Mechanism of Action

Urea in concentrations of 10 molar or greater acts as powerful protein denaturant.  Vitreous collagen fiber networks anchor the vitreous and retina by binding onto proteins, laminin and fibronectin, found in the internal limiting membrane (ILM) of the retina. Resolv ER™ acts at the back of the eye to denature collagen fibrils by disrupting the water network which acts to stabilize the collagen strands by hydrogen bonding. By delivering concentrated Urea at the vitreoretinal border region,Resolv ER acts to disrupt the hydrogen bonds within the triple helix structure of the collagen strands and cause the strands to unravel.  The denatured collagen fibers are no longer able to bind to the fibronectin and laminin on the ILM. As a result, a posterior vitreous detachment (PVD) is induced once the collagen networks of fibrils separate from the ILM of the retina.

References

1. The junction between the vitreous and the retina is formed by a chemical mechanism and anchoring. At the vitreoretinal border region, vitreous fibrils (contains collagen) insert and anchor into the ILM. Just as in other basement membranes, the ILM has three structures: the fusing points of the anchoring vitreous fibrils, the lamina densa and the lamina lucida. Among the mass of type IV collagen, there are type I collagen, LN, FN and proteoglycans. The FN (Fibronectin) and LN (laminin) can connect collagen between the posterior vitreous cortex and the ILM. Furthermore, FN has high affinity with hyaluronic acid and type II collagen.

Li X, Shi X, Fan J. Posterior vitreous detachment with plasmin in the isolated human eye. Graefes Arch Clin Exp Ophthalmol. 2002;240(1): 56–62.

2. The posterior hyaloid membrane is a true basement membrane enveloping the posterior hyaloid surface. Because this membranous structure is observed only after posterior vitreous detachment, the results of this study indicate that it forms part of the internal limiting membrane when the vitreous is in its attached state….collagen fibrils of the posterior vitreous cortex are firmly adherent to the internal limiting membrane of the retina by proteoglycans, including laminin and fibronectin….The generally accepted consensus regarding the definition and diagnosis of posterior vitreous detachment is that there is a separation of the condensed outer layers of type II collagen fibrils of the vitreous, known as the posterior vitreous cortex, from the internal limiting membrane of the retina.

Fincham GS, James S, Spickett C, et al. Posterior Vitreous Detachment and the Posterior Hyaloid Membrane. Ophthalmology. 2017.

3. Direct urea interactions consisted of hydrogen bonding to the polar moieties of the protein, particularly peptide groups, leading to screening of intramolecular hydrogen bonds. Solvation of the hydrophobic core proceeded via the influx of water molecules, then urea. Urea also promoted protein unfolding in an indirect manner by altering water structure and dynamics, as also occurs on the introduction of nonpolar groups to water, thereby diminishing the hydrophobic effect and facilitating the exposure of the hydrophobic core residues. Overall, urea-induced effects on water indirectly contributed to unfolding by encouraging hydrophobic solvation, whereas direct interactions provided the pathway.

Bennion BJ, Daggett V. The molecular basis for the chemical denaturation of proteins by ureaProceedings of the National Academy of Sciences of the United States of America. 2003;100(9):5142-5147. doi:10.1073/pnas.0930122100.

Case Studies

Prospective assessment of proliferative diabetic retinopathy with observations of posterior vitreous detachment

The purpose was to study the relation between posterior vitreous detachment (PVD) and progression of diabetic retinopathy (DR), based on our observation that proliferative DR is rare in patients with complete PVD. The medical records of 403 patients with diabetes were reviewed for the relation between progressive DR and the status of PVD and HbA(1c) over 3 years. There was no progression of DR over 3 years of eyes with complete PVD with collapse. Complete PVD is a strong negative risk factor for DR. The PVD status in patients with diabetes should be evaluated.

https://www.ncbi.nlm.nih.gov/pubmed/16779571

The Oman Journal of Ophthalmology

Macular Edema is rare in patients with Complete Posterior Vitreous Detachment(CPVD) as shown by Figure 1. There were no cases in Macular Edema with complete PVD.

Study from Oman Journal of Ophthalmology