Bioinspired Thermosensitive Hydrogel as a Vitreous Substitute: Synthesis, Properties, and Progress of Animal Studies

Abstract

In many vitreal diseases, the surgeon removes the natural vitreous and replaces it with silicone oils, gases, or balanced salt solutions to fill the eyeball and hold the retina in position. However, these materials are often associated with complications and have properties that differ from natural vitreous. Herein, we report an extension of our previous work on the synthesis of a biomimetic hydrogel that is composed of thiolated gellan as an analogue of type II collagen and poly(methacrylamide-co-methacrylate-co-bis(methacryloyl)cystamine), a polyelectrolyte, as an analogue of hyaluronic acid. This thermosensitive hydrogel can be injected into the eye as a viscous solution at 45 °C. It then forms a physical gel in situ when it reaches body temperature, and later forms disulfide covalent crosslinks. In this article, we evaluated two different formulations of the biomimetic hydrogels for their physical, mechanical, and optical properties, and we determined their biocompatibility with several cell lines. Finally, we report on the progress of the four-month preclinical evaluation of our bio-inspired vitreous substitute in comparison to silicone oil or a balanced salt solution. We assessed the eyes with a slit-lamp examination, intraocular pressure measurements, electroretinography, and optical coherence tomography. Preliminary results are very encouraging for the continuing evaluation of our bio-inspired hydrogel in clinical trials.

Macro- and Microscale Properties of the Vitreous Humor to Inform Substitute Design and Intravitreal Biotransport

“…A big discrepancy in the number of publications on hydrogel vitreous substitutes and vitreous humor in the years 1995-2000 (9 publications and 0 publications, respectively) should be noted, considering the approval of silicone oil for use as a vitreous substitute by the Food and Drug Administration (FDA) in 1994. 58 Synthetic 33,34,59-91 and semisynthetic [92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108] hydrogels have been more common materials for experimental vitreous substitutes in recent years, while natural hydrogels 37,[109][110][111][112][113][114][115][116][117][118][119][120][121][122][123] were much more prevalent in the early years ( Figure 3B). The foldable capsular vitreous body (FCVB) is a different polymeric design for a vitreous substitute that is currently undergoing clinical trials in China.…”

“…However, stiff hydrogels can be difficult to inject through a small gauge needle into the vitreous chamber. The storage and loss moduli of synthetic hydrogels 34,[59][60][61][62]69,73,74,76,[81][82][83] (G' = 1203 ± 755 Pa, n = 18 and G" = 373 ± 330 Pa, n = 12) and semisynthetic hydrogels [92][93][94]97,98,[100][101][102]104 (G' = 1330 ± 1090 Pa, n = 9 and G" = 291 ± 223 Pa, n = 9) are approximately two orders of magnitude higher, while natural hydrogels' 37,110 (G' = 99.4 ± 53.4 Pa, n = 3 and G" = 51.5 ± 48.5 Pa, n = 2) are about one order of magnitude higher compared to the human vitreous [15][16][17] (G' = 5.09 ± 1.86 Pa, n = 3 and G" = 1.81 ± 0.98 Pa, n = 3). Hydrogels with different mechanisms of injection into the eye also have a wide variation in storage and loss moduli ( Table 5 and Figure 4B).…”

Pars Plana Vitrectomy and the Risk of Ocular Hypertension and Glaucoma: Where Are We?

“…Biomimetic gels with tunable mechanical properties have been developed with lengthy research [ 48 ] and the most promising at present are possibly those injected as a double liquid component that gel at 37° within the eye and have been considered safe for porcine retina up to 4 weeks before undergoing liquefaction. The many difficulties encountered in decades of vitreous substitute research and the promising results [ 49 ] yet incomparable to the magnificent and amazing physical, chemical, optical, biological and time-enduring qualities of the human vitreous increase, if possible, the wonder of even life-long students for this pristine and mysterious tissue.…”

Current Situation and Challenges in Vitreous Substitutes

“…However, the mechanical properties of most of these is modified during the injection process when they are pushed through a small‐gauge needle. [ 124 ] The shear degradation causes the rupture of polymeric chains, resulting in loss of elasticity and fluidification. [ 137 ]…”