of the poly (propylene glycol) components aggregating spontaneously via hydrophobic interactions. The authors report suitable optical, mechanical and functional properties as well as biocompatibility in rabbit and nonhuman-primate retinal-detachment models. Most notably, it was stated that degeneration of the hydrogel-based vitreous substitute was accompanied by regeneration of a vitreous-like body that possessed structural proteins similar to the native vitreous. Although the proteomic analyses are very promising, further analyses are needed to support vitreous regeneration. Here, it should be briefly mentioned that the same group has recently developed a thermogelling vitreous substitute based on polyhydroxyalkanoates[41] underlining the great potential of thermogelling strategies.

The design of vitreous substitutes beyond tamponading properties was recently described by Tram et al..[18,19] In-situ physically crosslinked hydrogels based on poly (ethylene glycol) methacrylate and poly (ethylene glycol) diacrylate demonstrated suitable optical and mechanical properties as well as in-vitro biocompatibility. Going beyond these essential properties of a vitreous substitute, antioxidants were additionally incorporated into the gel matrix to address the biochemical functions of the vitreous. Simultaneous administration of ascorbic acid and glutathione as antioxidants has been identified in in-vitro studies as potential therapeutic agents to prevent oxidative damage to intraocular tissue after vitrectomy.

However, a major disadvantage of physically crosslinked hydrogels is their relatively rapid degradation due to the lack of permanent crosslinks. In contrast to the multitude of above-mentioned degradable substitutes, preformed physically crosslinked hydrogels based on alginate have recently been described in vitro that have the potential to permanently mechanically support and protect the surrounding ocular tissue as alginates are inherently nondegradable in mammals.[26] Hydrogels based on high molecular weight and high purity alginates crosslinked with calcium sulfate demonstrated suitable optical and mechanical properties as well as in-vitro biocompatibility with respect to ocular cells. Here, the required viscoelasticity was still present after fragmentation of the preformed gels into a tangle of coiled bead strings by injection through a 23G needle.[26] Future studies should address the in-vivo biocompatibility and functionality of alginate-based vitreous substitutes in animal models.