Self‐assembling hydrogel loaded with 5‐FU PLGA microspheres as a novel vitreous substitute for proliferative vitreoretinopathy

Abstract

The vitreous substitute for proliferative vitreoretinopathy (PVR) surgery remains an unmet clinical need in ophthalmology. In our study, we developed an in situ formed hydrogel by crosslinking polyvinyl alcohol (PVA) and chitosan as a potential vitreous substitute. 5-fluorouracil (5-FU) Poly (lactic-co-glycolic acid) (PLGA) microspheres were developed and loaded onto the PVA/chitosan hydrogels to treat PVR. In vitro, PVA/chitosan hydrogels at four concentrations were subjected to morphological, physical, rheological analyses, and cytotoxicity was evaluated together with the characterization of 5-FU PLGA microspheres. In vivo, pharmacologically induce PVR rabbits were performed a vitrectomy. In the PVA group, 3% PVA/chitosan hydrogel was injected into the vitreous cavity. In the PVA/MS group, 3% PVA/chitosan hydrogel and 5-FU PLGA microspheres were injected. In the Control group, phosphate-buffered saline was injected. Therapeutic efficacy was evaluated with postoperative examinations and histological analyses. This study demonstrated that the 3% PVA/chitosan hydrogel showed properties similar to those of the human vitreous and could be a novel in situ crosslinked vitreous substitute for PVR. Loading 5-FU PLGA microspheres onto this hydrogel may represent an effective strategy to improve the prognosis of PVR.

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

“…Hydrogel vitreous substitutes with direct injection mechanism 59,62,73,76,[81][82][83]94,110 (G' = 49.9 ± 31.3 Pa, n = 9 and G" = 26.3 ± 21.8 Pa, n = 9) have the closest modulus to the human vitreous, followed by thermogelling/in situ crosslinking hydrogels 37,96,100,101 (G' = 136 ± 33.1 Pa, n = 4 and G" = 28.9 ± 23.8 Pa, n = 4). The moduli of hydrogels with in situ crosslinking 34,69,93,97,98,104 (G' = 1626 ± 1031 Pa, n = 13 and G" = 338 ± 332 Pa, n = 6) or thermogelling 60,61,74,102 (G' = 2946 ± 2360 Pa, n = 4 and G" = 1206 ± 937 Pa, n = 4) mechanisms are, on average, more than two orders of magnitude higher than those of the natural human vitreous. Scatter plots of different hydrogel types ( Figure 4C) and injection mechanisms ( Figure 4D) highlight the widespread differences in both storage and loss modulus for current experimental hydrogel vitreous substitutes.…”

“…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).…”

“…[130][131][132]136,137,141 More recently, a PVA/chitosan hydrogel loaded with fluorouracil-containing poly(lactic-co-glycolic acid) microspheres was proposed as a new vitreous substitute for proliferative vitreoretinopathy. 93 Besides providing treatments for vitreoretinal diseases, it may Figure 1a) compared to the number of publications on hydrogel vitreous substitutes (A). There has been an increase in the publications on hydrogel vitreous substitutes concurrent with publications on the mechanical properties of the vitreous humor.…”

A sustained dual drug delivery system for proliferative vitreoretinopathy

“…Although detailed interactions between these stimulating factors remain incompletely understood, ocular fluid samples from eyes with PVR clearly demonstrate high expression of inflammatory cytokines (Kaneko et al., 2018 ). Studies using combined therapy (anti-proliferation and anti-inflammation) in experimental PVR also suggest the potential for better outcomes (Cardillo et al., 2004 ; Yu et al., 2020 ). We have previously demonstrated that loading DNR or DEX into pSiO2 microparticles can extend their vitreous half-lives from hours to days (Hou et al., 2015 ; 2016 ).…”