Tissue Adhesives
C. Stephen Foster
Coover and associates, studying the chemistry and characteristics of cyanoacrylate adhesives, published, in 1959, a seminal paper on the basic characteristics of these chemical compounds, including their adhesive properties (1). Carton and associates quickly exploited the first commercially available cyanoacrylate adhesive, Eastman 910 (methyl 2-cyanoacrylate monomer), modified with a plasticizer (a sebacate), a thickening agent (polymethylmethacrylate), and an inhibitor (SO2) for joining blood vessels in dogs (2). This began then the series of experiments in the use of cyanoacrylate adhesives and their interaction with tissues, and the exploitation of this “tissue glue” in medicine (particularly surgery) and dentistry. And although the original Eastman 910 product (indeed, all lower alkyl cyanoacrylate derivatives) proved to have considerable secondary toxic effects (all polycyanoacrylates release formaldehyde and other breakdown products as they interact with water and degrade), the search for less toxic tissue glues involved not only experimentation with higher-alkylated cyanoacrylates, but the potential medical utility of other adhesives of other categories, including epoxy adhesives, polyurethane adhesives, fibrin “glue,” and marine products.
As far as I can judge, Steve Bloomfield, an ophthalmologist in New York City, was the first to explore the potential utility of cyanoacrylate tissue adhesive for ocular use, engaging in a series of experiments in rabbit eyes using the Eastman 910 product in 1963 (3,4). Additional derivatives, particularly higher-alkylated forms of cyanoacrylate, were then prepared and studied, most notably by Lehman and associates at the Walter Reed Army Medical Center (5, 6, 7, 8, 9, 10). By 1969, higher-alkylated derivatives of cyanoacrylate were commercially available, and these were then systematically tested by Claes H. Dohlman of the Harvard Medical School, and his associates at the Massachusetts Eye and Ear Infirmary and, most notably, by his research colleague, Miguel Refojo of the Eye Research Institute in Boston (11, 12, 13, 14, 15). Researchers determined that the alkyl cyanoacrylate derivatives with four or more carbon atoms in the side chain, known to degrade very slowly, were much better tolerated by living tissues than the lower derivatives, such as methyl derivatives of cyanoacrylate. Refojo classified the tolerance level of the available cyanoacrylate adhesives in the following order: 1-decyl, N-octyl, N-atptyl, N-hexyl, N-butyl, and isobutyl 2-cyanoacrylate (16). N-butyl cyanoacrylate quickly became the standard against which all other tissue adhesives were compared. Robert Webster and Harvey Slansky and the rest of the Dohlman team at the Massachusetts Eye and Ear Infirmary were the first to report on the use of cyanoacrylate tissue adhesive for the closure of corneal perforations, reporting two cases in the Archives of Ophthalmology in 1968 (17). The same group, a year later, reported on an expanded series in which adhesives had been used in various applications in corneal surgery (18). Many others subsequently confirmed these early promising results (19, 20, 21), and the potential uses of tissue adhesive began to expand, to include not only the original indications of impending or actual corneal perforations, but leaking conjunctival filtering blebs, scleral defects, punctal occlusion, and temporary tarsorrhaphy.
INDICATIONS AND TECHNIQUES
The preeminent indication for the use of tissue adhesive in ophthalmology has been for impending or actual corneal perforation. This use alone of tissue adhesive in ophthalmology revolutionized the care of patients with corneal perforation or impending perforation, and actually set the standard of care for management of such problems, obviating the need for the so-called “keratoplasty à chaud” and allowing the surgeon to maintain the integrity of the globe, definitively deal with the underlying cause of the corneal ulcer, and allow the inevitably present inflammation of the eye to quiet. This in turn set the stage for elective keratoplasty for attempted visual rehabilitation, a strategy vastly superior, in terms of outcomes achieving the desired goal of successful grafting with improved vision, compared with keratoplasty à chaud.
Gluing the descemetocele or otherwise impending perforation is considerably easier than gluing a frank perforation,
and the technique for managing these two problems is strikingly different. Descemetoceles or deep ulcers can typically be managed very successfully through the following series of steps, which can be performed either at the slit lamp or under the operating microscope in the minor surgery room; I prefer the patient supine, so that I can work under an operating microscope with the benefit of gravity helping me to get the adhesive precisely where I wish it to be. I find the following steps to be particularly helpful in achieving the desired goal: firm adhesion of an extremely thin layer of adhesive that seals the corneal defect but does not produce a bump or bulge above the normal contour of the cornea. Adhesive adheres best to corneal basement membrane, less well to corneal stroma, less well still to conjunctiva, and least well to sclera and corneal epithelium. Therefore, I typically remove epithelium from an area surrounding the corneal ulcer, searching for normal basement membrane, approximately 1 mm in width, circling the ulcer, which will provide the primary point of adhesion for the tissue adhesive (Fig. 52-1). I remove debris from the ulcer crater, and dry the basement membrane. I then apply adhesive to the area, in very small (microdrop) aliquots, beginning with the denuded basement membrane, either with the supplied applicator of the product used or with a 23-gauge Angiocath catheter, needle removed, having used capillary attraction to “load” adhesive into the Angiocath from the supply source (Fig. 52-2). I try to ensure that all the ring of bared basement membrane is coated with an ultrathin layer of the adhesive, and then begin to apply tiny amounts of adhesive onto the naked stroma, making no specific effort to fill the divot, down to Descemet’s membrane. Packing the ulcer crater with glue can actually be counterproductive because ultimately one would like to have fibroblast proliferation, with good wound healing characteristics, new collagen production, and so forth. And although it may seem counterintuitive that the less glue used, the better the outcome, in fact the primary function of the glue is not to provide structural support for the cornea, but rather to prevent further proteoglycan and collagen degradation by excluding from the ulcerating area the source of such degradation: matrix metalloproteinases, including the “classic” collagenase delivered to the area through neutrophils, the primary source of which is the preocular tear film (22). I use a Weck cell sponge in the event that an inadvertent excess amount of glue, during any one attempt at glue application, appears, which can be, with very rapid movement, removed with Weck cell sponge; failure to be extremely rapid with the maneuver, however, can result in the Weck cell sponge becoming glued to the cornea, clearly a result that is not very desirable.
and the technique for managing these two problems is strikingly different. Descemetoceles or deep ulcers can typically be managed very successfully through the following series of steps, which can be performed either at the slit lamp or under the operating microscope in the minor surgery room; I prefer the patient supine, so that I can work under an operating microscope with the benefit of gravity helping me to get the adhesive precisely where I wish it to be. I find the following steps to be particularly helpful in achieving the desired goal: firm adhesion of an extremely thin layer of adhesive that seals the corneal defect but does not produce a bump or bulge above the normal contour of the cornea. Adhesive adheres best to corneal basement membrane, less well to corneal stroma, less well still to conjunctiva, and least well to sclera and corneal epithelium. Therefore, I typically remove epithelium from an area surrounding the corneal ulcer, searching for normal basement membrane, approximately 1 mm in width, circling the ulcer, which will provide the primary point of adhesion for the tissue adhesive (Fig. 52-1). I remove debris from the ulcer crater, and dry the basement membrane. I then apply adhesive to the area, in very small (microdrop) aliquots, beginning with the denuded basement membrane, either with the supplied applicator of the product used or with a 23-gauge Angiocath catheter, needle removed, having used capillary attraction to “load” adhesive into the Angiocath from the supply source (Fig. 52-2). I try to ensure that all the ring of bared basement membrane is coated with an ultrathin layer of the adhesive, and then begin to apply tiny amounts of adhesive onto the naked stroma, making no specific effort to fill the divot, down to Descemet’s membrane. Packing the ulcer crater with glue can actually be counterproductive because ultimately one would like to have fibroblast proliferation, with good wound healing characteristics, new collagen production, and so forth. And although it may seem counterintuitive that the less glue used, the better the outcome, in fact the primary function of the glue is not to provide structural support for the cornea, but rather to prevent further proteoglycan and collagen degradation by excluding from the ulcerating area the source of such degradation: matrix metalloproteinases, including the “classic” collagenase delivered to the area through neutrophils, the primary source of which is the preocular tear film (22). I use a Weck cell sponge in the event that an inadvertent excess amount of glue, during any one attempt at glue application, appears, which can be, with very rapid movement, removed with Weck cell sponge; failure to be extremely rapid with the maneuver, however, can result in the Weck cell sponge becoming glued to the cornea, clearly a result that is not very desirable.
After the desired adhesive result has been obtained, irrigation of the surface with balanced salt solution or physiologic saline provides assurance that all polymerization of the adhesive has occurred, after which a large bandage soft contact lens [e.g., the 18-mm Kontur (Kontur Kontact Lens Co., Richmond, CA)] must be applied, in an effort to ensure patient comfort; the glue surface is always extremely rough, no matter how elegant the adhesive application has been, and the wiping action of the upper lid with each blink produces the sensation of the eyelid wiping over sandpaper if a barrier, such as a contact lens, in not used. Glue that is properly applied in the previously described manner may remain in place indefinitely; I have patients with glue that has remained in place for 3 or more years (Fig. 52-3).
The technique appropriate for the cornea with a frank perforation differs from the preceding description in several important ways. The preparation of the site of most importance for glue adhesion (corneal basement membrane) remains the same, but because of the continual egress of aqueous from the site of perforation, it is virtually impossible to apply glue into the ulcer crater without instant polymerization of a bubble-type dome of glue. Therefore, unless specifically contraindicated, positioning a small air bubble into the anterior chamber, such that it occludes, by its surface tension, the site of perforation, preventing continual aqueous egress from the perforation site, can eliminate this problem, allowing the surgeon then to apply the glue in the manner described previously. Obviously, larger air bubbles would be required for larger perforations, and larger air bubbles then pose a risk of pupillary occlusion and high intraocular pressure. If for no other reason, we suggest that perforations larger than 1 mm not be managed with tissue adhesive, but rather with a blowout patch graft, amniotic membrane packing of the crater, or some other technique. Intraocular Healon for accomplishing this same goal may also be attempted, but one then also runs the risk of retained Healon producing significant spikes in intraocular pressure.
Tissue adhesive may also be used to close microperforations or leaks in conjunctiva, with the most notable example of the need for such a strategy being a leaking glaucoma filtration bleb. Maintaining glue on the site for a very long period of time is usually not necessary, and therefore preparation of the site of application need not be as meticulous and extensive as that described previously for the cornea. I simply have the patient massage the eye, softening it, and of course ballooning the bleb in the process. Five minutes later, the rate of egress of aqueous from the bleb leak site is usually less than before the massage, and after drying of the site of with a Weck cell sponge, one tiny drop from the applicator onto the site of the leak is usually sufficient for coverage of the leak. Application of the 18-mm Kontur soft contact lens then ensures stability of the glue, free from the rubbing action of the blinking upper lid, and also patient comfort.
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