Structural changes in the retina after implantation of subretinal three-dimensional implants in mini pigs

Abstract

The retinal structural changes after subretinal implantation of three-dimensional (3D) microelectrodes were investigated in a mini pig. Three types of electrode were implanted into the subretinal spaces of nine mini pigs: 75-μm-high 3D electrodes on a 200-μm-thick right-angled polydimethylsiloxane (PDMS) substrate (group 1); a 140-μm-thick sloped PDMS substrate without electrodes (group 2); and a 140-μm-thick sloped PDMS substrate with 20-μm-high 3D electrodes (group 3). One mini pig was used as a control. Spectral domain–optical coherence tomography (SD–OCT) images were obtained at baseline and 2, 6, and 12 weeks post-surgery. Retinal specimens were immunostained using a tissue-clearing method 3 months post-implantation. The 75-μm-high 3D electrodes progressively penetrated the inner nuclear layer (INL) and touched the inner plexiform layer (IPL) 2 weeks post-surgery. At 6 weeks post-operatively, the electrodes were in contact with the nerve-fiber layer, accompanied by a severe fibrous reaction. In the other groups, the implants remained in place without subretinal migration. Immunostaining showed that retinal ganglion and bipolar cells were preserved without fibrosis over the retinal implants in groups 2 and 3 during the 12-week implantation period. In summary, SD–OCT and immunohistology results showed differences in the extent of reactions, such as fibrosis over the implants and penetration of the electrodes into the inner retinal layer depending on different types of electrodes. A sloped substrate performed better than a right-angled substrate in terms of retinal preservation over the implanted electrodes. The 20-μm-high electrodes showed better structural compatibility than the 75-μm-high 3D electrodes. There was no significant difference between the results of sloped implants without electrodes and 20-μm-high 3D electrodes, indicating that the latter had no adverse effects on retinal tissue.

Recent Progress in Photoreceptor Cell-Based Therapy for Degenerative Retinal Disease

“… 93 Stiff, nondegradable materials can be associated with fibrosis. 94 Thus, the development of scaffolds to support cell delivery requires in vitro as well as in vivo testing.…”

Double‐Sided, Thin‐Film Microelectrode Array with Hemispheric Electrodes for Subretinal Stimulation

“…For example, height by initial photoresist thickness, lateral dimension by lithographic pattern, and roundness by temperature and time. [29] We chose the round profile which was expected to minimize mechanical stress on the retina [23] and corrosion of the electrode. [24][25][26] The height of the hemispheric electrode, 23 μm, was chosen for closer proximity with target cells, the bipolar cells in the inner nuclear layer (INL).…”

“…[39] In a previous study, it was reported that ≈200 μm-thick implant with sloped corners and smooth protrusions didn't induce thinning of the inner retinal layer. [23] The DMEA bonded to the stimulator IC chip in Figure 1e had a total thickness of 199 μm (160 μm for chip, 10 μm for underfiller, 6 μm for DMEA, and 23 μm for hemispheric protrusion). Although we implanted the hemispheric DMEA alone, it did not result in the thinning of the inner nuclear layer, which validates the biocompatibility of the novel, photoresist-infilled, smooth hemispheric electrode.…”

“…Previous studies have suggested that 3D protruded electrodes for subretinal stimulation, formed by silicon micromachining, [16][17][18] electroplating, [19,20] or laser milling, [21] may improve the stimulation efficiency by minimizing the electrode-target distance imposed by residuals in the degenerated photoreceptors layer. [22] However, pointed corners and sharp edges of the 3D electrodes are known to result in mechanical stresses on the tissue, inducing retinal atrophy, [23] and concentrated current distributions on the edge, inducing electrode corrosion during stimulation. [24][25][26] In this work, we develop a high-density, double-sided microelectrode array with 294 hemispheric or disk-shaped electrodes for subretinal stimulation.…”

Retinal Prostheses: Engineering and Clinical Perspectives for Vision Restoration

“…Since subretinal prostheses are located in the INL, they are the ones that benefit the most from such integration of cells into the 3D geometry of MEAs. It was shown that both the protruding and recessed 3D geometries of subretinal implants benefit from this retinal migration, which reduces the separation distance between the INL and the implanted electrodes [14][15][16][17][18]. However, while this advantage applies to subretinal prostheses, both epiretinal and suprachoroidal implants were reported to have a gradually increasing ER distance over time.…”