The physical properties of OVDs are the result of chain length and intrachain, and interchain molecular interactions. It is important to realize that the diverse rheologic properties of any given OVD have a direct impact on the clinical characteristics of that particular material. A thorough understanding of these properties will allow ophthalmic surgeons the opportunity to choose an OVD that is task specific. For example, a specific substance may be selected because of its space maintenance qualities, its corneal endothelial protection qualities, or its coating qualities.

TABLE 1. Physical Properties of Viscoelastic Substances

TABLE 2. Physical Properties of Various Viscoelastic Materials

Viscoelasticity

Elasticity refers to the ability of a solution to return to its original shape after being stressed. The rheologic property of viscoelasticity is the essence of the usefulness of these materials as surgical tools in ophthalmology. Elasticity allows the anterior chamber to reform after deformation by depression on the cornea when external forces are released. A nonelastic solution, such as balanced salt solution (BSS), will show no such reformation after release of forces.

The terms viscosity and viscoelasticity are not synonymous. Viscosity, viscoelasticity, and pseudoplasticity are, however, interrelated. The amount of elasticity of an elastic compound increases with increasing molecular weight and greater chain length of the molecules. Unfortunately, comparison of the different OVDs with regard to elasticity is not easily made because of the different ways and nonuniform expression of values by the various manufacturers.

Viscosity

Viscosity (Table 1) reflects a solution's resistance to flow, which is, in part, a function of the molecular weight of the substance. Viscosity of OVDs is measured in centipoise (cPs) or centistokes (cSt), which are measures of the resistance to flow relative to a given shear force. Liquid solutions are generally considered to have viscosities of less than 10,000 cSt at rest, whereas solutions with resting viscosities greater than 100,000 cSt are gel-like. The higher the solution's molecular weight, the more it resists flow. Molecular weight, on the other hand, reflects the size of the solution's molecules. Viscosity is dependent on the degree of movement of a solution, which is also known as the shear rate, and varies inversely with temperature. The viscosity of a solution can be increased by increasing either the concentration or the molecular weight of the solution.

To facilitate optimal intraocular manipulation, an OVD should maintain space and protect tissues (possess a high viscosity at low shear rates), allow movement of instruments, aid in IOL (Intraocular Lens) implantation (possess a moderate viscosity at medium shear rates), and allow easy introduction into the eye through a small cannula (possess a low viscosity at high shear rates).² At the present time, no single OVD fulfills all of these requirements optimally.

Pseudoplasticity

Pseudoplasticity refers to a solution's ability to transform when under pressure, from a gel-like substance to a more liquid substance. The more pseudoplastic a material is, the more rapidly it changes from being highly viscous at rest to a thin, watery solution at high shear rates. A change in molecular structure accompanies this pseudoplastic behavior. In clinical terms, a high molecular weight, high viscosity OVD at rest (zero shear force) acts as an excellent lubricant and coats tissues and maintains space very well. When under the influence of stress (i.e., a high shear rate), however, the OVD will become an elastic molecular system behaving as an excellent shock absorbing gel. The highest shear rates occur when a solution is passed through a cannula, and viscosity becomes independent of molecular weight. When the molecules align themselves in the direction of flow, the viscosity is determined solely by the concentration. Pseudoplastic solutions, therefore, have a low viscosity at high shear rates and can be extruded easily through a small diameter cannular (27 or 30 gauge) (Fig. 1) It is important to emphasize that the viscosity of a viscoelastic substance at rest (0 shear rate) is a function of concentration, molecular weight, and the size of the flexible molecular coils of the material (Figs.2A and 2B). At high shear rates, the viscosity is independent of molecular weight and is determined mainly by the concentration.³

Surface Tension

The coating ability of an OVD is not only determined by the surface tension of the material itself, but also by the surface tension of the contact tissue, surgical instrument, or IOL. By measuring the angle formed by a drop of the OVD on a flat surface (the contact angle), the coating ability of a substance can be estimated. Lower surface tension and lower contact angle indicate a better ability to coat. In this respect, a solution of sodium hyaluronate has a significantly higher surface tension and contact angle than does a solution of chondroitin sulfate, sodium hyaluronate/chondroitin sulfate in combination, or HPMC, thus indicating these latter solutions provide superior coating.³ A comparison of the various physical properties of OVDs is summarized in Tables 1 and 2.

ViscoDispersive OVDs exhibit opposite characteristics. They possess lower viscosity and adhere well to external surfaces, for instance, tissues and instruments. These materials tend to break apart easily compared to cohesive materials, exhibit lower molecular weight, lower surface tension, and lower pseudoplasticity.

Although cohesiveness and dispersiveness are not measurable rheologic properties in themselves, they are useful constructs when considering the clinical behavior of OVDs.

Recently, a new descriptive term has been introduced by Arshinoff, “viscoadaptive.” This term refers to the ability of an OVD to adapt its behavior to the intended surgical task without the surgeon having to do anything except perform the task at hand. Unlike devices that fit one or the other of the previously mentioned categories, the viscoadaptive agent ideally functions as both, adapting its behavior to changing parameters in its environment. That changing parameter under most circumstances is the degree of turbulence present.

TABLE 3. Desired Properties of an Ideal OVD

Sodium Hyaluronate

Sodium hyaluronate (NaHa) is a biopolymer occurring in many connective tissues throughout the body, including both the aqueous and vitreous humors. Its basic structural unit is a disaccharide, joined by a β_1–4 glucosidic bond, which is linked in a repeating fashion with β glucosidic bonds to form a long unbranched chain. This mucopolysaccharide chain subsequently forms a random coil when placed in a solution, such as physiologic saline. As the concentration of large sodium hyaluronate molecules is increased (>0.5 mg/mL), individual molecular coils start to overlap and are compressed (Fig. 2). This crowding of the chains increases the chances for various noncovalent chain–chain interactions. This, in turn, causes a considerable increase in the viscosity of the solution. For example, the kinematic viscosity of a 2 mg/mL concentration of sodium hyaluronate in physiologic buffer is only in the 100-cSt range: at 10 mg/mL, it is in the 100,000 cSt range. Therefore, a fivefold increase in the concentration causes a 1000-fold increase in the viscosity of the solution. With this increase in viscosity, the elastic properties of the solution also increase. This forms the rationalization of Amvisc Plus and Healon GV. The elastic behavior of a concentrated (>0.5mg/mL) sodium hyaluronate solution is greatly dependent on the mechanical energy (shear force) applied to the solution. On a molecular level, this means that under the imposed strain, the polysaccharide coils slip by each other, and conformational and configurational rearrangements occur while the solution exhibits viscous flow (Fig. 2). The hyaluronate acid fraction (NIF-NaHa)⁵ used for ophthalmic procedures has a high molecular weight (2–5 million d), a low protein content (<0.5%), and carries a single negative charge per disaccharide unit.

This fraction is highly purified and has been shown to be sterile, nontoxic, nonantigenic,⁶ noninflammatory,⁷ and pyrogen-free. In primate vitreous humors, sodium hyaluronate has a half-life of approximately 72 days.⁸ In primate aqueous humors the half-life is 2 to 7 days depending on the viscosity.⁹ Clinical observations in humans have supported this result.

Chondroitin Sulfate

Chondroitin sulfate (CDS) is another biopolymer possessing viscoelastic characteristics and has been identified as one of the three major mucopolysaccharides in the cornea. Its structure is similar to hyaluronic acid, consisting of the same repeating disaccharide unit. CDS is of medium molecular weight in the range of 50,000 d. Chondroitin sulfate, like sodium hyaluronate, does not appear to be metabolized but is eliminated from the anterior chamber in approximately 24 to 30 hours.

Hydroxypropyl Methylcellulose

Hydroxypropyl Methylcellulose (HPMC) is yet another viscoelastic material used for intraocular procedures.¹⁰ Unlike the previous two compounds, it does not occur naturally in animals but is distributed widely as a structural substance in plant fibers, such as cotton and wood. It is a cellulose polymer composed of D-glucose molecules linked together by β-glycosidic bonds.

Special care must be taken in the filtration of this material to ensure a highly purified preparation, as Rosen et a1.¹¹ noted the presence of vegetable fibers and other contaminates in samples they examined. Methylcellulose is a nonphysiologic compound and, as such, does not appear to be metabolized intraocularly but is eliminated from rabbit anterior chambers in approximately 3 days. It is also quite hydrophilic and hence can be irrigated from the eye.

Healon®, Healon GV®, Healon 5®

The first commercially available sodium hyaluronate, Healon®, was developed by Balazs,¹² who sold the rights to Pharmacia. In 1958 Balazs suggested the use of hyaluronic acid as a vitreous substitute and, subsequently, two different ophthalmic preparations were developed. Etamucaine (Laboratories Chibert, Clermount-Ferrand, France), a bovine hyaluronic acid preparation of low viscosity and concentration, was found to be well tolerated as a vitreous replacement, despite a mild intravitreal inflammatory response.¹³

The second preparation, Healon®, truly initiated the age of viscosurgery. This high viscosity, high molecular weight sodium hyaluronate derived primarily from roosters' combs was developed and purified by Balazs et al.^7,8,12,14 to produce a specific noninflammatory fraction. In 1972, the first human intraocular injections of Healon into the vitreous and anterior chambers were reported, and its use in surgical procedures varying from vitreoretinal diseases to cataract extraction and keratoplasty was suggested. These suggestions have been pursued actively and, subsequently, OVDs have become an invaluable tool in a broad array of applications.

By increasing both the molecular weight and concentration, Pharmacia introduced Healon GV® (greater viscosity) in 1992. With a resting viscosity of 2,000,000 cSt (at least 10 times more viscous than most other viscoelastics), Healon GV® provides superior viscosity for particularly demanding surgery.¹⁵ Despite positive vitreous pressure, Healon GV® is able to create and maintain a deep anterior chamber where other OVDs may fail. (Three times the resistance to pressure as Healon® in the presence of high positive vitreous pressure). Procedures dealing with small pupils, pediatric cataract extraction, and capsulorhexis during positive vitreous pressure are facilitated with the use of Healon GV®. However, because of its highly cohesive nature, Healon GV® leaves the anterior chamber very quickly during irrigation/aspiration or phacoemulsification, leaving the corneal endothelium susceptible to compromise.

Pharmacia and Upjohn developed a new OVD, which they believe possesses all of the best properties of Healon GV® and yet is retained in the anterior chamber throughout the phacoemulsification procedure. Healon 5® is the result of this effort and has been described as the first viscoadaptive OVD by the manufacturer. When exposed to low flow rates, it behaves as a super-viscous cohesive device, like an enhanced Healon GV®. However, as flow rates increase, Healon 5® begins to fracture into smaller pieces, making its behavior mimic some of the properties of dispersive OVDs. The properties of Healon 5® allow this OVD to also provide excellent capacity to mechanically dilate and maintain dilation of the pupil during intraocular maneuvers. It was released for sale in the United States in early 2001.

Amvisc®, Amvisc Plus®

Amvisc® is another sodium hyaluronate product extracted from rooster combs. It was first distributed by Precision-Cosmet and is now distributed by Bausch and Lomb Surgical. Released in 1983, Amvisc® is slightly less viscous than Healon®. Amvisc Plus, a 1.6% sodium hyaluronate product with a higher viscosity than Amvisc®, is also available. The viscosity of Amvisc Plus® is 55,000 cps compared with Amvisc® (40,000 cps). This higher viscosity obtained by increasing the total concentration (16 mg/mL) and using a sodium hyaluronate molecule of lower molecular weight allows for improved space maintenance, tissue manipulation, and tissue immobilization when compared to Amvisc.¹⁶

AMOVitrax®

AMOVitrax® (Advanced Medical Optics) is a low–molecular weight OVD preparation of a highly purified, noninflammatory fraction of sodium hyaluronate dissolved in BSS. Despite the relatively low molecular weight, AMOVitrax® is highly concentrated, which provides for a significantly viscous material. Unlike other sodium hyaluronic compounds, AMOVitrax® requires no refrigeration with a shelf life of 18 months. AMO Vitrax® (like Viscoat®) possesses a lower viscosity than Healon® at rest (0 shear) but maintains its viscosity under medium shear, whereas Healon® decreases sharply in a linear fashion.

ProVisc®

ProVisc® (Alcon Surgical, Inc.) is a sterile nonpyrogenic, high molecular weight, noninflammatory, highly purified fraction of sodium hyaluronate dissolved in physiologic sodium chloride phosphate buffer. The hy-aluronate material is obtained from microbial fermentation by a purified proprietary process. In this respect, it is similar to the process involved in the sodium hyaluronate fraction of Viscoat®. Clinical testing demonstrates that ProVisc® is equal to Healon® in its efficacy for protecting the corneal endothelium and in its level of safety.¹⁷ Like Viscoat®, ProVisc® requires refrigeration.^14a

Viscoat®

Viscoat® is a 1:3 mixture of 4% chondroitin sulfate and 3% sodium hyaluronate manufactured by Alcon Surgical, Inc. The sodium hyaluronate fraction, like ProVisc®, is produced by bacterial fermentation through genetic engineering techniques. The chondroitin sulfate is obtained from shark fin cartilage. This combination of the compounds combines the higher viscosity and chamber-maintaining properties of sodium hyaluronate with the coating and cell protection properties of chondroitin sulfate. Koch, in a prospective randomized study, compared the endothelial protective effect of Healon® and Viscoat® during iris-plane phacoemulsification and posterior chamber phacoemulsification.¹⁸ In the iris-plane phacoemulsification group, Viscoat® provided greater corneal endothelial cell protection than Healon®. In the posterior chamber phacoemulsification group, however, no significant differences in cell protection were noted with both materials exhibiting excellent endothelial cell protection.

Ocucoat®

Ocucoat® (Bausch and Lomb Surgical) is a highly purified synthetic, nonprotein, nontoxic preparation of 2% HPMC. Ocucoat® has been marketed as a visco-adherent rather than a viscoelastic because of its significant coating ability and its relative lack of elastic properties. The reader must be aware that formulations produced by individual hospital pharmacies are not consistent proprietary products and can contain various solid particles, mainly vegetable matter remaining from the raw material.¹¹ Ocucoat® is manufactured from the highest pharmaceutical grade HPMC and is subjected to a special dual-filtration process. A study presented in 1988 verified that Ocucoat® is as free of particulate debris as Healon® (Smith SG, European Intraocular Implant Council Meeting, 1988). Because of its poor elastic properties, a larger bore cannula and increased infusion pressure are necessary for injection. Unlike other OVDs, Ocucoat® can be sterilized by autoclaving and stored at room temperature. Because the raw materials are ubiquitous, there is potential for decreased cost. The complex biotechnical processes required to ensure purity, however, may limit this.

Cellugel®

Cellugel® (Alcon Surgical, Inc.) is a sterile, nonpyrogenic, noninflammatory, single-use, OVD, of highly purified 2% HPMC supplied in a disposable syringe delivering 1.0 mL, packaged in a sterile peel pouch, and is terminally sterilized by autoclaving. Like Ocucoat®, Cellugel® can be stored at room temperature. Unlike Ocucoat®, Cellugel® has a 10-fold greater viscosity and 4-fold higher molecular weight. As a result, the ability to maintain space is greater with Cellugel® than with Ocucoat®, despite both being 2% HPMC.

TABLE 4. Clinical Uses of OVDs

A review of each of the OVD's attributes should make it apparent that the use of a single agent during most ophthalmic intraocular procedures is accompanied by compromises in surgical suitability. In phacoemulsification, for example, the ideal single OVD would offer a combination of cohesive and dispersive characteristics that would fulfill the range of needs through the course of the phacoemulsification procedure (Table 5).

TABLE 5. OVD Requirements During Phacoemulsification

Although a combination of agents can fulfill both cohesive and dispersive needs, the use of multiple agents may be cost prohibitive. Therefore, by employing a needs-specific approach that takes into account the surgical needs (requirements), surgeons can more astutely match agent with task to improve clinical outcomes. Healon 5® viscoadaptive is an attempt to provide both cohesive and dispersive properties in a single agent. Continued experience with this agent will determine whether this claim holds true.

The clearance of an OVD through the trabecular meshwork is believed to be dependent upon a combination of the material's viscosity and molecular weight.²² Theoretically, materials possessing lower viscosities and lower molecular weights clear the eye faster, thereby creating less intraocular pressure elevation.

Recently, our attention has been directed at the importance of early (1–8 hours) postoperative intraocular pressure measurements when evaluating the effects of Healon²³ and other OVDs^21,24 on postoperative intraocular pressure. Significant intraocular pressure spikes can be missed if only 24-hour postoperative measurements are taken.

Lane et al.²⁵ compared the early postoperative intraocular pressures after the use of Healon®, Viscoat®, and Ocucoat® in ECCE and IOL implantation. In this study, the Viscoat® and Ocucoat® groups were further randomized into subgroups in which the material was either retained at the conclusion of surgery or removed with irrigation/aspiration. The results of this study showed significant increases in intraocular pressure in all groups at the 4±1 hour postoperative period. At 24 hours all groups except for the Viscoat®-removed group showed significant elevations in intraocular pressures from baseline values. More recently, Ranier et al.^25a confirmed this, noting a significant IOP rise over baseline for both Healon 5 and Viscoat in the early postoperative period.

In an attempt to blunt the postoperative intraocular pressure rise, diluting, removing, and/or aspirating the OVD from the eyes at the conclusion of cataract surgery has been advocated by many.^{13,21,26–30} It must be stressed, however, that this procedure has been shown only to shorten or reduce the incidence rather than to eliminate the elevation of intraocular pressure.^28,29,31 Others recommend the use of pharmacologic prophylactic treatment in minimizing postoperative intraocular pressure rises. Acetazolamide,³² intracameral miotics, β-blockers, such as timolol^24,33 or levobunolol,³⁴ and/or pilocarpine 4% gel³⁵ have all been shown to be effective in reducing postoperative intraocular pressure.

It must be stressed, however, that all OVDs as well as the surgical procedure alone are capable of increasing the intraocular pressure in the early postoperative period. Removal of the viscoelastic substance and use of acetazolamide as well as other glaucoma medications, blunt intraocular pressure elevations but not in a predictable fashion. It is important to realize that the intraocular pressure response in any given individual after cataract surgery is, only in part, caused by which OVD is used.

Several other disadvantages of viscosurgery deserve brief mention. Because of the viscous nature and electrostatic charge of these materials, inflammatory and red blood cells may remain suspended in the anterior chamber after surgery, giving the appearance of a plastic anterior uveitis. Intraocular hemorrhage may also be trapped between the vitreous space and the OVD within the anterior chamber and hence mimic the appearance of a vitreous hemorrhage.³⁶

Calcific band keratopathy has occurred as a complication peculiar to the initial formulation of chondroitin sulfate-containing OVDs. Several investigators noted that postoperative subepithelial corneal deposits identified histochemically as calcium phosphate precipitates were associated with the use of the intracameral Viscoat.^28,37–39 Since the reformulation of Viscoat, this complication has not recurred.

Finally, OVD induced capsular distension syndrome was described by Davison⁴⁰ and Masket.⁴¹ In this condition OVD is retained at the conclusion of uneventful cataract surgery and becomes entrapped behind the IOL. As the anterior capsulorhexis adheres to the anterior surface of the IOL for 360 degrees and the entrapped OVD denatures, the IOL is forced anteriorly by the pressurized capsule, and the posterior capsule is distended posteriorly. Clinically, the patient complains of decreased distance, visual acuity, and improved near acuity due to the induced myopia from the forward shift of the IOL. By slit lamp examination a large space is noted between the IOL and posterior capsule while the anterior chamber is slightly shallowed. Intraocular pressure is usually normal, despite the shallow anterior chamber. Treatment usually involves YAG laser application to the anterior capsule from the edge of the capsulorhexis out peripherally to the edge of the IOL optic, which allows the OVD to escape anteriorly. Alternatively, the posterior capsule may undergo laser capsulotomy with escape of OVD posteriorly.

Widespread success in clinical situations has been achieved with the pure hyaluronate and combination hyaluronate sodium chondroitin sulfate material. Ocucoat® and Cellugel® possess the potential advantages of lower cost, no requirement of refrigeration, and a larger quantity of the material per unit (1 mL) while maintaining absolute purity because of the extensive refinement and filtration process. Because of the success of all of these products, a great deal of interest has been stimulated to develop other OVDs. We would expect that a number of new materials may become available in the coming years.

At the present time, no single OVD is ideal under all circumstances. For any particular surgical task, the surgeon should consider the multiple physiochemical characteristics of each OVD available as well as their desirable and undesirable clinic effects, and then choose the most appropriate substance. With our current armamentarium of OVDs the ophthalmic surgeon can now optimize the surgical result by selecting the OVD most appropriate for the procedure. As new materials are developed, and as our knowledge of the physical properties, clinical effects, and surgical indications are better defined, the selection process for choosing the best product should improve.

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