Induction of posterior vitreous detachment (PVD) by non-enzymatic reagents targeting vitreous collagen liquefaction as well as vitreoretinal adhesion

Abstract

induction of posterior vitreous detachment (pVD) by pharmacologic vitreolysis has been largely attempted through the use of enzymatic reagents. ocriplasmin has been the only fDA-approved clinical reagent so far. Several adverse effects of ocriplasmin have emerged, however, and the search for alternative pVD-inducing reagents continues. Since i) collagen forms an important structural component of the vitreous, and ii) strong vitreo-retinal adhesions exist between the cortical vitreous and the internal limiting membrane (ILM) of the retina, an effective PVD-inducing reagent would require both, vitreous liquefaction, and concurrent dehiscence of vitreoretinal adhesion, without being toxic to retinal cells. We designed a combination of two reagents to achieve these two objectives; a triple helix-destabilizing collagen binding domain (cBD), and a fusion of RGD (integrin-binding) tripeptide with cBD (RcBD) to facilitate separation of posterior cortical vitreous from retinal surface. Based on in vitro, ex-vivo, and in vivo experiments, we show that a combination of cBD and RcBD displays potential for safe pharmacologic vitreolysis. Our findings assume significance in light of the fact that synthetic RGD-containing peptides have already been used for inhibition of tumor cell invasion. proteins such as variants of collagen binding domains could have extended therapeutic uses in the future. The vitreous humor is a hydrogel present in the eye; an intact vitreous gel is important for ocular health. However, with aging, the gel undergoes a gradual, spontaneous process of liquefaction, and separates from the retina, resulting in posterior vitreous detachment or PVD 1-3. Therefore, it is not surprising that there is a high incidence of vitreo-retinal disorders in later decades of life, with the peak of incidence of retinal conditions matching the peak age of incidence of posterior vitreous separation 4-6. When the gel liquefaction exceeds the extent of vitreo-retinal dehiscence, anomalous PVD occurs, which is characterized by partial or incomplete detachment of vitreous from the retina. Anomalous PVD can involve exertion of excessive tractional forces acting upon the retina, which can lead to many ophthalmic complications such as hemorrhage, retinal tears, or detachment, macular hole formation, and vitreomacular traction syndrome 3,7,8. The mainstream treatment of incomplete PVD is surgical intervention or vitrectomy, to create a clean retinal surface devoid of any vitreous remnants and thus avoid further complications such as proliferative vitreoretinopathy (PVR). However, owing to its invasive nature and associated risks, surgical vitrectomy is not an ideal choice, except in cases complicated by retinal detachments. In paediatric patients, induction of posterior vitreous detachment (PVD) is an important and challenging step in the successful management of retinal detachment or traumatic macular hole, owing to the firm vitreoretinal adhesions. Pharmacological vitrectomy has been explored as a non-surgical, safer and cleaner al...

Macro- and Microscale Properties of the Vitreous Humor to Inform Substitute Design and Intravitreal Biotransport

“…Induction of posterior vitreous detachment was recently reported, with particular focuses on both vitreous liquefaction and dehiscence of vitreoretinal adhesion. 186 A mechanical model of posterior vitreous detachment and generation of vitreoretinal tractions has also been published. 187 These are all interesting biomechanical problems that should be further investigated in future studies.…”

The extracellular matrix complexity of idiopathic epiretinal membranes and the bilaminar arrangement of the associated internal limiting membrane in the posterior retina

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