Hydrodynamics of Intravitreal Injections into Liquid Vitreous Substitutes

Abstract

Intravitreal injections have become the cornerstone of retinal care and one of the most commonly performed procedures across all medical specialties. The impact of hydrodynamic forces of intravitreal solutions when injected into vitreous or vitreous substitutes has not been well described. While computational models do exist, they tend to underestimate the starting surface area of an injected bolus of a drug. Here, we report the dispersion profile of a dye bolus (50 µL) injected into different vitreous substitutes of varying viscosities, surface tensions, and volumetric densities. A novel 3D printed in vitro model of the vitreous cavity of the eye was designed to visualize the dispersion profile of solutions when injected into the following vitreous substitutes—balanced salt solution (BSS), sodium hyaluronate (HA), and silicone oils (SO)—using a 30G needle with a Reynolds number (Re) for injection ranging from approximately 189 to 677. Larger bolus surface areas were associated with faster injection speeds, lower viscosity of vitreous substitutes, and smaller difference in interfacial surface tensions. Boluses exhibited buoyancy when injected into standard S1000. The hydrodynamic properties of liquid vitreous substitutes influence the initial injected bolus dispersion profile and should be taken into account when simulating drug dispersion following intravitreal injection at a preclinical stage of development, to better inform formulations and performance.

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

“…Finally, there has been increased interest in the biotransport of the vitreous humor and vitreous substitutes, particularly due to increased clinical use of intravitreal injection to deliver therapeutics. 10,16,18,[168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183] The motion of fluid inside the vitreous (intact or liquefied) due to eye rotation or saccadic eye movement has been investigated by many groups, 168,169,171,180,183 with particular implications shown for drug delivery and pharmacokinetics in the vitreous. 170,172,173,178,184 A model of enzymatic degradation of the vitreous was created and used to study the mobility of intravitreal nanoparticles, which could better simulate the biotransport of a therapeutic injected into aged and liquefied vitreous.…”

“…18 An in vitro ocular flow model called the PK-Eye was proposed for use in preclinical drug development, 175 which can allow for testing of therapeutics in vitreous substitutes. 174,181,182 These advances will enable significant progress in determining pharmacokinetics and therapeutic feasibility at earlier stages. However, these advancements are still mostly based on the in vitro properties of the vitreous humor, which likely limits their usefulness and accuracy in in vivo applications.…”

Preclinical challenges for developing long acting intravitreal medicines

“…324 Convection effects has been reported to have a bigger influence to mixing than saccades. 24,[325][326][327][328] A study 329 reported the differences in transport mechanism between human and neonatal mouse eyes. 329 The transport mechanism in the eyes of a mouse was predominantly diffusive.…”

“…Computer modelling studies have been extensively conducted to understand how a drug is distributed within the vitreous after drug administration. 328 Two common methods of computational modelling of drug distribution recognised by the FDA include Compartmental Modelling (CM) and Finite Element Analysis (FEA). 335,336 CM is a cruder method, where the globe is divided into large segments and rules applied to each one; whereas FEA can map very specific local variations in greater detail.…”

“…There are several features about intravitreal injections that affect drug distribution and kinetics such as needle depth/size, location, angle, and injection speed/volume. 328,344 Some guidelines do exist for intravitreal injection strategy, 345 however, these features vary between different practices. Poiseuille's law describes the liquid flow resistance in a tube in relation to the radius of the tube.…”