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.2020 Jan 13;15(1):e0227641.
doi: 10.1371/journal.pone.0227641. eCollection 2020.

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

Affiliations

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

Jarel K Gandhi et al. PLoS One..

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 non-degradable 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.

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Conflict of interest statement

JSP and ADM have ownership interests in LAgen Laboratories LLC. ADM serves as CEO of LAgen Laboratories LLC. TWO has ownership of iMacular Regeneration LLC, none of the technology used in this study is relevant. However, none of the disclosures pertain directly to this paper and none of the companies provided financial support for this paper.

Figures

Fig 1
Fig 1. Fibrin hydrogel implant characterization.
(A) Brightfield image of a 1.5mm x 5.0mm fibrin implant colored with trypan blue (B) Scanning electron micrograph of the top surface of the fibrin implant showing characteristic crosslinking fibrils. (C) Optical coherence tomography (OCT) of the fibrin implant in cross-section, demonstrates uniform fibril formation and thickness.
Fig 2
Fig 2. Sub-retinal implantation device prototype.
(A) Photo of the device. The disposable tip assembly (B) is screwed into the metal (silver) handle. The actuator resides within the handle and is not visible. The blue luer lok tubing connector is attached to the actuator connector. (B) Image of the disposable tip assembly without the handle. (C) Close up image of the clear plastic housing. The wire plunger is visible within the clear plastic housing. (D) Surgical video screenshot showing the device entering through the sclera. The blue implant is visible within the device.
Fig 3
Fig 3. Montage of surgical procedure.
(A) Placement of the valved entry ports. (B) Vitrectomy. Triamcinolone is used as a contrast agent to perform the posterior vitreous detachment. (C) A subretinal bleb is created using a 40ga cannula. (D) A 1.8mm retinotomy is created using 25ga vertical scissors. The retina was pre-cauterized using a diathermy probe to prevent bleeding. (E) A 3.6mm wide sclerotomy is created using a slit knife. (F) The implantation device is used to place the fibrin implant into the subretinal space. The blue implant is visible under the retina.
Fig 4
Fig 4. Live post-operative imaging.
Time course of fundus and OCT en face and b-scan images for animal #11 from 1 week to 10 weeks post-operative showing serial degradation. On the OCT en face images, the circle is centered to the retinotomy site for comparable areas between images. The red line indicates the region of the b-scan. The color intensity scale represents the rough thickness of the retina on the en face image and is the same for all images. The scale bar applies to all OCT b-scan images.
Fig 5
Fig 5. Fibrin implantation histology.
(A) Photomicrograph of H&E stained histological sections from animals #12 (2 weeks) and #7 (8 weeks). The blue arrow indicates the retinotomy. The fibrin implant appears eosinophilic (blue star), with the bulk of the gel remaining at 2 weeks. By 8 weeks, there is no evidence of the fibrin gel. The neural retina within the implanted region appears healthy at both time points. The retinotomy appears to thicken over time. (B) Close up images of regions where the implant was placed showing the healthy retina. The blue star indicates the fibrin gel. In the 8 week timepoint, the inner retina appears thicker because of the use of silicone oil as a tamponade. (C) Kaplan-meier graph showing the percent of animals within the cohort with evidence of remaining fibrin. In most cases, the fibrin implant is completely degraded by 8 weeks. INL: Inner nuclear layer. Ph: Photoreceptor layer. RPE: Retinal pigment epithelium. Ch: Choroid.
Fig 6
Fig 6. Faster degradation due to RPE debridement.
(A) Fundus and fluorescein angiogram (FA) images (early and late timepoints) showing the site of implantation. A window defect is seen in both early and late FA images, indicating the region of RPE debridement. (B) OCT en face and b-scan images for animal #15 from 1 week to 4 weeks post-operative. (C) Image of H&E stained histological sections from animal #13. The blue arrow indicates the retinotomy site and the green arrow indicates the RPE debrided region. (D) Close up image of region where the implant was placed showing the healthy retina. (E) Graph showing the thickness of the retinal detachment in OCT images over time for animals with and without debridement. The thickness is suggestive of the remaining fibrin implant. There is a statistically significant difference between the debrided and not debrided groups (p<0.001). INL: Inner nuclear layer. Ph: Photoreceptor layer. RPE: Retinal pigment epithelium. Ch: Choroid.
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