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

Chemically Crosslinked Hydrogels

Based on the experimental evidence that noncrosslinked polymer solutions were limited by short residence time and lack of tamponading effect, chemically crosslinked hydrogels were studied as vitreous substitutes with either preformed or gelled in-situ systems that were classified into material systems of natural or synthetic origin. Hyaluronic acid as the main polymeric component of native vitreous is still intensively investigated in the context of hydrogel-based vitreous substitutes. Schramm et al.[25] pioneered using hyaluronic acid conjugated with light-sensitive units and crosslinked by UV irradiation. The advantage of these preformed chemically crosslinked hydrogels compared to in situ gelling systems is the ability to remove potentially toxic noncrosslinked monomers and crosslinkers by dialysis prior to intravitreal injection. After the first promising results of the photocrosslinked hyaluronic acid gels in cell experiments and in rabbits,[25] the suitability of the system as a vitreous substitute was recently confirmed with new findings regarding the optical and mechanical properties as well as the biocompatibility with ocular cells in vitro[26] and in vivo as nano-formulations in rabbit experiments.[27]

To circumvent the risk of toxic effects of unreacted crosslinkers, Schnichels et al.[28] used thiolated hyaluronic acid forming disulfide bridges by air oxidation without additional chemical crosslinkers.[29] Here, two hydrogels of different stiffness (663 and 418 Pa) showed transparency, low toxicity and effectiveness in a retinal detachment model. Tamponading with the softer gel was more successful than with the stiffer gel that tended to cause mechanical damage to the rabbit retina.[28] As a consequence, transparent hydrogels with a lower stiffness of 129 Pa were recently evaluated showing no significant effect on intraocular pressure as well as retinal integrity in ex-vivo studies in porcine eyes.[29]

Another candidate for hyaluronic acid-based vitreous substitutes is Healaflow (Aptissen, Geneva, Switzerland) that has been developed and marketed as a transparent hydrogel for glaucoma surgery. Healaflow has a water content of 97% and consists of a network of hyaluronic acid crosslinked by 1–4-butanediol diglycidyl ether. Barth et al.[30,31] evaluated Healaflow as a potential vitreous substitute and reported transparent microgels injectable through a 25G needle showing good biocompatibility in rabbits for several weeks with no signs of excessive conjunctival swelling, abnormal retinal morphology or inflammatory reactions. In a rabbit model of rhegmatogenous retinal detachment, they recently reported an adequate tamponading effect of Healaflow for retinal reattachment.[32] However, the authors found that Healaflow lost most of its viscosity in vivo within a few weeks, suggesting that Healaflow is more suitable as a short-term vitreous substitute. In addition to the animal testing, in-vitro studies have recently demonstrated appropriate transparency, refractive index, viscoelasticity and in-vitro biocompatibility of Healaflow[26] supporting it as a short-term vitreous substitute.

Apart from the above-mentioned preformed chemically crosslinked hyaluronic acid gels, Raia et al.[33] recently described a silk-hyaluronic acid composite hydrogel enzymatically crosslinked in-situ using horseradish peroxidase and hydrogen peroxide (H2O2) within 10–15 min. The resulting hydrogels possessed suitable optical properties as well as a gel stiffness ranging from 6 to 240 Pa depending on the H2O2 content used. The authors also reported that higher silk content resulted in significant aging of the hydrogel after 1 month and less swelling, suggesting hydrogels with lower silk ratios may be appropriate as vitreous substitutes. After injection of the silk-hyaluronic acid composite hydrogel into an ex-vivo porcine eye model, the normalized intraocular pressure was comparable to postmortem eyes treated with silicone oil. A previous publication demonstrated the tolerability of silk hydrogels in rabbit eyes while releasing incorporated anti-VEGF therapeutics over a 3-month period.[34] Nevertheless, all hyaluronic acid-based vitreous substitutes have in common that they are rather short-term substitutes due to enzymatic biodegradation in the eye.

Rapid biodegradation within 2 weeks was also recently described for an in-situ gelling vitreous substitutes based on the synthetic polymers polyvinyl alcohol and polyethylene glycol, named PYK-1105.[35] In an extensive, preclinical study, Stryjewski et al.[35] reported PYK-1105 as non (cyto)toxic, nonirritant, nonpyrogenic and nonmutagenic. The local and systemic biocompatibility of PYK-1105 without toxicity or evidence of anatomic or functional changes was demonstrated in three animal models (rabbits, minipigs, mice) and in vitro using standardized cell lines (mouse fibroblast cell line L929 and mouse lymphoma cell line L5178Y/TK+/-). The intraocular pressure and retinal function were found to be not significantly different between PYK-1105 treated and control eyes. Although the authors expect a tamponading effect of PYK-1105 in case of retinal detachment, results dealing with reattachment rates are still to be provided. In addition, it will be of further interest whether the high stiffness of the gel (1000 Pa) compared to the native vitreous (~10 Pa) might be harmful to the surrounding structures in the long term.

The major drawbacks of in-situ chemically crosslinked hydrogels are the toxicity of the monomers and/or crosslinkers remaining in the eye, and the need for precise control over the injection time. Next to purified, preformed chemically crosslinked hydrogels, physically crosslinked hydrogels might be an appropriate approach.