Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2014, Article ID 351804, 12 pages
http://dx.doi.org/10.1155/2014/351804
Review Article

Vitreous Substitutes: The Present and the Future

1Department of Surgical and Morphological Sciences, Section of Ophthalmology, School of Medicine, University of Insubria, Via Guicciardini 9, 21100 Varese, Italy
2Endocrine Unit, Department of Clinical and Experimental Medicine, School of Medicine, University of Insubria, 21100 Varese, Italy
3Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Second University of Naples, 80121 Naples, Italy
4Department of Ophthalmology, Polytechnic University of Ancona, 60121 Ancona, Italy
5Genetic Laboratory, Department of Surgical and Morphological Sciences, School of Medicine, University of Insubria, 21100 Varese, Italy

Received 19 February 2014; Revised 15 April 2014; Accepted 16 April 2014; Published 4 May 2014

Academic Editor: Mario R. Romano

Copyright © 2014 Simone Donati et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Vitreoretinal surgery has advanced in numerous directions during recent years. The removal of the vitreous body is one of the main characteristics of this surgical procedure. Several molecules have been tested in the past to fill the vitreous cavity and to mimic its functions. We here review the currently available vitreous substitutes, focusing on their molecular properties and functions, together with their adverse effects. Afterwards we describe the characteristics of the ideal vitreous substitute. The challenges facing every ophthalmology researcher are to reach a long-term intraocular permanence of vitreous substitute with total inertness of the molecule injected and the control of inflammatory reactions. We report new polymers with gelification characteristics and smart hydrogels representing the future of vitreoretinal surgery. Finally, we describe the current studies on vitreous regeneration and cell cultures to create new intraocular gels with optimal biocompatibility and rheological properties.

1. Introduction

In recent times vitreoretinal surgery has made important progress regarding instruments, drugs, and materials [1, 2]. Numerous pathologies, such as retinal detachment, diabetic retinopathy, and proliferative vitreoretinopathy, require partial or total vitreous removal [3]. Presently, temporary and permanent intraocular vitreal substitutes mainly have a structural function to ensure retinal adherence following cryo or laser retinopexy for the necessary time, to control intraocular hemorrhages, and to maintain intraocular pressure. Future polymers will interact with intraocular anatomy and physiology, as well as intraocular drug distribution [4]. One of the main challenges is the control of inflammatory and immune-system reactions that modify the stability of the vitreous substitute and the integrity and functionality of intraocular structures [5].

In this review, we examine the characteristics of the vitreous, the advantages and disadvantages of presently available tamponades, the characteristics of several vitreal substitutes studied some years ago but actually not used for several reasons, and new substances for vitreous substitution that are under research.

2. Characteristics of the Vitreous

The vitreous body appears as a gelatinous structure (98-99% water) filling the space between the lens and the retina, the so-called vitreous chamber. The molecular structure of the vitreous is composed mainly of hyaluronic acid and different types of collagen that create the gelatinous structure. Water is present on a bounded form to the glycosaminoglycans for about 15–20%; this ensures the stability of the vitreal structure. Table 1 shows various molecules contained in the normal vitreous body.

tab1
Table 1: Biochemical composition of the vitreous.

Vitreous physical characteristics need to be well known in order to recognize its active role in ocular physiology, as shown in Table 2 [6]. The vitreous appears as a complex structure with its own viscoelastic properties due to a high hyaluronic acid concentration that maintains and absorbs the stress and strain of the bulb during its continuous movement during the day. The collagen-glycosaminoglycan and water frame ensure the transparency of the media, also acting as support for the vision and accommodation mechanism.

tab2
Table 2: Physical characteristics of the vitreous.

Its anatomical structure has been long studied, with recognition of its modifications due to physiological aging or pathological processes [7, 8]. The gelatinous structure is denser adjacent to the posterior hyaloid membrane (vitreous cortex) and more at the ora serrata.

The presence of active molecules allows control over inflammation, proliferation, and neovascularization, acting as a barrier to infection (bacterial not viral) [5, 9]. Finally, the vitreous body revealed its role as a repository: oxygen and nutrient as well as drugs transportation inside the eye follow definite diffusion and releasing processes [10]. These facts justify the role of the vitreous body not only as a filling substance but also as an element that has an active function on the physiology eye [11].

2.1. Ideal Vitreous Substitute

Since 1960, clinical and bioengineering researches have tried to find a substance that might replicate either the molecular structure of the vitreous or the physical characteristics of this gelatinous substance [12, 13]. In vitro or in vivo testing allowed evaluating not only the physical and biological parameters required to satisfy the needs of the surgeon but also the anatomy and physiology of the eye (Table 3).

tab3
Table 3: Characteristics of the ideal vitreous substitute.

We considered the fact that the vitreal substitutes could show some properties that correlated to a simple filling function (passive properties) and some properties that show interaction with intraocular structures or ocular physiology (active properties) [14, 15]. We considered as passive properties the filling action to maintain IOP, the viscoelastic characteristics to reduce shear stress on the retina, and the general inertness and biocompatibility without inflammatory ortoxic reactions [16, 17]; we considered as active properties the possibility of the new substance to interact with the biology and metabolism of the eye to permit the transportation of substances, ions, and oxygen and to maintain integrity and transparency over time [18].

An ideal testing protocol to evaluate the optimal vitreous substitute and the above properties could be summarized as follows: light transmittance, kinetics of hydration and water swelling, oscillatory and shear-stress analysis, shear-creep analysis, evaluation of solute diffusion, in vitro and in vivo biocompatibility, and degradation during injection.

These points represent the above-mentioned characteristics of the ideal long-term vitreous substitute. Numerous experimental phases must be applied to test these properties, and we are hopeful that a standardized effective model will be available in the future [15, 16].

3. Currently Available Vitreous Substitutes

Some of the listed substances have been known from more than 20 years, while others were developed only recently to ameliorate tolerability, tamponade effect, and stability. Here below we analyzed the advantages and disadvantages of available substances to show their current use and the short- and long-term ocular effects. Vitreal substitutes could be classified in different ways. A functional classification referred to as the surgical application is described in the literature: (i) vitreal substitutes as temporary fillers of vitreous cavity during the surgical procedure to maintain the ocular tone; (ii) vitreal substitutes used as surgical tools themselves during different phases of vitreoretinal surgery, requiring a short intraocular permanence; (iii) vitreal substitutes left inside the eye after vitreoretinal surgery with different permanence time [16, 17]. A different classification according to their molecular status, air- or gas-based and liquid, has been applied below in this paper.

3.1. Air

The gas used is filtered room air, composed of different gases (mainly N2, O2, CO2, and others at lower concentrations). Colorless and inert, it diffuses easily in the blood circulation, reducing its tamponade effects in a few days [19]. It presents a variable refractive index (approximately 1,0003). The low refractive index causes a complete reflection of the light, reducing the possibility of fundus exploration.

Air was the first gas injected into the eye. It is used in vitreoretinal surgery for retinal detachment therapy: its tamponade effect depends on the dimension and the position of the intraocular bubble, consequent to the position of the patient’s head [20]. It is naturally replaced by an aqueous humor produced by the metabolism of ciliary bodies [21].

3.2. Gases

Sulfur hexafluoride (SF6), perfluoroethane (C2F6), and perfluorocarbon (C3F8) are colorless, odorless, inert, nontoxic, and expansive gas. They present a high surface tension and a specific gravity lower than water to maintain the tamponade effect [22]. When gas is injected in the vitreous cavity, it is possible to distinguish three different phases: expansion, equilibrium, and dissolution. The first phase is the result of the absorption into the bubble of nitrogen oxygen and carbon dioxide from the surrounding tissue fluid; the equilibrium phase is characterized by a balancing of the partial pressures of the media. During dissolution gases are ultimately absorbed into the bloodstream.

Sulfur hexafluoride (SF6) and perfluorocarbon (C3F8) are the more commonly used gases. SF6 expands to about the double of the volume injected within 24 to 48 hours and exerts an effect for 1 to 2 weeks; C3F8 expands to about four times its original volume within 72 to 96 hours and persists for 6 to 8 weeks. For these reasons, these gases are commercially available at a definite nonexpansive concentration (SF6 20% and C3F8 12–14%) in order to avoid errors during presurgical dilution.

Nowadays they represent the standard gases used in pneumatic retinopexy and vitreoretinal surgery, as for their longer permanence compared to the air characteristics [21, 23]. As for the air, the intraocular gas bubble has buoyancy that keeps the retina against the pigment epithelium, and this effect is greatest at the upper of the bubble. The tamponade effect is conditioned by the dimension and position of the bubble and therefore by the position of the patient’s head [24, 25]. The lower refractive index, compared to corneal tissue or aqueous humor, causes almost complete reflection of light, creating fundus evaluation problematic until gas reabsorption.

Patients with intraocular gases should be advised against air travel or traveling to high altitude, since the reduction of atmospheric pressure will lead to expansion of intraocular gas bubble and cause considerable increase of intraocular pressure. At the same time they should avoid diving: the hyperbaric pressure occurring during scuba diving causes hypotony and partial globe collapse.

A great care must be applied if we expect to use these gases: if the surgery is performed in general anesthesia, dinitrogen monoxide (N2O) is strictly forbidden as anesthetic and analgesic due to its strong diffusion tendency. In this case the rapid vascular/eye exchange of these gases causes a rapid expansion of the intraocular bubble with severe intraocular pressure increase [26].

3.3. Liquids
3.3.1. Saline Solution

The physical characteristics are very similar to those of the aqueous humor regarding transparency, refractive index, and density [4]. The Balanced Salt Solution (BSS, Alcon Laboratories, Randburg, USA) contains sodium chloride, potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium acetate trihydrate, sodium citrate dihydrate, sodium hydroxide and/or hydrochloric acid (to adjust pH), and water for injection. The pH is approximately 7.5; the osmolality is approximately 300 mOsm/Kg. BSS PLUS (Alcon Laboratories, Randburg, USA) contains in addition dibasic sodium phosphate, sodium bicarbonate dextrose, and glutathione disulfide (oxidized glutathione). The reconstituted product has a pH of approximately 7.4; the osmolality is approximately 305 mOsm.

Saline solutions are used as temporary vitreous substitutes during exchange with air or liquids. They could change during intraocular permanence: proteins, cytokines, metabolites, and cells could transform this transparent fluid [27, 28] together with the aqueous fluid reaching the vitreous cavity. The solution represents a simple filling liquid, with no tamponade properties on the retina due to its low surface tension [5].

The use of different chemical compositions, like the BSS PLUS, represented a more expensive alternative. An in vivo study in rabbits has shown that BSS PLUS is more suitable than normal saline or Balanced Salt Solution for intravitreal irrigation because BSS PLUS contains the appropriate bicarbonate, pH, and ionic composition necessary for the maintenance of normal retinal electrical activity.

3.3.2. Perfluorocarbon Liquids (PFCls)

They are completely fluorinated, synthetic, carbon-containing compounds that comprise exclusively fluorine-carbon bonds [29]. They are clear, colorless, and odorless; they present a density that is approximately twice that of water, low viscosity, and a refractive index similar to that of water. They are hydrophobic and lipophobic and so immiscible but they could form emulsions; they maintain the possibility of gases like CO2 and O2 to diffuse [430]. Three molecules are nowadays in use: perfluorodecalin (PFD), perfluoro-n-octane (PFO), and Perfluoro-tetradecahydrophenantrene that present different interface evidence when used with other fluids during surgery (PFD is at the moment the leading compound) [31].

They have been used as temporary tamponades to unfold and stabilize the retina during surgical manipulation. They have to be removed at the end of the surgical procedure [32, 33].

These substances present, if left into the eye after surgery, a retinal toxicity and intraocular inflammatory reactions, inducing the formation of epiretinal membranes and intraretinal layer disruption [34, 35].

Recently, a PFCl stained molecule has been tested to improve its surgical use with interesting results. Its usefulness will be evident during air or fluid exchange phases in which the stained tamponade will be well visible for a complete removal. Indeed, small little bubbles of PFCl adherent to the retina have been often observed a long time after the removal [36].

3.3.3. Semifluorinated Alkanes

Semifluorinated alkanes (SFAs) are also known as partially fluorinated alkanes or fluorinated alkanes. These materials consist of short alkyl chains joined at one or both ends to a perfluorocarbon chain [37]. SFAs are colorless, immiscible with water, and physically and chemically inert. They present a lower viscosity and density (1.35 g/mL) than PFCls. They present solubility in PFCl, hydrocarbons, and silicone oil [3840].

They were the first intraocular tamponades used beyond surgical time [41]. In addition, it has been demonstrated that SFAs can be successfully used also as intraoperative tools to unfold and lay down the retina. Finally they have been marketed also as biocompatible solvents for silicone oil to facilitate its removal [40].

These tamponades currently are not used owing to their tendency towards emulsification and epiretinal membrane formation and for toxic and inflammatory reactions in case of long permanence [42].

Actually they are mixed to silicone oils to form the so-called third-generation silicone oils or “heavy oils” (see the following) [43, 44].

3.3.4. Silicone Oils

Silicone Oil. Silicone oil (SO) for ophthalmic use is a synthetic polymer belonging to the class of polydimetilsiloxanes. It presents a refractive index that is similar to the vitreous, a lower density than water, and a differing viscosity according to the type of molecule, generally 1000–5000 Centistokes (cinematic viscosity measured in Centistokes—Cs) [5].

Used in the past as an intraoperative tool to stabilize the retina and unroll the flaps of retinal tears, it is nowadays considered and recommended for long-term retinal support and tamponades, due to its chemical inertness and permanent optical transparency [45]. Its use is recommended in difficult cases as the presence of giant retinal tears, retinal detachment complicated by proliferative vitreoretinopathy [46, 47]. Due to its surface tension and hydrophobic properties it could be considered a good tamponade that depends on the position of the bubble and the patient’s head (the tamponade floats over residual vitreous or water). Its intraocular presence reduces the movements and compartmentalizes cytokines and cellular factors between the anterior and posterior segment of the eye [48].

Surgical experience shows several disadvantages of long-term persistence. The complications of silicone oil use as an intraocular tamponade are mainly cataract induction, corneal toxicity, glaucoma, and so-called “silicone retinopathy” [49, 50]. A frequent modification occurring to silicone oil is emulsification. Emulsification is defined as a dispersion of fine liquid particles in another liquid medium and results from shearing forces between the two media, causing droplets to be pinched off into the other media because of surface tension. There are multiple factors affecting the emulsification of silicone oil: viscosity and physiochemical properties present an important role. Clinical research observed that the less viscous oils (1000 and 5000 Cs) tend to emulsify earlier than more viscous heavy silicone oils (see below: Oxane HD, Densiron, and HWS 46-3000) and that silicone oils containing hydroxyl and phenyl side groups emulsify earlier than purified polydimethylsiloxane. Surface-active agents (surfactants) are agents that lower the surface tension of the medium increasing its emulsification: various biological substances like blood, fibrin, and gamma globulins could act as emulsifiers and destabilize intraocular applied silicone oils [51, 52].

Macular edema represents another severe complication of silicone oil; it is present just after the exchange or increases during intraocular SO presence. This fact could take origin from different reasons: the diffusion of intraocular molecules is slowed down, reducing transport in the vitreous cavity of molecules such as oxygen and other nutrients, growth factors, and cytokines; the vitreous tamponade provides a mechanical “flotation force” at its apex against the macular region, being responsible for macula inflammation and secondary ME, especially in dynamic patients [53].

During removal procedures, problems can arise, such as hypotony and/or persistence of diffused small emulsion particles on the retina causing chronic inflammation [49, 50].

A double-fill of silicone oil and SFAs has been studied for a complete tamponade of the superior and inferior retina. The critical phase is to maintain a regular filling and to avoid the “egg effect”: in this case the separation of the two substances into two phases interrupts the correct tamponade effect [44].

Second-Generation Silicone Oils. Also called fluorinated silicones, they present similar characteristics to silicone oil, in particular the same viscosity and refractive index, but a higher density (greater than water) [54, 55].

They were used as vitreal substitute after surgery due to their efficacy on inferior retina tamponade. Surgical experience showed also the possibility to use them as temporary vitreal substitute to facilitate surgical procedures. Among them, the silicone fluorosilicone copolymer, a polysiloxane derivate, presents same characteristics to the fluorosilicones but due to its low viscosity facilitating injection and removal it has been used as temporary intrasurgical substitute.

All fluorosilicones present a higher emulsification rate and retinal toxicity, due probably to their high density and this fact limited their clinical use [56, 57].

Heavy Silicone Oils (HSO). They have been created by the combination of silicone oil and fluorinated alkanes in a homogenous solution. Like silicone oils, they have good transparency, higher density than water, and higher viscosity. They are chemically inert, presenting an emulsification tendency less than that of silicone oils [58]. We identified four molecules: Oxane HD, Densiron 68 and 68 LV, and HWS 46-3000, as the result of the mixture of silicone oil with various SFAs. Oxane HD is a mixture of ultrapurified silicone oil (Oxane 5700) and RMN3, a partially fluorinated and hydrocarbonated olefin with a density of 1.02 g/cm3 and a viscosity of 3300 mPas (dynamic viscosity measured in milliPascal—mPas) [59]. Densiron 68 has been designed to take advantage of the high specific gravity of F6H8 and the high viscosity of silicone oil. The resulting solution has a density of 1.06 g/cm3 (higher than water) and a viscosity of 1400 mPas (substantially higher than F6H8). Densiron 68 LV is a mixture of silicone oil (siluron 1000) and F6H8 with a density of 1.05 g/cm3 and a viscosity of 300 mPas at 25°C [6062]. HWS 46-3000 is a new silicone oil composed of 100,000 Cs silicone oil (45%) and F4H5 (55%) with a density of 1.118 g/cm3 and a viscosity of 2903 mPas [63].

They are used as long-term tamponades due to their high density and stability, in all cases where a tamponade effect on the inferior parts of the retina is necessary [64, 65].

Its removal requires strong active aspiration due to its high viscosity. The heavy SO may remain strictly adherent to the retina surface (“sticky oil phenomenon”) causing inflammation and tissue reactivity [66].

The inflammatory and toxic effects are evident on cataract induction, glaucoma, and keratopathy proving toxicity for the whole eye [67, 68].

Magnetic Silicones. They represent an interesting surgical experience to take advantage of the good chemical and physical properties of silicone oils. In particular, the dispersion of nanoparticles of metal (nickel, iron, cobalt, and rare metals) increases the superficial tension of the oil and therefore the tamponade effect [69].

This is carried out with the positioning of an encircling scleral magnetic band (scleral buckle). This interesting experimental project has been limited by the high toxicity of silicone oil metal dispersion on intraocular tissue [4, 69].

4. Experimental Substitutes

Clinical research for vitreous substitutes has essentially tried to reproduce two aspects of the original vitreous: on the one hand, a substance with the same vitreous molecular structure (simple filling function, to control elasticity and pressure of the eye), and on the other hand a structural molecule presenting its chemical and physiological properties (to assure diffusion of metabolites and gases, to allow the perfusion of drugs, and to interact actively with intraocular structures). This approach has led research toward functional biomimicry: the use of synthetic molecules that not only mimic the rheological function of the vitreous but also might interact with the intraocular structure without time-dependent degeneration or optical transparency loss [13].

4.1. Natural Polymers

Natural polymers, such as hyaluronic acid (HA) and collagen, have been evaluated as the basis for vitreous substitutes. As the main components of the vitreous, they present great biocompatibility. Hyaluronic acid and its derivatives are present in various formulations for ocular use, but due to the short degradation time they cannot be used as intraocular tamponades. Collagen derivatives, such as gelatine, polygeline, and methylated collagen types I-II, as well as chitosan (a natural crustacean product), have been studied as structural polymer proteins for experimental vitreous substitutes with poor results [4, 5, 70, 71].

The intraocular gel hylan, created using cross-linked molecules of sodium hyaluronate formaldehyde, divinyl sulfone, and gellan molecule, could represent an interesting short-term vitreal substitute for its stability and composition. Its excessive water solubility made it at the moment not available for clinical experiments [66].

The above-described vitreous substitutes are not effective due to the tendency of the molecules towards degradation, their low viscosity, and poor tamponade effect [72, 73].

A promising approach, compromising the biocompatibility of HA and the duration of a complex polymer, is the application of dihydrazide photo-cross-linking reaction. This type of cross-linked HA presents good transparency, viscosity, and tamponade effect due to its hydrophilic properties. Degradation time is quite long (more than 4 weeks) [74]. The advantages of this substitute are the limited tissue inflammatory and toxic reaction [75]; the disadvantage is already the short time of degradation (from 60 to 150 days) due in part to the injection procedure that alters the gel molecular structure reducing the integrity and stability. The cross-linking processes by in situ gelification [76] and the intraocular injection of cellular components to actively produce polymer matrix represent a possible solution of this problem.

4.2. Hydrogels

Polymeric and Smart Hydrogels represent the new class of experimental vitreal substitute [77].

These substances are hydrophilic polymers that form a gel network when cross-linked and are capable of swelling by absorbing several times their own weight in water [78]. They present good and stable transparency, good biocompatibility, and viscoelastic properties like the vitreous body, mimicking its biofunctionality, yet they have different chemical and physical properties [4, 79]. Both types of molecule are synthetic polymers with different characteristics. In particular, Smart Hydrogels are able to respond to the environment and to external physical stimuli. Their characteristics determine long-term vitreous stability without toxic effects. The passive action of these molecules as tamponades is coupled with the active action as drug releasers or exchangers to ensure therapeutic and clinical effects [80].

Hydrogel molecules have been developed and carefully selected not only owing to their chemical-physical properties, but also due to their possible toxicity [77]. They represent the first biomaterials ever synthesized for human use and have various clinical applications.

Here we list the principal molecules, showing their advantages and disadvantages; several of these ones have been discarded due to toxicity or unable characteristics. We underline that in vivo research is as yet applied only to animal models [81].(i)Poly(vinyl alcohol) (PVA): it is selected for its good optical properties making it a valid vitreous substitute; it is indistinguishable from the vitreous during the initial months following injection. PVA presents good biocompatibility and rheological properties. Adding different chemical reactants, in particular trisodium-triphosphate cross-linking agent, the molecule changes and improves its properties, particularly its rheological characteristics and diffusion behavior [82]. Further studies must be carried out on its ability to act as a retinal tamponade [83].(ii)Poly(1-vinyl-2-pyrrolidone) (PVP): it is the first studied element for vitreous substitution. This molecule is the result of the polymerization of 1-vinyl-2-pyrrolidone with different cross-linking agents [84]. Experimental research has created several molecules of PVP, presenting a density and viscosity similar to the human vitreous, but with intraocular reactivity [85]. Transient or permanent vitreous opacification is the most frequent adverse event, as well as inflammation with vacuoles and granules, indicating early PVP degradation due to phagocytosis [86]. Further studies are underway to evaluate more tolerable and more stable PVP polymers [87, 88].(iii)Polyacrylamide (PAA): it is created by the polymerization of toxic acrylamide by cross-linking agents (once injected into the vitreous cavity after the monomer) [89]. Experimental PAA polymers have been created with a disulfide cross-linking agent to produce highly purified molecules [90]. PAA presents similar density and viscosity to the vitreous, as well as good biocompatibility and long-term stability. Better results are expected in the future. Severe complications such as ocular inflammation and vitreous opacification were reported on the first experimental phases of these materials.(iv)Copoly(acrylamide) (CPA): it is a variant of PAA presenting better gelification properties, acquiring polymerization after reduction of disulfide cross-linking bridges [90]. With the same refractive index and viscoelastic parameters of the vitreous, as well as good biocompatibility, it seemed to be a valid long-term substitution. The tested molecule showed clinical suitability and lack of significant ocular toxicity.(v)Poly(glyceryl methacrylate) (PGMA): this polymer is nowadays excluded from research owing to its fragmentation upon injection [4]. The dehydrated molecule has been tested by direct intraocular positioning: in contact with intraocular fluids the molecule swells and became the vitreal substitute. The experimental evaluation found this process too slow and not effective for clinical use [91]. Although it has good biocompatibility and excellent physical properties, the molecule did not become clinically available [92].(vi)Poly(2-hydroxyethyl methacrylate) (PHEMA): this polymer presents solid features. Experimental research has shown good inertness to degradation and inflammatory reactivity [89]. Because of its solid feature, it caused important surgical difficulties for its implantation, so it was considered unsuitable for clinical use [93, 94].(vii)Poly(2-hydroxyethylacrylate) (PHEA): this hydrogel presents excellent physical properties similar to those of the human vitreous. Due to reported inflammatory reactions following injection, cataract, glaucoma, and the formation of fibrous membranes it was abandoned for human clinical research [4, 5].(viii)Hydroxypropyl methylcellulose (HPMC): it presents good physical-chemical properties as well as good biocompatibility [95]. Different experimental polymers have been studied, varying the molecular weight [96]. Researchers have tried to reduce intraocular degradation time, but as of today it is not yet available as a long-term vitreal substitute [97].(ix)Pluronic F127 (p-F127): it is a thermoreversible gelatin. It could form a gel at 21°C but it shows severe retinal toxicity making it unsuitable for clinical use [98, 99].(x)Silicone gel: it is a hydrophobic polymer that maintains good intraocular transparency and cohesiveness. Its poor tamponade effect has deemed it unsuitable as an intraocular retinal surgical tool [100].(xi)ADCON hydrogel: it is a polymer of proteoglycan esters in porcine gelatine and it is already used in neurosurgery. This hydrogel is highly biocompatible but presents potential retinal toxicity and postoperative inflammation. It is unsuitable for ocular use [101].(xii)Poly(vinyl alcohol methacrylate) (PVA-MA): this polymer contains a photoinitiator that forms a gel network after irradiation at 365 nm. The degree of gelification can be regulated by polymer concentration and light intensity. PVA-MA properties must be tested in vitro and in vivo to evaluate vitreous biomimicry and biocompatibility [102].

Beyond all different experimental problems described above, a critical phase during physical tests for all these polymers was the injection through small caliper needles, a critical phase for clinical use. The shear stress of the needle during intraocular injection causes a loss on elasticity and a fluidification of the preformed molecules of hydrogel, due to the rupture of polymeric chains [77].

To resolve this criticality, hydrogel could be injected in an aqueous state and transformed into a gel in situ by light exposure or air oxidation, thanks to cross-linking processes. According to the different polymers, the liquid hydrogel could reach final gelification with defined elasticity and swelling in the presence of a photoinitiator or a disulfide cross-linker. In particular, PVA-MA is sensitive to a defined UVA wavelength, not yet applicable in eye surgery; differently, CPA is injected on a reduced form, sensitive to air oxidation for the gelification process [102].

Smart Hydrogels present similar characteristics compared to the polymeric hydrogels, but they have more interactive properties with the environment, such as glucose-, glutathione-, and pH-dependent activity and reactivity to light, pressure, and electric fields. These properties mean that these molecules could interact with retinal tissue, injected drugs, lasers light, or other chemicals and physical stimuli. These interactions induce an increased gelification, better drug diffusion, and increased gel expansion [103106]. Little information regarding their toxicity or inflammatory action is available at present [107, 108]. Thermosetting gels are Smart Hydrogels that modify their status according to temperature (e.g., WTG-127 gel) [109]. This is important for the gelification status and viscosity, for their injection and handling. The disadvantage of this molecule is its reduced degradation time and its tendency to drift under the retina in the presence of tears before complete gelification [105].

All these molecules, as we described above, could actually cause adverse reactions of the ocular tissues at different stage, such as inflammation, phagocytosis, and vacuolization, due to molecular degradation and immune reaction. One of the major challenges is to make these molecules more and more compatible with the immune and biological systems [103].

Despite the above reasons, hydrogels seem to be the best candidates for vitreous substitution. They present all the characteristics needed to mimic the physical-chemical behavior of the vitreous, plus its biological function. We need to perform more experimental evaluations to tailor density and rigidity, as well as degradation times to match those of the natural vitreous [74, 75, 78].

4.3. Transplant and Implants

Many years ago, some authors described the first attempt to transplant vitreal tissue [110112]. They observed that, if correctly stored, the vitreous body could maintain its structure and also its enzymatic properties, as described in the literature [8, 9, 11]. The implanted tissue showed a degradation time on the host, with a low inflammatory reaction and interesting surgical results on 40% of patients. Cataract, glaucoma, and more severe adverse events until ocular atrophy were described [110112].

Regarding implants, bioengineering studies have shown interesting results in the use of artificial capsular bodies, made of silicone rubber elastomer and filled with a saline solution, silicone oil, controlled using a valve system. The system was described as being well tolerated on an experimental model. This foldable capsular vitreous body (FCVB) presented good mechanical, optical, and biocompatible properties in vitro and in vivo and has been seen to be effective as a vitreous substitute in the treatment of severe retinal detachment. The presence of a filled capsule reduces the toxic effect, such as intraocular toxicity, emulsification, high IOP, and keratopathy [113]. A new polyvinyl alcohol (PVA) filling molecule has been evaluated in recent studies on a rabbit model. The 3% concentration showed the best results in rheological, physical, and cytotoxicity tests. This type of approach combines the efficacy of hydrogel as a vitreous substitute to the presence of an implant as an isolator that could reduce degradation time. In the PVA-FCVB rabbit implanted eyes, the structure of the retina was intact at 90 days postoperatively (a lensectomy was performed in all eyes due to frequent cataract induction of the implant); at 180 days retinal disorders were reported due to long-term capsule-induced mechanical pressure to the retina [114]. The advantages of this type of approach have also been reported on a therapeutic target: several nanometer wide apertures are available on the implanted capsule, so drugs could be added to the hydrogel and long-term release could be performed [115, 116].

4.4. Vitreous Regeneration

The challenge to create a new vitreous with the critical 3D structure might be very interesting and for this purpose different studies were performed. Controlled hyalocytes proliferation with specific growth factors (bFGF stimulates and TGF-B1 inhibits) and the production of HA with related components were evaluated [117, 118]. Reverse transcriptase polymerase chain reaction (RT-PCR) analyzed and compared the expression profiles for several genes in the human vitreous tissue-derived cells. The regulation of hyaluronan production in response to cytokine stimulation, the expression of hyaluronan synthase isoforms using RT-PCR, and hyaluronan production using enzyme-linked immunosorbent assay (ELISA) were also investigated[119].

5. Conclusions

The vitreous is a fundamental component of the eye. It has filling functions and extremely active properties on the stability and metabolism of the retina complex. Current long-term vitreous substitutes are clinically largely used but present some disadvantages. Many studies evaluated the possibility to realize the ideal vitreal substitute: long-term persistence and good biocompatibility to maintain transparency and integrity. Polymeric hydrogels have shown suitable characteristics with great variability of chemical composition: ideal substitution must be performed correctly, and experimental research is advancing.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. S. G. Schwartz, H. W. Flynn Jr., and W. F. Mieler, “Update on retinal detachment surgery,” Current Opinion in Ophthalmology, vol. 24, no. 3, pp. 255–261, 2013. View at Publisher · View at Google Scholar
  2. F. M. Recchia, I. U. Scott, G. C. Brown, M. M. Brown, A. C. Ho, and M. S. Ip, “Small-gauge pars plana vitrectomy: a report by the American academy of ophthalmology,” Ophthalmology, vol. 117, no. 9, pp. 1851–1857, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. E. Stefánsson, “Physiology of vitreous surgery,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 247, no. 2, pp. 147–163, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. F. Baino, “Towards an ideal biomaterial for vitreous replacement: historical overview and future trends,” Acta Biomaterialia, vol. 7, no. 3, pp. 921–935, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. T. T. Kleinberg, R. T. Tzekov, L. Stein, N. Ravi, and S. Kaushal, “Vitreous substitutes: a comprehensive review,” Survey of Ophthalmology, vol. 56, no. 4, pp. 300–323, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. M. M. Le Goff and P. N. Bishop, “Adult vitreous structure and postnatal changes,” Eye, vol. 22, no. 10, pp. 1214–1222, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. J. Sebag, “Macromolecular structure of the corpus vitreus,” Progress in Polymer Science, vol. 23, no. 3, pp. 415–446, 1998. View at Google Scholar · View at Scopus
  8. E. A. Balazs, “Fine structure and function of ocular tissues. The Vitreous,” International Ophthalmology Clinics, vol. 13, pp. 442–465, 1973. View at Google Scholar
  9. L. I. Los, R. J. van der Worp, M. J. A. van Luyn, and J. M. M. Hooymans, “Age-related liquefaction of the human vitreous body: LM and TEM evaluation of the role of proteoglycans and collagen,” Investigative Ophthalmology & Visual Science, vol. 44, no. 7, pp. 2828–2833, 2003. View at Publisher · View at Google Scholar · View at Scopus
  10. B. A. Filas, Y. B. Shui, and D. C. Beebe, “Computational model for oxygen transport and consumption in human vitreous,” Investigative Ophthalmology & Visual Science, vol. 54, no. 10, pp. 6549–6559, 2013. View at Publisher · View at Google Scholar
  11. J. Sebag and E. A. Balazs, “Morphology and ultrastructure of human vitreous fibers,” Investigative Ophthalmology & Visual Science, vol. 30, no. 8, pp. 1867–1871, 1989. View at Google Scholar · View at Scopus
  12. G. K. Edwards and J. C. Locke, “The collection, storage and selection of human vitreous. For use in retinal detachment surgery,” American Journal of Ophthalmology, vol. 50, no. 1, pp. 108–110, 1960. View at Google Scholar · View at Scopus
  13. T. V. Chirila, S. Tahija, Y. Hong, S. Vijayasekaran, and I. J. Constable, “Synthetic polymers as materials for artificial vitreous body: review and recent advances,” Journal of Biomaterials Applications, vol. 9, no. 2, pp. 121–137, 1994. View at Google Scholar · View at Scopus
  14. F. Docchio, C. Azzolini, and R. Brancato, “Refractive properties of interfaces due to the use of vitreous substitutes in vitreoretinal surgery: a ray tracing approach. Part 3: modelling the effect of an air bubble within the irradiation path in endo-ocular laser photocoagulation,” Lasers and Light in Ophthalmology, vol. 7, pp. 25–30, 1995. View at Google Scholar
  15. D. Steijns and J. S. Stilma, “Vitrectomy: in search of the ideal vitreous replacement,” Nederlands Tijdschrift voor Geneeskunde, vol. 153, article A433, 2009. View at Google Scholar · View at Scopus
  16. C. Azzolini, F. Docchio, R. Brancato, and G. Trabucchi, “Interactions between light and vitreous fluid substitutes,” Archives of Ophthalmology, vol. 110, no. 10, pp. 1468–1471, 1992. View at Google Scholar · View at Scopus
  17. C. Azzolini, P. G. Gobbi, R. Brancato et al., “Interaction between infrared radiation and vitreous substitutes,” Archives of Ophthalmology, vol. 115, no. 7, pp. 899–903, 1997. View at Google Scholar · View at Scopus
  18. N. Soman and R. Banerjee, “Artificial vitreous replacements,” Bio-Medical Materials and Engineering, vol. 13, no. 1, pp. 59–74, 2003. View at Google Scholar · View at Scopus
  19. H. S. Tan, S. Y. Oberstein, M. Mura, and H. M. Bijl, “Air versus gas tamponade in retinal detachment surgery,” British Journal of Ophthalmology, vol. 97, no. 1, pp. 80–82, 2013. View at Publisher · View at Google Scholar
  20. D. M. Marcus, D. J. D'Amico, and S. Mukai, “Pneumatic retinopexy versus scleral buckling for repair of primary rhegmatogenous retinal detachment,” International Ophthalmology Clinics, vol. 34, no. 3, pp. 97–108, 1994. View at Google Scholar · View at Scopus
  21. A. M. Montoya and M. D. de Smet, “Air as tamponade for retinal detachment,” European Journal of Ophthalmology, vol. 24, no. 2, pp. 242–246, 2014. View at Publisher · View at Google Scholar
  22. M. Dogramaci, “The effect of the anterior ocular structures on the fluid dynamics in eyes with gas tamponades,” Investigative Ophthalmology & Visual Science, vol. 53, no. 3, article 1324, 2012. View at Google Scholar · View at Scopus
  23. A. M. Mansour, “Pneumatic retinopexy for inferior retinal breaks,” Ophthalmology, vol. 112, no. 10, pp. 1771–1776, 2005. View at Publisher · View at Google Scholar · View at Scopus
  24. E. J. Sigler, J. C. Randolph, S. Charles, and J. I. Calzada, “Intravitreal fluorinated gas preference and occurrence of rare ischemic postoperative complications after pars plana vitrectomy: a survey of the American Society of Retina Specialists,” Journal of Ophthalmology, vol. 2012, Article ID 230596, 5 pages, 2012. View at Publisher · View at Google Scholar
  25. J. T. Thompson, “The absorption of mixtures of air and perfluoropropane after pars plana vitrectomy,” Archives of Ophthalmology, vol. 110, no. 11, pp. 1594–1597, 1992. View at Google Scholar · View at Scopus
  26. A. D. Fu, H. R. McDonald, D. Eliott et al., “Complications of general anesthesia using nitrous oxide in eyes with preexisting gas bubbles,” Retina, vol. 22, no. 5, pp. 569–574, 2002. View at Google Scholar · View at Scopus
  27. S. de Bustros, B. M. Glaser, and M. A. Johnson, “Thrombin infusion for the control of intraocular bleeding during vitreous surgery,” Archives of Ophthalmology, vol. 103, no. 6, pp. 837–839, 1985. View at Google Scholar · View at Scopus
  28. R. H. Y. Asaria, C. H. Kon, C. Bunce et al., “Adjuvant 5-fluorouracil and heparin prevents proliferative vitreoretinopathy: results from a randomized, double-blind, controlled clinical trial,” Ophthalmology, vol. 108, no. 7, pp. 1179–1183, 2001. View at Publisher · View at Google Scholar · View at Scopus
  29. G. A. Peyman, J. A. Schulman, and B. Sullivan, “Perfluorocarbon liquids in ophthalmology,” Survey of Ophthalmology, vol. 39, no. 5, pp. 375–395, 1995. View at Publisher · View at Google Scholar · View at Scopus
  30. C. A. Wilson, B. A. Berkowitz, and R. Srebro, “Perfluorinated organic liquid as an intraocular oxygen reservoir for the ischemic retina,” Investigative Ophthalmology & Visual Science, vol. 36, no. 1, pp. 131–141, 1995. View at Google Scholar · View at Scopus
  31. F. Bottoni, M. Sborgia, P. Arpa et al., “Perfluorocarbon liquids as postoperative short-term vitreous substitutes in complicated retinal detachment,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 231, no. 11, pp. 619–628, 1993. View at Publisher · View at Google Scholar · View at Scopus
  32. I. U. Scott, T. G. Murray, H. W. Flynn Jr., W. J. Feuer, and J. C. Schiffman, “Outcomes and complications associated with giant retinal tear management using perfluoro-n-octane,” Ophthalmology, vol. 109, no. 10, pp. 1828–1833, 2002. View at Publisher · View at Google Scholar · View at Scopus
  33. J. Mackiewicz, K. Maaijwee, C. Lüke et al., “Effect of gravity in long-term vitreous tamponade: in vivo investigation using perfluorocarbon liquids and semi-fluorinated alkanes,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 245, no. 5, pp. 665–675, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. S. Mertens, J. Bednarz, and K. Engelmann, “Evidence of toxic side effects of perfluorohexyloctane after vitreoretinal surgery as well as in previously established in vitro models with ocular cell types,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 240, no. 12, pp. 989–995, 2002. View at Google Scholar · View at Scopus
  35. N. Orzalesi, L. Migliavacca, F. Bottoni, and S. Miglior, “Experimental short-term tolerance to perfluorodecalin in the rabbit eye: a histopathological study,” Current Eye Research, vol. 17, no. 8, pp. 828–835, 1998. View at Publisher · View at Google Scholar · View at Scopus
  36. S. Rizzo, C. Belting, F. Genovesi-Ebert, and N. Hagedorn, “Colored perfluorocarbon liquids as novel intraoperative tools,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 250, no. 5, pp. 653–659, 2012. View at Publisher · View at Google Scholar · View at Scopus
  37. D. Wong and N. Lois, “Perfluorocarbons and semifluorinated alkanes,” Seminars in Ophthalmology, vol. 15, no. 1, pp. 25–35, 2000. View at Google Scholar · View at Scopus
  38. D. Tognetto, L. Lepori, R. Lapasin et al., “A new heavy internal tamponade in vitreoretinal surgery: an in vitro study,” Eye, vol. 22, no. 8, pp. 1082–1088, 2008. View at Publisher · View at Google Scholar · View at Scopus
  39. H. Meinert and T. Roy, “Semifluorinated alkanes—a new class of compounds with outstanding properties for use in ophthalmology,” European Journal of Ophthalmology, vol. 10, no. 3, pp. 189–197, 2000. View at Google Scholar · View at Scopus
  40. J. Roider, H. Hoerauf, K. Kobuch, and V.-P. Gabel, “Clinical findings on the use of long-term heavy tamponades (semifluorinated alkanes and their oligomers) in complicated retinal detachment surgery,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 240, no. 12, pp. 965–971, 2002. View at Google Scholar · View at Scopus
  41. D. Zeana, J. Becker, R. Kuckelkorn, and B. Kirchhof, “Perfluorohexyloctane as a long-term vitreous tamponade in the experimental animal,” International Ophthalmology, vol. 23, no. 1, pp. 17–24, 1999. View at Publisher · View at Google Scholar · View at Scopus
  42. B. Kirchhof, D. Wong, J. van Meurs et al., “Use of perfluorohexyloctane as a long-term internal tamponade agent in complicated retinal detachment surgery,” American Journal of Ophthalmology, vol. 133, no. 1, pp. 95–101, 2002. View at Publisher · View at Google Scholar · View at Scopus
  43. M. I. Stefaniotou, M. V. Aspiotis, G. D. Kitsos, C. D. Kalogeropoulos, I. C. Asproudis, and K. G. Psilas, “Our experience with perfluorohexyloctane (F6H8) as a temporary endotamponade in vitreoretinal surgery,” European Journal of Ophthalmology, vol. 12, no. 6, pp. 518–522, 2002. View at Google Scholar · View at Scopus
  44. E. Herbert, T. Stappler, C. Wetterqvist, R. Williams, and D. Wong, “Tamponade properties of double-filling with perfluorohexyloctane and silicone oil in a model eye chamber,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 242, no. 3, pp. 250–254, 2004. View at Publisher · View at Google Scholar · View at Scopus
  45. W. J. Foster, “Vitreous substitutes,” Expert Review of Ophthalmology, vol. 3, no. 2, pp. 211–218, 2008. View at Publisher · View at Google Scholar · View at Scopus
  46. J. C. Pastor, “Proliferative vitreoretinopathy: an overview,” Survey of Ophthalmology, vol. 43, no. 1, pp. 3–18, 1998. View at Publisher · View at Google Scholar · View at Scopus
  47. S. P. Azen, I. U. Scott, H. W. Flynn Jr. et al., “Silicone oil in the repair of complex retinal detachments: a prospective observational multicenter study,” Ophthalmology, vol. 105, no. 9, pp. 1587–1597, 1998. View at Publisher · View at Google Scholar · View at Scopus
  48. C. Azzolini, R. Brancato, F. I. Camesasca, M. Codenotti, and M. S. Blumenkranz, “Influence of silicone oil on iris microangiopathy in diabetic vitrectomized eyes,” Ophthalmology, vol. 100, no. 8, pp. 1152–1159, 1993. View at Google Scholar · View at Scopus
  49. M. Inoue, A. Iriyama, K. Kadonosono, Y. Tamaki, and Y. Yanagi, “Effects of perfluorocarbon liquids and silicone oil on human retinal pigment epithelial cells and retinal ganglion cells,” Retina, vol. 29, no. 5, pp. 677–681, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. G. G. Giordano and M. F. Refojo, “Silicone oils as vitreous substitutes,” Progress in Polymer Science, vol. 23, no. 3, pp. 509–532, 1998. View at Google Scholar · View at Scopus
  51. C. Azzolini, L. Pierro, M. Codenotti, F. Bandello, and R. Brancato, “Ultrasound biomicroscopy following the intraocular use of silicone oil,” International Ophthalmology, vol. 19, no. 3, pp. 191–195, 1995. View at Publisher · View at Google Scholar · View at Scopus
  52. Y. Toklu, H. B. Cakmak, S. B. Ergun, M. A. Yorgun, and S. Simsek, “Time course of silicone oil emulsification,” Retina, vol. 32, no. 10, pp. 2039–2044, 2012. View at Publisher · View at Google Scholar
  53. C. Azzolini, S. Donati, S. M. Caprani et al., “Macular edema and silicone oil tamponade,” BioMED Research International, submitted.
  54. S. Yamamoto and S. Takeuchi, “Silicone oil and fluorosilicone,” Seminars in Ophthalmology, vol. 15, no. 1, pp. 15–24, 2000. View at Google Scholar · View at Scopus
  55. P. Versura, M. Cellini, A. Torreggiani et al., “The biocompatibility of silicone, fluorosilicone and perfluorocarbon liquids as vitreous tamponades. An ultrastructural and immunohistochemical study,” Ophthalmologica, vol. 215, no. 4, pp. 276–283, 2001. View at Publisher · View at Google Scholar · View at Scopus
  56. C. Wetterqvist, D. Wong, R. Williams, T. Stappler, E. Herbert, and S. Freeburn, “Tamponade efficiency of perfluorohexyloctane and silicone oil solutions in a model eye chamber,” British Journal of Ophthalmology, vol. 88, no. 5, pp. 692–696, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. L. Lepori, E. Matteoli, A. Spanedda, F. Genovesi-Ebert, and S. Rizzo, “Combined use of perfluorohexyloctane and silicone oil as intraocular tamponade: an in vitro study,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 244, no. 1, pp. 79–82, 2006. View at Publisher · View at Google Scholar · View at Scopus
  58. H. Heimann, T. Stappler, and D. Wong, “Heavy tamponade 1: a review of indications, use, and complications,” Eye, vol. 22, no. 10, pp. 1342–1359, 2008. View at Publisher · View at Google Scholar · View at Scopus
  59. S. Wolf, V. Schön, P. Meier, and P. Wiedemann, “Silicone oil-RMN3 mixture (“heavy silicone oil”) as internal tamponade for complicated retinal detachment,” Retina, vol. 23, no. 3, pp. 335–342, 2003. View at Google Scholar · View at Scopus
  60. M. R. Romano, T. Stappler, J. Marticorena et al., “Primary vitrectomy with Densiron-68 for rhegmatogenous retinal detachment,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 246, no. 11, pp. 1541–1546, 2008. View at Publisher · View at Google Scholar · View at Scopus
  61. S. Rizzo, F. Genovesi-Ebert, A. Vento, F. Cresti, S. Miniaci, and M. C. Romagnoli, “Heavy silicone oil (Densiron-68) for the treatment of persistent macular holes,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 247, no. 11, pp. 1471–1476, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. D. Sandner and K. Engelmann, “First experiences with high-density silicone oil (Densiron) as an intraocular tamponade in complex retinal detachment,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 244, no. 5, pp. 609–619, 2006. View at Publisher · View at Google Scholar · View at Scopus
  63. S. Rizzo, F. Genovesi-Ebert, A. Vento, F. Cresti, E. di Bartolo, and C. Belting, “A new heavy silicone oil (HWS 46-3000) used as a prolonged internal tamponade agent in complicated vitreoretinal surgery: a pilot study,” Retina, vol. 27, no. 5, pp. 613–620, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. A. M. Joussen, B. Kirchhof, N. Schrage et al., “Heavy silicone oil versus standard silicone oil as vitreous tamponade in inferior PVR (HSO Study): design issues and implications,” Acta Ophthalmologica Scandinavica, vol. 85, no. 6, pp. 623–630, 2007. View at Publisher · View at Google Scholar · View at Scopus
  65. H. Er, “Primary heavy silicone oil usage in inferior rhegmatogenous retinal detachment,” Ophthalmologica, vol. 224, no. 2, pp. 122–125, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. J. H. Dresp and D.-H. Menz, “The phenomenon of “sticky” silicone oil,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 245, no. 6, pp. 863–868, 2007. View at Publisher · View at Google Scholar · View at Scopus
  67. W. Li, J. Zheng, Q. Zheng, R. Wu, X. Wang, and M. Xu, “Clinical complications of Densiron 68 intraocular tamponade for complicated retinal detachment,” Eye, vol. 24, no. 1, pp. 21–28, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. W. W. Lai, D. Wong, K. K. Li, and P.-L. Leow, “Emulsification and inverted hypopyon formation of oxane HD in the anterior chamber,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 246, no. 11, pp. 1633–1635, 2008. View at Publisher · View at Google Scholar · View at Scopus
  69. J. P. Dailey, J. P. Phillips, C. Li, and J. S. Riffle, “Synthesis of silicone magnetic fluid for use in eye surgery,” Journal of Magnetism and Magnetic Materials, vol. 194, no. 1, pp. 140–148, 1999. View at Publisher · View at Google Scholar · View at Scopus
  70. H. Yang, R. Wang, Q. Gu, and X. Zhang, “Feasibility study of chitosan as intravitreous tamponade material,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 246, no. 8, pp. 1097–1105, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. C. Liang, G. A. Peyman, P. Serracarbassa, N. Calixto, A. A. Chow, and P. Rao, “An evaluation of methylated collagen as a substitute for vitreous and aqueous humor,” International Ophthalmology, vol. 22, no. 1, pp. 13–18, 1998. View at Publisher · View at Google Scholar · View at Scopus
  72. S. Suri and R. Banerjee, “In vitro evaluation of in situ gels as short term vitreous substitutes,” Journal of Biomedical Materials Research A, vol. 79, no. 3, pp. 650–664, 2006. View at Publisher · View at Google Scholar · View at Scopus
  73. R. C. Pruett, C. L. Schepens, and D. A. Swann, “Hyaluronic acid vitreous substitute. A six-year clinical evaluation,” Archives of Ophthalmology, vol. 97, no. 12, pp. 2325–2330, 1979. View at Google Scholar · View at Scopus
  74. C. Schramm, M. S. Spitzer, S. Henke-Fahle et al., “The cross-linked biopolymer hyaluronic acid as an artificial vitreous substitute,” Investigative Ophthalmology & Visual Science, vol. 53, no. 2, pp. 613–621, 2012. View at Google Scholar · View at Scopus
  75. M. Nakagawa, M. Tanaka, and T. Miyata, “Evaluation of collagen gel and hyaluronic acid as vitreous substitutes,” Ophthalmic Research, vol. 29, no. 6, pp. 409–420, 1997. View at Google Scholar · View at Scopus
  76. Y. Tao, X. Tong, Y. Zhang, Y. Huang, Y.-R. Jiang, and B.-H. Guo, “Evaluation of an in situ chemically crosslinked hydrogel as a long-term vitreous substitute material,” Acta Biomaterialia, vol. 9, no. 2, pp. 5022–5030, 2013. View at Publisher · View at Google Scholar
  77. J. Kopeček, “Hydrogel biomaterials: a smart future?” Biomaterials, vol. 28, no. 34, pp. 5185–5192, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. J. Kopeček, “Polymer chemistry: swell gels,” Nature, vol. 417, no. 6887, pp. 388–391, 2002. View at Publisher · View at Google Scholar · View at Scopus
  79. K. E. Swindle, P. D. Hamilton, and N. Ravi, “In situ formation of hydrogels as vitreous substitutes: viscoelastic comparison to porcine vitreous,” Journal of Biomedical Materials Research A, vol. 87, no. 3, pp. 656–665, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. H. Gupta, S. Jain, R. Mathur, P. Mishra, A. K. Mishra, and T. Velpandian, “Sustained ocular drug delivery from a temperature and pH triggered novel in situ gel system,” Drug Delivery, vol. 14, no. 8, pp. 507–515, 2007. View at Publisher · View at Google Scholar · View at Scopus
  81. F. Baino, “The use of polymers in the treatment of retinal detachment: current trends and future perspectives,” Polymers, vol. 2, no. 3, pp. 286–322, 2010. View at Publisher · View at Google Scholar
  82. S. Maruoka, T. Matsuura, K. Kawasaki et al., “Biocompatibility of polyvinylalcohol gel as a vitreous substitute,” Current Eye Research, vol. 31, no. 7-8, pp. 599–606, 2006. View at Publisher · View at Google Scholar · View at Scopus
  83. G. Leone, M. Consumi, M. Aggravi, A. Donati, S. Lamponi, and A. Magnani, “PVA/STMP based hydrogels as potential substitutes of human vitreous,” Journal of Materials Science: Materials in Medicine, vol. 21, no. 8, pp. 2491–2500, 2010. View at Publisher · View at Google Scholar · View at Scopus
  84. S. Vijayasekaran, T. V. Chirila, Y. Hong et al., “Poly(1-vinyl-2-pyrrolidinone) hydrogels as vitreous substitutes: histopathological evaluation in the animal eye,” Journal of Biomaterials Science, Polymer Edition, vol. 7, no. 8, pp. 685–696, 1996. View at Google Scholar · View at Scopus
  85. Y. Hong, T. V. Chirila, S. Vijayasekaran et al., “Biodegradation in vitro and retention in the rabbit eye of crosslinked poly(1-vinyl-2-pyrrolidinone) hydrogel as a vitreous substitute,” Journal of Biomedical Materials Research, vol. 39, no. 4, pp. 650–659, 1998. View at Google Scholar
  86. Y. Hong, T. V. Chirila, M. J. H. Cuypers, and I. J. Constable, “Polymers of 1-vinyl-2-pyrrolidinone as potential vitreous substitutes: physical selection,” Journal of Biomaterials Applications, vol. 11, no. 2, pp. 135–181, 1996. View at Google Scholar · View at Scopus
  87. H. A. Aliyar, W. J. Foster, P. D. Hamilton, and N. Ravi, “Towards the development of an artificial human vitreous,” Polymer Preparation, vol. 45, pp. 469–470, 2004. View at Google Scholar
  88. K. E. Swindle-Reilly, M. Shah, P. D. Hamilton, T. A. Eskin, S. Kaushal, and N. Ravi, “Rabbit study of an in situ forming hydrogel vitreous substitute,” Investigative Ophthalmology & Visual Science, vol. 50, no. 10, pp. 4840–4846, 2009. View at Publisher · View at Google Scholar · View at Scopus
  89. P. D. Hamilton, H. A. Aliyar, and N. Ravi, “Biocompatibility of thiol-containing polyacrylamide polymers suitable for ophthalmic applications,” Polymer Preparation, vol. 45, pp. 495–496, 2004. View at Google Scholar
  90. K. E. Swindle, P. D. Hamilton, and N. Ravi, “Advancements in the development of artificial vitreous humor utilizing polyacrylamide copolymers with disulfide crosslinkers,” Polymer Preparation, vol. 47, pp. 59–60, 2006. View at Google Scholar
  91. S. Daniele, M. F. Refojo, C. L. Schepens, and H. M. Freeman, “Glyceryl methacrylate hydrogel as a vitreous implant. An experimental study,” Archives of Ophthalmology, vol. 80, no. 1, pp. 120–127, 1968. View at Google Scholar · View at Scopus
  92. T. E. H. Esch, K. R. Shah, and C. R. Fitzgerald, “Development of injectable poly(glyceryl methacrylate) hydrogels for vitreous prosthesis,” Journal of Biomedical Materials Research, vol. 10, no. 6, pp. 975–976, 1976. View at Google Scholar · View at Scopus
  93. G. W. Plant, T. V. Chirila, and A. R. Harvey, “Implantation of collagen IV/poly(2-hydroxyethyl methacrylate) hydrogels containing Schwann cells into the lesioned rat optic tract,” Cell Transplantation, vol. 7, no. 4, pp. 381–391, 1998. View at Publisher · View at Google Scholar · View at Scopus
  94. M. F. Refojo and F. L. Leong, “Poly(methyl acrylate-co-hydroxyethyl acrylate) hydrogel implant material of strength and softness,” Journal of Biomedical Materials Research, vol. 15, no. 4, pp. 497–509, 1981. View at Google Scholar · View at Scopus
  95. Y. Robert, B. Gloor, E. D. Wachsmuth, and M. Herbst, “Evaluation of the tolerance of the intra-ocular injection of hydroxypropyl methylcellulose in animal experiments,” Klinische Monatsblätter für Augenheilkunde, vol. 192, no. 4, pp. 337–339, 1988. View at Publisher · View at Google Scholar
  96. J. Fernandez-Vigo, J. F. Sabugal, A. D. Rey, A. Concheiro, and R. Martinez, “Molecular weight dependence of the pharmacokinetic of hydroxypropyl methylcellulose in the vitreous,” Journal of Ocular Pharmacology, vol. 6, no. 2, pp. 137–142, 1990. View at Google Scholar · View at Scopus
  97. J. Fernandez-Vigo, M. F. Refojo, and T. Verstraeten, “Evaluation of a viscoelastic solution of hydroxypropyl methylcellulose as a potential vitreous substitute,” Retina, vol. 10, no. 2, pp. 148–152, 1990. View at Publisher · View at Google Scholar · View at Scopus
  98. F. H. Davidorf, R. B. Chambers, O. W. Kwon, W. Doyle, P. Gresak, and S. G. Frank, “Ocular toxicity of vitreal pluronic polyol F-127,” Retina, vol. 10, no. 4, pp. 297–300, 1990. View at Google Scholar · View at Scopus
  99. Y. S. Hwang, P. R. Chiang, W. H. Hong et al., “Study in vivo intraocular biocompatibility of in situ gelation hydrogels: poly(2-ethyl oxazoline)-block-poly(ε-caprolactone)-block-poly(2-ethyl oxazoline) copolymer, matrigel and pluronic F127,” PLoS ONE, vol. 8, no. 7, Article ID e67495, 2013. View at Publisher · View at Google Scholar
  100. G. A. Peymanl, M. D. Conway, M. Karacorlu et al., “Evaluation of silicone gel as a long-term vitreous substitute in non-human primates,” Ophthalmic Surgery, vol. 23, no. 12, pp. 811–817, 1992. View at Google Scholar · View at Scopus
  101. C. de Jong, E. Bali, J. Libert, and L. Caspers-Velu, “ADCON-L hydrogel as a vitreous substitute: preliminary results,” Bulletin de la Societe Belge d'Ophtalmologie, no. 278, pp. 71–75, 2000. View at Google Scholar · View at Scopus
  102. F. Cavalieri, F. Miano, P. D'Antona, and G. Paradossi, “Study of gelling behavior of poly(vinyl alcohol)-methacrylate for potential utilizations in tissue replacement and drug delivery,” Biomacromolecules, vol. 5, no. 6, pp. 2439–2446, 2004. View at Publisher · View at Google Scholar · View at Scopus
  103. S. Chaterji, I. K. Kwon, and K. Park, “Smart polymeric gels: redefining the limits of biomedical devices,” Progress in Polymer Science, vol. 32, no. 8-9, pp. 1083–1122, 2007. View at Publisher · View at Google Scholar · View at Scopus
  104. S. I. Kang and Y. H. Bae, “A sulfonamide based glucose-responsive hydrogel with covalently immobilized glucose oxidase and catalase,” Journal of Controlled Release, vol. 86, no. 1, pp. 115–121, 2003. View at Publisher · View at Google Scholar · View at Scopus
  105. S.-C. Chen, Y.-C. Wu, F.-L. Mi, Y.-H. Lin, L.-C. Yu, and H.-W. Sung, “A novel pH-sensitive hydrogel composed of N,O-carboxymethyl chitosan and alginate cross-linked by genipin for protein drug delivery,” Journal of Controlled Release, vol. 96, no. 2, pp. 285–300, 2004. View at Publisher · View at Google Scholar · View at Scopus
  106. H. Koo, G.-W. Jin, H. Kang et al., “A new biodegradable crosslinked polyethylene oxide sulfide (PEOS) hydrogel for controlled drug release,” International Journal of Pharmaceutics, vol. 374, no. 1-2, pp. 58–65, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. K. S. Soppimath, T. M. Aminabhavi, A. M. Dave, S. G. Kumbar, and W. E. Rudzinski, “Stimulus-responsive “smart” hydrogels as novel drug delivery systems,” Drug Development and Industrial Pharmacy, vol. 28, no. 8, pp. 957–974, 2002. View at Publisher · View at Google Scholar · View at Scopus
  108. I. R. Wheeldon, S. C. Barton, and S. Banta, “Bioactive proteinaceous hydrogels from designed bifunctional building blocks,” Biomacromolecules, vol. 8, no. 10, pp. 2990–2994, 2007. View at Publisher · View at Google Scholar · View at Scopus
  109. Y. Katagiri, T. Iwasaki, T. Ishikawa, N. Yamakawa, H. Suzuki, and M. Usui, “Application of thermo-setting gel as artificial vitreous,” Japanese Journal of Ophthalmology, vol. 49, no. 6, pp. 491–496, 2005. View at Publisher · View at Google Scholar · View at Scopus
  110. N. L. Cutler, “Transplantation of human vitreous: a preliminary report,” Archives of Ophthalmology, vol. 35, no. 6, pp. 615–623, 1946. View at Publisher · View at Google Scholar
  111. H. M. Katzin and J. Blum, “Transplantation of vitreous: a preliminary report,” British Journal of Ophthalmology, vol. 31, no. 12, pp. 760–766, 1947. View at Publisher · View at Google Scholar
  112. D. M. Shafer, “Human vitreous transplantation,” Annals of the Royal College of Surgeons of England, vol. 58, no. 1, pp. 25–33, 1976. View at Google Scholar · View at Scopus
  113. Q. Gao, S. Mou, J. Ge et al., “A new strategy to replace the natural vitreous by a novel capsular artificial vitreous body with pressure-control valve,” Eye, vol. 22, no. 3, pp. 461–468, 2008. View at Publisher · View at Google Scholar · View at Scopus
  114. Y. Liu, Z. Jiang, Q. Gao et al., “Technical standards of a foldable capsular vitreous body in terms of mechanical, optical, and biocompatible properties,” Artificial Organs, vol. 34, no. 10, pp. 836–845, 2010. View at Publisher · View at Google Scholar · View at Scopus
  115. X. Lin, J. Ge, Q. Gao et al., “Evaluation of the flexibility, efficacy, and safety of a foldable capsular vitreous body in the treatment of severe retinal detachment,” Investigative Ophthalmology & Visual Science, vol. 52, no. 1, pp. 374–381, 2011. View at Publisher · View at Google Scholar · View at Scopus
  116. X. Chen, Y. Liu, Z. Jiang, L. Zhou, J. Ge, and Q. Gao, “Protein kinase Cα downregulation via siRNA-PKCα released from foldable capsular vitreous body in cultured human retinal pigment epithelium cells,” International Journal of Nanomedicine, vol. 6, pp. 1303–1311, 2011. View at Google Scholar · View at Scopus
  117. K. Nishitsuka, Y. Kashiwagi, N. Tojo et al., “Hyaluronan production regulation from porcine hyalocyte cell line by cytokines,” Experimental Eye Research, vol. 85, no. 4, pp. 539–545, 2007. View at Publisher · View at Google Scholar · View at Scopus
  118. F. Sommer, K. Pollinger, F. Brandl et al., “Hyalocyte proliferation and ECM accumulation modulated by bFGF and TGF-β1,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 246, no. 9, pp. 1275–1284, 2008. View at Publisher · View at Google Scholar · View at Scopus
  119. Y. Kashiwagi, K. Nishitsuka, H. Takamura, T. Yamamoto, and H. Yamashita, “Cloning and characterization of human vitreous tissue-derived cells,” Acta Ophthalmologica, vol. 89, no. 6, pp. 538–543, 2011. View at Publisher · View at Google Scholar · View at Scopus