Fibrin hydrogels are safe, degradable scaffolds for sub-retinal implantation

Abstract

Retinal pigment epithelium (RPE) transplantation for the treatment of macular degeneration has been studied for over 30 years. Human clinical trials have demonstrated that RPE monolayers exhibit improved cellular engraftment and survival compared to single cell suspensions. The use of a scaffold facilitates implantation of a flat, wrinkle-free, precisely placed monolayer. Scaffolds currently being investigated in human clinical trials are nondegradable which results in the introduction of a chronic foreign body. To improve RPE transplant technology, a degradable scaffold would be desirable. Using human fibrin, we have generated scaffolds that support the growth of an RPE monolayer in vitro. To determine whether these scaffolds are degraded in vivo, we developed a surgical approach that delivers a fibrin hydrogel implant to the sub-retinal space of the pig eye and determined whether and how fast they degraded. Using standard ophthalmic imaging techniques, the fibrin scaffolds were completely degraded by postoperative week 8 in 5 of 6 animals. Postmortem histologic analysis confirmed the absence of the scaffold from the subretinal space at 8 weeks, and demonstrated the reattachment of the neurosensory retina and a normal RPE-photoreceptor interface. When mechanical debridement of a region of native RPE was performed during implantation surgery degradation was accelerated and scaffolds were undetectable by 4 weeks. These data represent the first in situ demonstration of a fully biodegradable scaffold for use in the implantation of RPE and other cell types for treatment of macular degeneration and other retinal degenerative diseases. OPEN ACCESS Citation: Gandhi JK, Mano F, Iezzi R, Jr., LoBue SA, Holman BH, Fautsch MP, et al. (2020) Fibrin hydrogels are safe, degradable scaffolds for subretinal implantation. PLoS ONE 15(1): e0227641.

Type I Collagen-Fibrin Mixed Hydrogels: Preparation, Properties and Biomedical Applications

“…Among recent examples of the use of fibrin hydrogels in tissue engineering, highly-concentrated (40 mg mL −1 ) fibrin hydrogels were used as sub-retinal implants. Small size hydrogels could directly injected through the sclera of pigs via a home-made device and were degraded over 8 weeks [ 104 ], allowing for the establishment of a new interface between retinal pigment epithelium and retina. In the field of cardiac repair, a bioreactor system with mechanical stimulation was developed allowing to obtain a new tissue resembling native muscle in terms of structure, gene expression and maturity.…”

Alteration of fibrin hydrogel gelation and degradation kinetics through addition of azo dyes

“…Fibrin gels were cast as described in the Section 2.3 above. A custom punch was used to generate 5.0 × 1.5 mm 2 gels as previously published 12 , 20 . The measured thickness of all the gels was 309 ± 69 μm.…”

“…In our efforts to improve the visibility of our fibrin gels during surgical implantation, 20 we discovered that the inclusion of Trypan blue (TB) solution in the gelation mix extended the gelation time and resulted in more uniform gels. As such, we set forth to characterize the effects of TB on fibrin gelation.…”

Trends of Stem Cell Therapies in Age-Related Macular Degeneration

“…Table 1 presents the details of ongoing clinical trials in other institutions. Due to recent breakthroughs in scaffold formation, fully biodegradable scaffolds made of fibrin hydrogel [ 32 , 33 ] or poly lactic-co-glycolic acid have attracted attention as advanced alternatives for RPE cell sheet transplantation.…”