Viscosurgery A Viscosurgical Use in the

The concept and the early experiments using elastoviscous hyaluronan, and the development of the first purified preparation to replace the vitreus after surgery and to be used as a 'soft tool' to manipulate the retina in retinal detachment surgery as well as to be used as a viscoelastic protector of the corneal endothelium in corneal transplantation, were the work of the author and his co-investigators (7,8) and a group of eye surgeons, who carried out the first clinical trials in the late 1960s and early 1970s (9-12). By the end of the 1970s the use of the first highly purified, non-inflammatory fraction of Na-hyaluronan, NIF-NaHA (manufactured under the trade name Healon®, Biotrics, Inc., Arlington, MA) in retinal surgery and to protect the corneal endothelium during corneal transplantation was well established (13). At the same time the increasing use of intraocular plastic lenses to replace cataractous lenses was slowed down by the problem presented by accidental contact of the corneal endothelium with the plastic lenses. The contact with the plastic stripped off the corneal endothelial cells and, since these cells do not regenerate, the endothelium could not properly continue to function as a water pump for the corneal stroma, resulting in swelling and cloudiness of this tissue and, eventually, blindness. Since it was well established that the elastoviscous hyaluronan solutions used to cover the corneal endothelium during corneal transplantation act as a mechanical buffer over this sensitive cell layer, it was logical to use these solutions in cataract surgery to protect the endothelium (14). The elastoviscous hyaluronan solution was expected to be useful for maintaining a deep anterior chamber during the extraction of the cataractous lens and to facilitate insertion of the plastic lens. This made the surgery safer and faster. The first clinical results were reported in 1979 to ophthalmic surgeons specializing in surgery of the anterior segment of the eye (15). In rapid succession several papers were published using animal studies to explain how the corneal endothelium is protected (16) and how the use of hyaluronan decreases the damage to the endothelium in clinical practice (17,18). In the early 1980s, when the first books were published in German (19) and in English (20,21) on viscosurgery in the eye, the use of the first therapeutic hyaluronan preparation (Healon®, developed and first manufactured by Biotrics, Inc., Arlington, MA and later by Pharmacia AB, Uppsala, Sweden) was extended to vitrectomy; it was used during excision of preretinal membranes (22) or removal of foreign bodies (23) from the vitreus. Use of Healon® was reported in difficult cases of retinal detachment surgery (20) and corneal transplantation (24), in trabeculectomy to prevent flat anterior chamber (17) and in extra or intracapsular lens extraction and for the implantation of plastic lenses using a variety of surgical techniques (for reviews, see Refs. 25-28).

During the next two decades the use of ophthalmic viscosurgical devices (OVDs) and the surgical techniques developed to take advantage of their availability exponentially increased. At the same time clinical scientists increasingly utilized the rheological properties of various formulations of hyaluronan products, taking advantage of these properties for the best therapeutic use of OVDs. While Pharmacia (now Pfizer, Inc.) developed new Healon® formulations with greater molecular weight and elastoviscosity (Healon®GV and Healon®5), other companies marketed lower viscosity products as well as low viscosity hyaluronan mixed with chondroitin sulfate (Viscoat®, Alcon Laboratories, Inc.). Today, more than a dozen hyaluronan preparations with a variation of average molecular weight from 0.1 to 7 million and with a concentration of 1-3% hyaluronan compete for the attention of eye surgeons. Naturally the usefulness of this great variety of hyaluronan products depends on their rheological properties and the inventiveness of the ophthalmic surgeons who demand broad applicability and various performances from these OVDs.

It was observed in clinical use that the cohesiveness and solidity of the elastoviscous solutions affect their dispersibility and solubility under the influence of the mixing process provided by the mechanical manipulation of the instruments and the flow of the irrigation fluids (29,30). The OVDs have been recently classified according to their cohesiveness and dispersive properties under the mechanical stresses provided by surgical procedures. The classification was based on their therapeutic performance that was assumed to parallel their extrapolated zero shear dynamic viscosity. This parameter varied between 25,000 and 7 million milliPascal second (mPa s) in 14 hyaluronan products (1 mPa s is the viscosity of water at all shear values) (25). The problem with using zero shear viscosity for characterization purposes is that it neglects completely the elastic properties of the solution. We suggest using the coil overlap parameter of the solution (concentration times average molecular weight), which expresses the crowding of the molecules as the concentration and/or the molecular weight increases. Molecular crowding means the restriction of the domains of neighboring molecules and the resulting decrease of the molecular volume, i.e., the size and possibly the conformation of the individual molecules. These cooperative molecular properties (concentration and molecular weight) determine all the qualities that are important for the optimal viscosurgical performance of OVDs. Applying the coil overlap parameter for the 13 hyaluronan-based OVDs listed by Arshinoff (25) two major categories could be differentiated: five OVDs with a very high overlap parameter (70,000-172,000 g/cc) and eight with much lower values (12,000-20,000 g/cc). The extrapolated zero shear viscosity for the first five OVDs is between 0.5 and 7.0 million mPa s. The OVDs with significantly lower coil overlap parameters have 0.025-0.28 million mPa s viscosities (for details see Ref. 25). As expected, the greater the elastoviscosity (coil overlap parameter) the more cohesive and less dispersive the OVDs.

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