Biocompatibility of a Conjugated Polymer Retinal Prosthesis in the Domestic Pig

Abstract

The progressive degeneration of retinal photoreceptors is one of the most significant causes of blindness in humans. Conjugated polymers represent an attractive solution to the field of retinal prostheses, and a multi-layer fully organic prosthesis implanted subretinally in dystrophic Royal College of Surgeons (RCS) rats was able to rescue visual functions. As a step toward human translation, we report here the fabrication and in vivo testing of a similar device engineered to adapt to the human-like size of the eye of the domestic pig, an excellent animal paradigm to test therapeutic strategies for photoreceptors degeneration. The active conjugated polymers were layered onto two distinct passive substrates, namely electro-spun silk fibroin (ESF) and polyethylene terephthalate (PET). Naive pigs were implanted subretinally with the active device in one eye, while the contralateral eye was sham implanted with substrate only. Retinal morphology and functionality were assessed before and after surgery by means of in vivo optical coherence tomography and full-field electroretinogram (ff-ERG) analysis. After the sacrifice, the retina morphology and inflammatory markers were analyzed by immunohistochemistry of the excised retinas. Surprisingly, ESF-based prostheses caused a proliferative vitreoretinopathy with disappearance of the ff-ERG b-wave in the implanted eyes. In contrast, PET-based active devices did not evoke significant inflammatory responses. As expected, the subretinal implantation of both PET only and the PET-based prosthesis locally decreased the thickness of the outer nuclear layer due to local photoreceptor loss. However, while the implantation of the PET only substrate decreased the ff-ERG b-wave amplitude with respect to the pre-implant ERG, the eyes implanted with the active device fully preserved the ERG responses, indicating an active compensation of the surgery-induced photoreceptor loss. Our findings highlight the possibility of developing a new generation of conjugated polymer/PET-based prosthetic devices that are highly biocompatible and potentially suitable for subretinal implantation in patients suffering from degenerative blindness.

In Vitro Cytotoxicity of D18 and Y6 as Potential Organic Photovoltaic Materials for Retinal Prostheses

“…This experiment suggested even further the safety of the materials and that D18/Y6 has no impact on the function of the retina, at least within the conditions of the experiment. These initial successful tests will be followed by in vivo biocompatibility tests, as recently reported for conjugated polymer-based retinal prostheses [ 47 ]. In addition, further studies will be necessary to carefully assess, for prolonged exposure in biological conditions, the functionality and reliability of the photocapacitive couples upon illumination and its use as a stimulating device with the interfaced retina.…”

The p-ERG spatial acuity in the biomedical pig under physiological conditions

“…Up to date, different pig models have been actually proposed as suitable animal models for different eye disorders such as retinitis pigmentosa, macular degeneration, glaucoma, and cataract 10 – 15 . Pigs are also considered good candidates to assess biocompatibility and functionality of retinal prostheses, as well as surgical insertion procedures of the exogenous devices 16 . As for any other species and field of interest, extensive characterization and deep knowledge of animal models are pivotal when designing a study protocol.…”

“…Several types of electroretinogram (ERG) paradigms have been implemented and widely described in literature 20 , such as full field ERG (ff-ERG), multifocal ERG (mf-ERG), and pattern ERG (p-ERG). The ff-ERG provides information regarding the overall retinal function by recording a mass potential from the whole retina 21 , and has been used in biomedical pigs 5 , 16 . The mf-ERG can measure electrical activity from more than a hundred retinal areas per eye, allowing for more topographically precise investigations 22 .…”

“…If accompanied by imaging and behavioral methods, the above-mentioned strategies allow for precise quantitative structure–function correlations of specific retinal regions. This experimental approach may provide important information to characterize retinal conditions and/or monitor the effects of retinal prosthesis on visual functions 16 , 27 – 30 .…”

Effect of NK-5962 on Gene Expression Profiling of Retina in a Rat Model of Retinitis Pigmentosa

“…Patients with RP experience slowly progressive loss in the peripheral visual field, finally leading to blindness in later decades [1]. Nowadays, many treatments including neurotrophic factors [2,3], antioxidants [4][5][6], retinal prostheses [7][8][9][10][11][12], and gene therapies [13] are used to rescue retinal degeneration and improve the visual function.…”