Review pubs.acs.org/Biomac
Recent Progress in Using Biomaterials as Vitreous Substitutes Xinyi Su,†,‡ Mein Jin Tan,§ Zibiao Li,§ Meihua Wong,† Lakshminarayanan Rajamani,‡ Gopal Lingam,† and Xian Jun Loh*,‡,§,∥ †
Department of Ophthalmology, National University Hospital, 1E Kent Ridge Road, NUHS Tower Block, Level 7, Singapore 119228, Singapore § Institute of Materials Research and Engineering (IMRE), A*STAR, 3 Research Link, Singapore 117602, Singapore ∥ Department of Materials Science and Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576, Singapore ‡ Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751, Singapore ABSTRACT: Vitreous substitutes are crucial adjuncts during vitreo-retinal surgery for retinal diseases such as complicated retinal detachment, macular holes, complications of diabetic retinopathy, and ocular trauma involving posterior segment. In retinal detachment surgery, an internal tamponade agent is required to provide internal pressure for reattachment of the detached neurosensory retina. Current available options serve only as a temporary surgical adduct or short-term solution and are associated with inherent problems. Despite many years of intensive research, an ideal vitreous substitute remains elusive. Indeed, the development of an ideal vitreous substitute requires the concerted efforts of synthetic chemists and biomaterial engineers, as well as ophthalmic surgeons. In this review, we propose that polymeric hydrogels present the future of artificial vitreous substitutes due to its high water composition, optical transparency, and rheological properties that closely mimic the natural vitreous. In particular, thermosensitive smart hydrogels, with reversible sol to gel change, have emerged as the material class with the most potential to succeed as ideal vitreous substitutes, facilitating easy implementation during surgery. Importantly, these smart hydrogels also display potential as efficacious drug delivery systems.
1. INTRODUCTION The vitreous humor is a spherical transparent globular gel (weight ∼ 4 g, volume ∼ 4 mL), composed mainly of collagen and sodium hyaluronate, that occupies a significant volume in the eye. It is made up of 98% water and only adheres to the retina at three positions: (1) the surrounding area of the anterior border of the retina, (2) the macula, and (3) at the optic nerve disc. Water contact angle of the vitreous indicates that it is hydrophilic with values of about 25°. Approximately 85−95% of light of wavelength between 400 and 700 nm is transmitted by the vitreous humor. The vitreous humor is an important part of the eye that is primarily determining the clarity of our vision. Vitreous substitutes are crucial adjuncts during vitreo-retinal (VR) surgery for retinal diseases such as complicated retinal detachment (RD), macular holes, and complications of diabetic retinopathy. In RD surgery, an internal tamponading agent is required to provide internal pressure for approximation of the detached neurosensory retina to the retinal pigment epithelium (RPE). Clinically, the most common agents used for medium and long-term tamponade are expansile gases and silicone oil, while perfluoro carbon liquids are used as intraoperative temporary tamponading agents. Although these substitutes have some important characteristics such as optical clarity and chemical inertness, they are far from perfect substitutes and are associated with © XXXX American Chemical Society
many drawbacks and limitations. This has fueled intensive research into the development of an ideal biomaterial for a vitreous substitute. However, despite many years of research, an ideal candidate for long-term vitreous substitution does not exist yet. Thus, the development of an ideal vitreous substitute remains one of the most challenging and complex fields in ophthalmic research requiring the concerted efforts of synthetic chemists and biomaterials engineers, as well as ophthalmic surgeons. In this review, we give an overview of the vitreoretinal conditions requiring vitreous substitution postsurgery, as well as the limitations of common vitreous substitutes that are currently used in clinical practice or have been tested experimentally. Particular emphasis will be placed on the newest developments in polymeric gels, which have proven to be the most promising candidates on the horizon for long-term vitreous replacement.
2. RETINAL CONDITIONS REQUIRING VITREOUS SUBSTITUTION Retinal detachment (RD) is the fifth leading cause of blindness in developing countries1 and the most common vitreo-retinal Received: September 5, 2015 Revised: September 5, 2015
A
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Biomacromolecules condition requiring emergency corrective surgery. Global annual incidence of rhematogenous RD range from 6.3 to 17.9 per 100000 population,2 with a higher incidence in the elderly population.2a RD severely threatens visual acuity, but proper and timely VR surgery can restore visual acuity and permit limited improvement in vision-related quality of life.3 Many of the complicated forms of retinal detachment would need some form of internal tamponading. Macular hole is a defect of the foveal retina involving its full thickness from the internal limiting membrane to the outer segment of the photoreceptor layer.4 Visual dysfunction is often severe and out of proportion to the size of the macular hole, as it affects the central fovea. Global incidence of full thickness macular holes range from 7.8 to 16 per 100000 population, with increasing prevalence rates among the high myopes and the elderly.5 Treatment involves the surgical removal of tangential vitreo-macular traction (via vitrectomy) and peeling of the inner limiting membrane (ILM) along with internal gas tamponade.3 Prevalence of diabetes is increasing dramatically, posing a serious public health issue. Globally there are 100 million patients with diabetic retinopathy (DR), of which 30 million have severe stages of DR. End-stage diabetic eye disease is an important cause of severe visual impairment in the working age group. The cumulative incidence rates of diabetic vitrectomy for diabetic patients with proliferative diabetic retinopathy were 1.6% after 5 years and 2.9% after 10 years (57% of which are due to tractional RD).6 The complexity of these cases often requires the use of internal tamponading agents such as gas or silicone oil. The incidence of vitreo-retinal pathologies is likely to increase with the increasing prevalence of diabeties, myopia, and a rapidly aging global population.2c The economic burden of VR surgery is not trivial, as the cost of each surgery varies from U.S. $4048 to U.S. $9607.7 Lastly, ocular trauma due to blunt injury or penetrating injury, often results in extensive damage to structures of the eye. They require repair with complex vitreo-retinal retinal procedures, using both temporary and long-term internal tamponade agents, albeit with poor visual prognosis.8 Ocular trauma is the leading cause of blindness in the United States, particularly in children and young adults.9 Approximately 75% of people with trauma-induced visual impairment are monocularly blind.8. One important step in VR surgery is to provide internal tamponade to facilitate the reattachment of retina (Figure 1).
Figure 1. Schematic diagram of endotamponade provided by intraocular gas bubble during vitreo-retinal surgery. (A) Detached retina due to presence of subretinal fluid entering through a defect in the retina. (B, C) Introduction of gas bubble intraocularly, to tamponade the detached retina to facilitate reattachment. Note that the gas bubble is situated superiorly (positional dependent). (D) Retina is eventually reattached as subretinal fluid is eventually pumped out from the subretinal space by the retinal pigment epithelium (RPE) cells.
carbons, such as perfluoroethane (C2F6) and perfluoropropane (C3F8).10 These gases are colorless, odorless, inert, and generally nontoxic. However, being in a gaseous phase, they are easily diffusible into the bloodstream, thus, making them suitable only as a temporary filler during surgery or short-term solution post surgery.11 Over time, they are eventually replaced by aqueous humor produced by the metabolism of ciliary bodies.11 SF6 and C3F8 have a longer permanence in the ocular cavity and are expansive in nature. SF6 expands twice its volume within 24 to 48 h, and exerts an effect for 1 to 2 weeks. C3F8, when injected in pure form during surgery, quadruples its volume within 72 to 96 h, and persists for 6−8 weeks. Briefly, these perfluorocarbon gases go through three phases namely: expansion, equilibration and dissolution. The initial expansion is due to diffusion of nitrogen and oxygen from tissues into the bubble. Rapid expansion is observed in the initial 6 h, reaching final volume by 48 h. This is the process of equilibration, whereby the amount of gases diffusing into the bubble and out of the bubble are equal. During dissolution, the volume of the bubble reduce progressively as all gas diffuses out slowly. This follows first order exponential decay.12 Importantly, these gases have a high surface tension, with a specific gravity lower than water, and are hence able to maintain a tamponade effect.10 However, these intrinsic characteristics that render them suitable as internal tamponade agents, also result in their pitfalls. The success of retina reattachment postsurgery hinges on the internal tamponade agent keeping the retina in place against the pigment epithelium for effective subretinal fluid resorption until chorioretinal adhesions are formed. Being gaseous compounds, the tamponade effect of SF6 and C3F8 is intrinsically linked to the dimension and position of the gas bubble and, therefore, by the position of the patient’s head.13 Unfortunately, this would imply that holes located in the inferior retina are not easily amenable to closure by intraocular
3. VITREOUS TAMPONADE AGENTS CURRENTLY USED IN CLINICAL PRACTICE Clinically, the most common agents used for medium and longterm tamponade are expansile gases and silicone oil, while perfluoro carbon liquids are used as intra operative tamponading agents. Although these substitutes have some important characteristics such as optical clarity and chemical inertness, they are far from perfect substitutes and are associated with many drawbacks and limitations. In this section, we will provide a brief overview of the currently available vitreous substitutes, segregated according to the state of matter they exist in. The reader is directed to reviews by Donati et al.1 and Swindle et al.2a and Baino et al.3 for a more detailed description of the current status. 3.1. Gas-Based Substitutes. Gas-based vitreous substitutes include air,2b sulfur hexafluoride (SF6), and perfluoro B
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Biomacromolecules gases.14 Rapid expansion of gas postsurgery causing an acute rise in intraocular pressure may result in sight threatening complication of central retinal artery occlusion. Furthermore, activities that result in the patient experiencing deviance in external pressure (such as air travel, rapid rise to altitudes by road or sea diving) must be avoided.4 The lower refractive index of SF6 and C3F8 compared to corneal tissue or aqueous humor causes almost complete reflection of light at the corneal−air interface. This poses a significant inconvenience to the clinician to examine the fundus or apply postsurgical treatment until the gas is reabsorbed. Lastly, the use of intraocular gas will inevitably result in cataract formation, necessitating a further cataract operation.15 3.2. Liquid-Based Substitutes. Liquid-based vitreous substitutes have been more extensively explored and thus cover a wider range of materials. Balanced salt solutions (BSS) have similar characteristics to aqueous humor, in terms of transparency, refractive index, and density, but lack sufficient tamponade properties (due to low surface tension) and longterm permanence to be a successful substitute.3 Thus, BSS is merely used as a temporary replacement for vitreous during vitrectomy until it is replaced by aqueous humor. Silicone oil (SO) is most frequently used for long-term retinal tamponade due to their chemical inertness and permanent optical transparency.5a Clinically, SO is indicated for complicated RD surgery, for example, giant retinal tears, presence of proliferative vitreoretinopathy, or tractional retinal detachment due to proliferative diabetic retinopathy.16 SO for ophthalmic use is a synthetic polymer belonging to the class of polydimethylsiloxanes. SO is viscous and transparent, with a specific gravity of 0.97 g/mL and a refractive index of 1.404. It has a wide range of viscosity from 1000−12000 centistokes, but 1300 and 5000 preferred for clinical usage. Its hydrophobicity (and thus good surface tension) provide for good tamponade effect, albeit less than that of gas. The surface tension of SO is approximately 40 mN/m. However, usage of silicone oils as a long-term substitute is not without complications. Complications results from emulsification of SO causing glaucoma, cataract, corneal damage, and “silicone retinopathy”, whereby fine emulsified material is known to impregnate into the retina.5b,17 Avoidance of these complications necessitates the surgical removal of the SO, which carries the inherent risk of retinal redetachment. Furthermore, complications also arise during the secondary removal process where the emulsified remnants “stick” to the retina leading to chronic retinal inflammation.5c Heavy silicone oils (HSO) consist of a combination of silicone oil and fluorinated alkanes. Similar to SO, they are transparent, of high viscosity, and have a higher density than water. Being chemically inert, they have less tendency to emulsify compared to SO.18 They have been used successfully as long-term tamponades, in particular, for inferior retinal detachments, due to their high density and stability. However, their removal requires high aspiration power due to their high viscosity. Any adherent SO to the retina surface “sticky oil phenomenon” may cause reactive inflammation.19 They also have similar disadvantages compared to SO such as cataract formation, risk of glaucoma, and corneal decompensation.20 Perfluorocarbon liquids (PFCLs) are synthetic, fluorinated carbon-containing compounds that comprise exclusively of fluorine−carbon bonds.2c These compounds are hydrophobic and immiscible with water, have low viscosity but are twice as dense as water.2c 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.21 Clinically, they are only suitable for use intraoperatively as temporary tamponades to unfold and stabilize the retina. Due to their tendency to emulsify and incite acute toxic inflammatory reactions, it is imperative to remove them at the end of the surgical procedure.4,22
4. EXPERIMENTAL VITREOUS SUBSTITUTES Evident from our prior discussion, the current clinically available vitreous substitutes are far from perfect, with multiple associated drawbacks and limitations. The search for the ideal vitreous substitutes still remains. Earlier clinical research has attempted to develop vitreous substitutes with similar molecular structure (elasticity, optical clarity) and physiological properties (to allow diffusion of metabolites, biocompatibility) to the native vitreous. This approach has led to research toward functional biomimicry: the use of synthetic molecules to mimic the rheological function of vitreous. However, these efforts are hampered by intrinsic toxicity of these synthetic compounds, as well as their inability to provide sufficient internal tamponade for VR surgery. Thus, their application to the eye has been limited.23 To overcome these obstacles, recent biomedical material research in this field has focused on the development of biocompatible, injectable hydrogels, which are also able to serve as medium and long-term internal tamponading agents. In addition, these materials due to their tunable porous matrix structure, have the potential for the therapeutic delivery of cells and bioactive molecules through drug encapsulation. These materials are especially useful for applications as vitreous substitutes due to their tunable porous matrix structure, controllable degradation, and drug encapsulation and release potential. In the rest of this review, we will provide a brief overview of polymers developed so far, with a focus with emphasis on the use of various hydrogel-based systems for vitreoretinal therapies. Briefly, the ideal vitreous substitute should possess all if not most of the following characteristics: Physical properties: 1. Transparent to facilitate visualization of fundus details, permit laser photocoagulation and afford some vision to patient. 2. Easy to inject and easy to extract (if needed). Best if it is absorbable due to bio degradation. 3. Sufficient surface tension to be able to close a retinal break. Biological properties: 1. Nontoxic to retinal tissues. 2. Cataract formation, if occurs, should not be instantaneous. Delayed cataract formation after several months is acceptable, as cataract removal can be performed as in a secondary surgical procedure. 3. Biodegradable, that is, degraded into nontoxic components that are easily absorbed into bloodstream. These degraded molecules should be small in size and should not block the aqueous drainage system. 4. Time to start of biodegradation should be amenable to clinician’s fine-tuning (to suit the time needed for internal tamponade). C
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similar inflammatory effects as HA implants and had a longer biodegradation duration, thereby indicating a more suitable filling material in the vitreous cavity.7b Some other polysaccharide materials, such as dextran, alginate, and chondroitin sulfate, have been also studied as vitreous substitutes in both animal models and humans, and no or only mild inflammation effects were reported.3,7c However, the above-described vitreous substitutes are not effective due to their tendency toward rapid degradation and low viscosity, as well as poor tamponade effect. Collagen and its derivatives (such as gelatin), the other main component in the natural vitreous, have also been evaluated for vitreous substitution. As early as 1960s, polygeline, a polypeptide derived from degraded gelatin, were implanted in both rabbits and human eyes, and the material was well-tolerated without adverse tissue reactions and even promoted immediate retinal reattachment in most patients.7c,24 Like HA materials, polygeline exhibited a short retention time in the vitreous cavity, which limited its application only as a short-term vitreous substitute. To mimic the nature of vitreous, a mixture of HA and collagen was injected into the rabbit vitreous after vitrectomy. Results revealed that mixing HA with collagen enhanced the half-life of the mixed materials and the substitutes caused no adverse effects on the ocular tissue even after 3 months.25 Methylated collagen (type I/III) was injected into the eyes of New Zealand white rabbits to evaluate its ocular tolerance. It was found that methylated collagen is tolerated by the rabbits’ eyes and it could be left in the vitreous cavity and does not cause toxicity to the retina.26 Although above studies showed the advantages of natural polymers as vitreous substitutes, there are still some concerns. Most natural polymers have a lower density than water, which limits their usage for inferior retinal tamponade. The rapid degradation rate remains the major issue for these biopolymer-based substitutes. Even with cross-linking, these biomaterials still tended to undergo degradation and lose their physicomechanical features in a short time. The biodegradation rate of the HA implants highly depends on its sources, molecular weight, and chemical structure, and most of them can only retain for 2−5 months.27 Therefore, such potential substitutes are only suggested for short-term use. Unlike HA, which is biocompatible, collagen has been observed to cause severe inflammatory response resulting in moderate to severe ocular pain.3,7c Moreover, collagen gels tend to fracture during injection, often losing their original structures and functions after implantation.3,7c In summary, the use of readily available derivatives such as HA and collagen (as opposed to that derived in vivo) are unsuitable for clinical use as they degrade too quickly, possess low viscosity, and have poor tamponade effect;6b moreover, it is also too costly to produce biograde derivatives for mass market use. 4.2. Synthetic Hydrogels. 4.2.1. Poly(meth)acrylateBased Hydrogels. Polymeric hydrogels present the next step toward reaching the ideal vitreous substitute. These materials are hydrophilic polymers that form a gel network when crosslinked and are capable of absorbing and swelling in the presence of water.28 Poly(1-vinyl-2-pyrrolidone) (PVP),29 polyacrylamide (PAA),30 and poly(2-hydroxyethyl acrylate) (PHEA)5d all possess the required transparency and rheological properties, but were ultimately unsuccessful due to complications arising from inflammation and toxicity. Other polymers explored include poly(glyceral methacrylate) (PGMA)31 and hydroxypropyl methylcellulose (HPMC),32 but these exhibited short degradation time and were also not brought to the clinical phase. Polymers of greater interest include poly(vinyl alcohol)
5. Able to incorporate drugs in the substitute for slow release if needed. 4.1. Natural Polymer-Based Hydrogels. Natural polymers such as hyaluronic acid (HA) and collagen are obvious candidates for evaluation as vitreous substitutes as they are the main components of the native vitreous.5d They were believed to be the most promising substances in the development of new vitreous substitutes as they are hydrophilic compounds with much better compatibility compared to current hydrophobic synthetic tamponade materials.3,5d Indeed, HA and its derivatives, such as sodium hyaluronate, have been widely studied as vitreous substitutes in humans since the early 1970s.6a For example, a clear, easily injectable and highly viscous HA solution was obtained by extraction and purification of sodium hyaluronate at concentration of 0.9% (W/V). In a six-year clinical evaluation, this HA solution was used as a vitreous substitute in 294 eyes of 286 patients, and the biopolymer was found to be biocompatible6a and helpful in the preservation of corneal epithelial integrity and clarity during closed vitrectomy. Although it was found to be useful in conjunction with scleral buckling techniques in the previtrectomy era, its application following vitrectomy procedures, however, cannot be substantiated. An in situ hydrogel of gellan and HA (8:2 w/w) was evaluated for vitreous substitution. Gellan gum formed a gel formation at room temperature and maintained the gel integrity when increasing to body temperature, showing potential as vitreous replacement. However, the insufficient rheological and mechanical properties have limited its application. An attempt to improve these gel properties was made by increasing the cross-linking density. By adding CaCl2 to the gellan gum/hyaluronic acid mixture, a highly cross-linked hydrogel was obtained. With further optimization of the biophysical properties of the gel similar to that of the vitreous, it was felt that the HA gel might be a promising alternative to silicone oil as a short-term vitreous substitute.6b Its use has been limited due to their short degradation time and, hence, ineffectiveness as an intraocular tamponade. To extend the degradation period, HA was further modified to glycidyl methacrylate-hyaluronic acid (GMHA) conjugates and its further UV crosslinked hydrogel formation with N-vinylpyrrolidinone was evaluated as an artificial vitreous substitute. The clear and transparent hydrogel showed a refractive index similar to human vitreous, displayed a sufficient viscosity and elasticity for intraocular use, and degraded only a small amount (about 10%) over 1 month. Both in vitro and in vivo studies revealed excellent biocompatibility with retinal pigment epithelial cells and ocular tissues.7a In the case of HA crosslinked by dihydrizide, the hydrogels did not entirely prohibit harmful biological effects, especially in the cell viability staining. Another finding with the ADH-HA cross-linked gel was the slightly increased cellular mitochondrial activity. However, even with two different cross-linking, both biomaterials still tended to undergo degradation and lose their physicomechanical features in a short time. Besides HA, various polysaccharides have occasionally been studied as vitreous substitutes. Chitosan has been investigated as a potential vitreous substitute due to its similarity (in physiological characteristics) to natural vitreous. Results of in vivo studies on rabbits’ eyes indicated that the chitosan intravitreous tamponade had no obvious influence on the intraocular tissues and did not cause the fluctuation of intraocular pressures. Additionally, chitosan implants showed D
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Biomacromolecules (PVA),33 copolymers of PAA (CPA),34 and poly(vinyl alcohol methacrylate) (PVA-MA),35 as well as poly(2-hydroxylethyl methacrylate) (PHEMA).36 These polymers have so far shown good transparency, rheological properties, and more importantly, biocompatibility; however, further clinical studies are needed to ascertain their long-term stability and compatibility.37 Nonetheless, polymeric hydrogels also hold the potential of being drug eluting carriers, thus, not only providing sufficient tamponade, but also supplying nutrients and drugs to aid in recovery.38 It should be noted that most of these polymers exist in the gel state and, in many cases, tend to lose its structural integrity through fragmentation when injected through a small-gauge needle.38 In the case of PHEMA, it is not amenable for introduction into the eye through a small bore hole during vitreo-retinal surgery, thus, necessitating a large surgical wound for implantation that increases the complexity of surgery and induces greater trauma to the eye.39 Therefore, a suggested alternative would be to first inject the soluble monomers, followed by the cross-linkers and initiators (chemical or physical such as oxygen or light) to form a gel in situ. A classic example is the use of acrylamide monomers cross-linked via disulfide cross-linkers under air oxidation.34 Related to this work, acrylamide hydrogels containing disulfide bonds were prepared by free radical polymerization in aqueous ethanol.40 Liquefaction of the hydrogels was accomplished using dithiothreitol to produce water-soluble acrylamide copolymers containing pendant thiol groups. Regelation of the aqueous solutions of thiol-containing copolymers were oxidized with 3,3′-dithiodipropionic acid or air to reform the hydrogels. Rapid endocapsular gelation yielded optically clear gel within the lens capsular bag. Although the resultant in situ gel showed excellent rheological properties and biocompatibility, acrylamide monomers are toxic and carcinogenic.41 Any unreacted monomers can cause severe irritation and inflammation. Furthermore, the gelation time required was estimated to be 1 h. PVA-MA is also known to be polymerizable using a photoinitiator to form clear hydrogels. This methacryloyl derivative increased the hydrophobicity of PVA with increasing methacrylate content, while the polymer backbone remained hydrophilic enough to form a hydrogel upon irradiation. Interestingly, the degree of cross-linking could be modulated by varying irradiation time and photoinitiator content. It showed that hydrogel degradation occurred in the presence of a low degree of cross-linking. Therefore, potentially suitable PVA-MA hydrogels were deemed to be those synthesized at high polymer concentrations and with a high degree of cross-linking. However, such gels were found to be significantly stiffer than natural vitreous. In addition, the efficacy of utilizing a UVA wavelength light during surgery is not proven and the full understanding of PVA-MA properties in vitro and in vivo must be made to evaluate vitreous biomimicry and biocompatibility.35 Feng et al. reported the development of foldable capsular vitreous body (FCVB) tamponade with 3% PVA hydrogel (Figure 2).42 This material preserves its stability and transparency in the vitreous cavity for at least 6 months. The team observed that the FCVB effectively lengthens the PVA hydrogel retention time and significantly enhances its stability performance in the vitreous cavity. The team further proposed the potential development of the FCVB with other hydrogels, such as PVP or PAA tamponade. Particularly, the structural properties including degradation behavior and mechanical strength can be modulated by cross-linking density. Further-
Figure 2. (A1−A3) FCVB-supported retina operates perfectly in the vitreous cavity after 180 days, and the FCVB injected with 3% PVA hydrogel was clear and transparent. (B1−B3) The vitreous cavity in the PVA group was still full of 3% PVA hydrogel after 90 days, and the 3% PVA hydrogel remained very clear and transparent. (C1−H2) Histology revealed the normal structure and cell morphology of the cornea, ciliary body, and retina in the three groups’ eyes after 90 days and 180 days. H3: Retinal disorder was seen in the PVA + FCVB group eyes after 180 days. The retina displayed an aggregation of the inner nuclear layer and the outer nuclear layer and a thinning of the ganglion cells layer. (H&E staining: conera and ciliary body, ×100; retina, ×200). Reprinted with permission from ref 42. Copyright 2013 Macmillan Publishers Ltd.: Scientific Reports; http://www.nature. com/srep/.
more, the addition of therapeutics to the hydrogels could also provide clinicians with a slow-release drug device. 4.2.2. PEG-Based Hydrogels. In another approach, the aqueous sols of poly(ethylene oxide) were tested as potential vitreous substitutes in an in vivo rabbit model.43 Aqueous solutions of 5 wt % poly(ethylene oxide) with a molecular weight of 400 kDa were viscoelastic fluids with similar physical and optical properties to natural vitreous. These solutions were well tolerated by the retina. The authors did not observe significant histological or electrophysiolosical changes, except for the upregulation of glial fibrillary acidic protein (GFAP) expression over 6 weeks. It appears that the solutions did not remain in the posterior body throughout the postoperative period showing that the use of a cross-linked poly(ethylene oxide) hydrogel as a potential artificial vitreous substitute could be better suited. In another work, the development of a novel injectable PEG-based vitreous substitute for intraocular E
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realization of a simple surgical procedure. The flexibility in the hydrogels’ form or “smartness” lies in the use of supramolecular forces, that is, physical, noncovalent forces such as hydrogen bonds, hydrophobic interactions as the main driving forces for gel formation.48 The nonpermanence of these forces make the sol-to-gel transition reversible, therefore, making the secondary removal procedure (if required) to be just as facile. Furthermore, like polymeric hydrogels, these smart hydrogels can also function as drug eluting carriers with a greater control over the release profile of the payload via its stimuli response.49 Particularly, sensitivity to thermal environment (i.e., with temperature as the sole stimulus for the gelation with no other requirements for chemical or environmental treatment) would be favorable for vitreo-retinal surgery. Thermosensitive gels are easy to apply clinically, as they can be injected in liquid form at ambient temperature and gelates at physiological temperature upon contact with the eyeball. Recently, significant technological advances have been made to overcome the drawbacks of Pluronic F127. For example, a group of new biodegradable temperature-responsive hydrogel systems with improved rheological and biological properties was developed by incorporation of oligoester segments.50 In a typical example, Loh and co-workers reported a novel biodegradable thermogelling copolymer consisting of PHB, PEG, and PPG blocks (Figure 4).50e,f,51 Aqueous solutions of the PHB contained thermogelling copolymer underwent a sol−gel transition as the temperature increased from 4 °C to body temperature and showed a very low critical gelation concentration (CGC) ranging from 2 to 5 wt %. Such low concentrations ensure that the large majority of the formed gel is water, as well as reduces the costs involved when utilizing such copolymers as potential vitreous substitutes. Interestingly, the copolymer hydrogels were hydrolytically degraded in phosphate buffer at pH 7.4 and 37 °C for a period of up to 6 months, which was controlled by adjusting the copolymer composition.52 The drug release study showed that the release rate could also be tuned by the formulation and copolymer composition. Together with the good cell proliferation, the as-developed hydrogel could be potentially used as vitreous substitutes with minimized inflammation effects.52 In another report, Li and co-workers also developed a similar polyurethane-based hyperbranched copolymer by using trifunctional hydroxyl groups terminated PCL-triol as the branching unit.53 It was shown that the effect of hyperbranch architecture was more prominent in the gelation of the copolymers.50a,g,54 The aqueous solutions of copolymers exhibited thermogelling behaviors at gelation temperature of 30 °C and CGCs ranging from 4.3 to 7.4 wt % (Figure 5). The CGC values are much lower than Pluronic F127 copolymer (15−20 wt %). More importantly, cell viability assay with mouse fibroblast L929 cells yielded excellent viability, thus indicating its potential suitability as vitreous substitutes, though cell culture tests with retinal cells will need to be carried out first. Smart hydrogels responsive to other kinds of stimuli such as pH55 and glucose56 have also been reported. Recently, in-situforming zwitterionic hydrogel was synthesized and tested for its potential as a vitreous substitute (Figure 6).57 The surface of these polymers show excellent antifouling properties. Additionally, these hydrogels are biocompatible when administered subcutaneously in a mice implantation test. Nonetheless, these materials were developed to be drug delivery systems and further optimization in terms of rheological properties as well as in vitro cell viability tests
applications was described. 44 This gel is based on a thermosensitive hydrophobically modified poly(ethylene glycol). These polymers can form flower-like micellar aggregates, which associate above a given polymer concentration, giving rise to highly viscous fluids. This nontoxic polymer exhibits rapid gelation through the formation of highly interconnected hydrophobic domains leading to the constitution of a network structure to form a transparent gel in the vitreous cavity at body temperature. The gel provides adequate support for the retina, and allows light to reach the sensory elements at the back of the eye. Normal levels of postoperative intraocular pressure were observed (Figure 3).
Figure 3. (a; (i)) Retinal breaks were created by using a needle. (ii) From the sclerotomy port, a 21-gauge cannula connected to a syringe filled with PEG-based polymer was inserted near the detached retina. (iii) 25 wt % PEG-based polymer in saline was injected into the vitreous cavity. (iv) PEG-based polymer forms a transparent gel and provides the tamponade effect. (b) Changes in intraocular pressure (n = 10) after the implantation of the PEG-based gel. No significant differences are found between the PEG-based gel-injected eyes and the saline-injected eyes during the observation period. Reproduced with permission from ref 44. Copyright 2011 American Chemical Society.
4.3. Smart Hydrogels. Smart hydrogels on the other hand present the future direction and potential toward developing the ideal vitreous substitutes. These materials not only possess properties as exhibited by polymeric hydrogels, but also respond to external environmental stimuli such as temperature, pH, light, and ionic strength.45 As such, these smart hydrogels can be stored, prepared, and injected in a solution state and undergo in situ gelation via external stimuli. Early examples of such smart hydrogels used as vitreous substitutes include Pluronic F12746 and WTG-127;47 however, F127 was found to induce severe retinal toxicity, whereas WTG-127 exhibited a short degradation time and a tendency to drift under retinal tears before complete gelation. As such, new generation smart hydrogels need to be developed that not only mimic the optical and rheological properties of the natural vitreous, but also retain flexibility in its form to allow easy application for F
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Figure 4. (a) Structure of urethane-based copolymer; (b) Schematic of associated micelle model depicting network polymer packing gelation; (c) Photographs showing transition from solution at low temperatures, to a clear gel at 37 °C and turbid solution at 75 °C. Reproduced with permission from ref 50f. Copyright 2007 American Chemical Society.
Figure 5. (a) Structure of urethane-based multiblock copolymer; (b) Rheological measurements indicating the “crossover” point or gelation temperature; (c) Viability assay L929 cells incubated with variants of the multiblock copolymer using different polymer concentrations. Reproduced with permission from ref 50a. Copyright 2012 American Chemical Society.
results obtained from this model were similar to in vivo data collected from other studies.
with retinal cells need to be performed before being considered as suitable vitreous substitutes. Recently, a new model for in vitro assessment of novel vitreous substitute candidates was reported that presents a method of biocompatibility testing prior to more costly and cumbersome in vivo experiments.58 The biological impact of vitreous substitute candidates was studied using a retinal explant culture model. The gels were applied to explanted adult rat retinas in culture for up to 10 days. Hematoxylin and eosin staining of cryosections of the specimens together with the assessment of the immunohistochemical markers (GFAP, Vimentin, Neurofilament 160, PKC, Rhodopsin) and TUNEL were carried out. Reactions within the retina, including disruption of layers, cell death, and gliosis, can be observed with the explant culture system. The
5. CONCLUSIONS AND FUTURE PERSPECTIVES A concise overview of the progress in research devoted to the development of biomaterials as vitreous substitutes has been provided in this Review. Efforts toward the discovery of new biomaterials as vitreous substitutes have been recently motivated by the clinical drawbacks of the most commonly used agents used for medium and long-term tamponade such as expansile gases, silicone oil and perfluoro carbon liquids. The large number of clinical and academic studies cited and the different materials mentioned in this work reflect the breadth and depth of this field of study. The vitreous is a fundamental component of the eye, and the search for an ideal substitute is G
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third, the material should have long-term stability in a wet, oxygen-, and enzyme-rich environment. The eye (lens, cornea, and retina) possesses glutathione and other related enzymes (such as glutathione reductase and glucose-6-phosphate dehydrogenase) as the defensive protective unit of the eye, shielding against chemical and oxidative stress.60 Other enzymes that are present in the eye include the matrix metalloproteinases (MMPs), which are a family of proteolytic enzymes that maintain tissue architecture in the eye.61 MMPs are found in every tissue of the eye under conditions of health and disease. The presence of these enzymes could affect the stability of the materials that are implanted into the eye. Future materials development should place an emphasis and consideration of these factors as well. Polymeric hydrogels present the future of artificial vitreous substitutes due to its suitable chemical composition (main component is water), density, optical transparency, and rheological properties that can closely mimic that of the natural vitreous. Smart hydrogels in particular have emerged as the material class with the most potential to succeed as an ideal vitreous substitutes due to it not only possessing the properties of polymeric hydrogels, but with added functionalities, such as reversible sol-to-gel change due to external stimuli to facilitate easy implementation during surgery. Besides these, most of these smart hydrogels have shown efficacy as a drug delivery system, the mechanism and rate of drug release of these systems have to be studied in depth if it is desired to use this system for drug release in the eye. Further tests to prove its biocompatibility with retinal cells should also be completed prior to in vivo studies. In the assessment of the suitability of the polymeric hydrogels, not only must the materials properties be accurately and strictly examined, the clinical signs of the eye must also be examined in depth. For example, postoperative intraocular pressure has to be maintained as closely to normal values as possible. Slit lamp biomicroscopy should be carried out to observe for the detachment of the retina as well as the condition of the eye’s blood vessels, which are critical in determining the functionality of sight. Posterior segment optical coherence tomography can be used to provide an in vivo histological section of the retina, which will be used to detect any changes in structure of the retina, including the RPE and choroidal thickness. Color fundus photography (CFP) and fundus fluorescein angiography (FFA) can be used to detect any changes in the retina such as inflammation and pigmentation. All the basic information relating to the function of the eye must be present for an accurate assessment of the efficacy of such a synthetic system. A collection and thorough analysis of all this information will allow the well-informed clinician to determine a material’s ultimate suitability as a successful long-term vitreous substitute.
Figure 6. Transparency of zwitterionic hydrogels prepared with different cross-linkers (from left to right): (1) disulfide cross-link by H2O2; (2) thiol−ene Michael addition cross-link with PEGDA (MW 700); (3) thiol−ene Michael addition cross-link with α-PEG-MA (MW 2000). Reproduced with permission from ref 57. Copyright 2015 The Royal Society of Chemistry; http://dx.doi.org/10.1039/ C4TB01775G.
still an ongoing challenge. Current available options serve only as a temporary surgical adduct or short-term solution, coupled with inherent problems, too. Polymeric nanotechnology and self-assembly of soft materials, in particular, open new horizons in materials for vitreous substitute research and have been presented one of the most promising approaches for the production of effective vitreous substitutes. Soft materials such as hydrogels are well adapted for clinical use for minimally invasive surgical procedures.50b,59 Hydrogels may be derived from natural or synthetic sources. The physical or chemical cross-links designed within hold these highly hydrated networks together. The cross-links can be made biodegradable and stimuli-responsive to pH and temperature and can be engineered to deliver therapeutic cells and soluble factors in a sustained and controlled fashion. The successful use of hydrogel systems for clinical applications depends on biomimetic design and engineering, understanding the cell− material interactions, and material characteristics and their effect on cell fate and functions. The incorporation of biologically relevant tissue elements derived from our knowledge of cellular processes in the tissue environment of normal and injured/diseased tissue is critical to the compatibility of these materials to the body. Attention also has to be paid to the ease of adaptation in a clinical setting. Oxidative stress and inflammation are just some of the tissue and environment elements that have impact over the outcome of the biomaterialbased regenerative therapies. The formation of cataracts after intraocular surgery can occur due to the loss of the oxidant scavenging function of the natural vitreous. Future design of the vitreous substitutes could focus on the incorporation of antioxidant moieties such as vitamin E, carotenoids, bioflavonoids, and ascorbic acid. The main deficiency of vitreous substitutes based on natural polymers is their short residence time in the vitreous cavity. The reabsorption of the polymers take place far too quickly in the eye. On the other hand, the use of silicone oil has led to questions on the tolerability of the material and the leaching out of the oil to other parts of the eye leading to complications post-operation. For ophthalmic applications there exists stringent requirements for an in situ gel-forming system: first, an optically clear material is required; second, very low toxicity is a must; and
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[email protected]. Notes
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REFERENCES
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