Dispositivos biotecnológicos implantáveis como terapias para doenças degenerativas retinianas

• Ano de defesa: 2018
• Autor(a) principal: Falabella, Paulo [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• dARK ID: ark:/48912/001300001wr2f
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Retinal pigment epithelium; Implantable biomedical devices; Human embryonic stem cells; Próteses e implantes; Transplante de células; Célulastronco; Degeneração macular; Epitélio pigmentado da retina; Cirurgia vitreorretiniana
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=6746825; https://repositorio.unifesp.br/handle/11600/52902

Objectives: To evaluate the safety profile and functionality of two implantable biomedical devices, bioelectronic retinal prostheses and nonbiodegradable implants seeded with retinal pigment epithelium cells derived from human embryonic stem cells (hESCRPE), as therapies for degenerative retinal diseases. Methods: 1. Longterm followup clinical study performed with patients implanted with Argus I (n=1) and Argus® II (n=30) prostheses, assessing the impact of chronic electrical stimulation on the retinal structure, visual function, functional vision, and functional magnetic resonance imaging (fMRI), in 2 patients; 2. Preclinical study performed with nonbiodegradable implants inserted into the subretinal space of a retinal degeneration rat model, Royal College of Surgeons. Group 1 (n = 46) received implants without cells, group 2 (n = 59) received implants with hESCRPE, and the control group (n = 13) received no implants. Animals were evaluated by optokinetic reflex, superior colliculus (SC) electrophysiology and histological analysis 21 weeks after surgery; 3. Preclinical study performed with implants inserted into the subretinal space of healthy Yucatan minipigs, immunosuppressed systemically and/or intravitreally. Group 1 (n=11) received implants with hESCRPE cells while the control group (n=3) received sham surgery. Animals were evaluated 1 month after implantation via histological and immunohistochemistry analyses and imaging assessment. Results: 1. Argus I and Argus® II demonstrated functionality and a favorable safety profile after chronic electrical stimulation of 10 (n=1) and 3 years (n=30), respectively. Acquisition of structural and functional data was achieved via fMRI scans with an inactive Argus® II implant, showing artifacts around the patient’s implanted eye. The correlation between the functional responses in the primary visual cortex and the primary somatosensory cortex was reduced after prolonged use with the Argus II; 2. Group 2 demonstrated survival of hESCRPE in 87% of cases, and a higher number of responsive SC sites. A significant number of host outer retinal cells was rescued in groups 1 and 2, associated with an improvement in the optokinetic reflex test; 3. The implants appeared to be stable in the subretinal space in 91% of cases as shown by optical coherence tomography, without evidence of rupture or migration of the substrate. Histological analysis demonstrated intraretinal localization of the implant in 1020% of cases, whereas immunohistochemistry indicated survival of hESCRPE cells on the implant without cell migration or tumor formation. Conclusions: 1. The anatomical and functional results after chronic electrical stimulation with Argus I and Argus® II support the safety and feasibility of retinal prostheses as a longterm treatment for some types of blindness. Successful acquisition and quantification of structural and functional images with fMRI are feasible in the presence of an inactive Argus® II, despite of localized artifacts. Preliminary data suggests that functional changes in the brain may follow sight restoration treatments; 2. Preclinical results suggest that implants seeded with hESCRPE may be considered suitable as a treatment strategy to address the degeneration of outer retinal cells; 3. The safety profile of the surgical technique used to introduce the implant in a large animal model provides an encouraging starting point for human studies.