Novel Vitreous Substitutes: The Next Frontier in Vitreoretinal Surgery

André Schulz; Kai Januschowski; Peter Szurman


Curr Opin Ophthalmol. 2021;32(3):288-293. 

In This Article

Requirements for Vitreous Substitutes

The design of suitable replacement materials should best be guided by the properties of the tissue to be replaced. The native vitreous body is a compound hydrogel composed of 98–99% water and a framework of collagen fibres and hyaluronic acid. The high water content translates into optical transparency, refractive indices and densities close to water, as well as biocompatibility. Due to the polymeric network, soft and viscoelastic vitreous bodies are formed protecting the eye against physical impacts spanning from internal low frequency mechanical stress and vibrations to external mechanical trauma. Recently, rheological studies reported on the age-related changes in viscoelasticity of the human vitreous and highlighted the importance of viscoelasticity.[14,15] An ideal vitreous substitute should be based on the viscoelastic properties of the natural, juvenile and healthy human vitreous (~10 Pa). In contrast, a majority of the previously proposed vitreous substitutes have stiffnesses that are orders of magnitude higher than those of the reported human vitreous body, reviewed by Tram et al.,[13] and may thus cause mechanical damage to the surrounding tissue.

In addition, the native vitreous network is also characterized by porosity that is relevant both as a barrier and for mass transport in the eye. Here, the understanding of transport mechanisms in vitreous substitutes is gaining importance and has recently been extended on liquid and hydrogel-based substitutes.[16,17] Apart from biotransport, the vitreous also has biochemical functions such as the establishment of an oxygen gradient between the retina (high oxygen concentration) and lens (low oxygen concentration) adjusted mainly via antioxidants such as glutathione. The removal of the native vitreous disrupts oxygen homeostasis in the eye and causes oxidative damage to the lens, likely leading to cataract formation. Recent approaches are therefore addressing the loading of hydrogel-based vitreous substitutes with antioxidants.[18,19] Here, it should be briefly noted that the delivery of therapeutics from vitreous substitutes have also recently been researched to address vascular diseases such age-related macular degeneration and diabetic retinopathy using antivascular endothelial growth factor (anti-VEGF) proteins[20] or proliferative vitreoretinopathy (PVR) using 5-fluorouracil (5-FU).[21]

Regarding the duration for which the vitreous substitute should remain in the eye, scientific assessments differ. Material systems are designed as short or long-term tamponades depending on their resorbability or biodegradation. For retinal reattachment, a few days to weeks of substitute residence are sufficient, depending on the severity of the retinal detachment. After resorption, biodegradation or surgical removal, the endotamponade will be replaced by (body's own) fluid lacking viscoelasticity and porosity, among others. So far, almost all approaches focus exclusively on the tamponade properties of vitreous substitutes. However, biomechanical and biochemical functions of the native vitreous must be also ensured by suitable substitutes over an extended period of time. Potential hydrogel-based solutions that address this challenge will be discussed later in the text.

Furthermore, the vitreous substitute should be easily injectable through a small gauge needle (23G or less) for application during vitreoretinal surgery to support the trend towards minimally invasive treatment methods without losing its physical properties.

Current clinically used tamponades (oils, gases, semifluorinated alkanes) cannot meet the requirements of suitable vitreous substitutes due to their hydrophobicity, deviating refractive indices and densities, limited residence times as well as lack of viscoelasticity and porosity. By contrast, hydrogel-based vitreous substitutes offer the required properties due to their similarity to the natural vitreous body. Here, the design of vitreous substitutes is supported by recent scientific findings, for example the structure of vitreous main polymers by enzymatic degradation studies,[22] the behaviour of hydrogels in the presence of simulated vitreous haemorrhage[23] or the comparison of fluidic viscosity and surface tension on the tamponading effect.[24]