Abstract
BACKGROUND: Retinal therapeutics has been revolutionized by anti-vascular endothelial growth factor (VEGF) therapies, whereby intravitreal injection is the accepted delivery method. To date, the possibility of direct surgical delivery to the subretinal space or an endovascular approach has yet to be explored. Herein, we investigate the feasibility of a microinvasive approach for anti-VEGF therapies using microneedles as small as 49G in internal diameter. METHODS: In vitro microinjections of commercially available anti-VEGF products, including broliucizumab, faricimab, aflibercept, and ranibizumab, were used to measure the consistency of 1µL droplet formation and needle occlusion thresholds. A validated fresh ex vivo porcine model used to examine microinjections of anti-VEGF solutions with fluorescent microbeads in the subretinal space and intravascular delivery. Spectral domain optical coherence (SD-OCT) imaging and histological retinal wholemounts were used to analyse the drug distribution. RESULTS: In vitro, we find that of the commercially available formulations of aflibercept, brolucizumab, faricimab and ranibizumab, a 5% aflibercept solution and 2.5% ranibizumab solution can be reliably injected as 1µL droplets repeatedly through a microneedle. Using a fresh porcine ex vivo closed vitrecomy model, we demonstrate that ranibizumab admixed with fluorescent microbeads, can be reliably injected in ca. 25µL volumes into the subretinal space and endovascularly, without any risk of needle occlusion. We demonstrate using SD-OCT, retinal whole mounts and immunofluorescent microscopy, that direct retinal anti-VEGF delivery is feasible. CONCLUSIONS: We conclude that further study is warranted to determine whether such an approach has any advantages over the conventional approach of intravitreal injections in terms of treatment safety, efficacy and durability. KEY MESSAGES: What is known Injections of anti-vascular endothelial growth factor (VEGF) therapies in the intravitreal 23 space are widely used to treat retinal diseases, requiring repeated and frequent 24 injections due to the limited durability of these therapies. New approaches to address this include implantable reservoir systems to reduce the 26 need for repeated injections. What is new The feasibility of a microinvasive approach to deliver anti-VEGF therapies is explored 30 using microneedles as small as 49G. Low concentrations of the commercially available anti-VEGF products ranibizumab and 32 aflibercept can be injected into the subretinal space and intravascularly in an ex vivo 33 porcine model. These results warrant further study to understand if such approaches affect efficacy and 35 durability of anti-VEGF therapies.