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New Dendritic Adhesives for Sutureless Ophthalmic Surgical Procedures
In Vitro Studies of Corneal Laceration Repair
Andrew J. Velazquez, MD;
Michael A. Carnahan;
Johannes Kristinsson, MD, PhD;
Sandra Stinnett, DrPH;
Mark W. Grinstaff, PhD;
Terry Kim, MD
Arch Ophthalmol. 2004;122:867-870.
ABSTRACT
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Objective To compare a biodendrimer adhesive with a conventional suture for repairing linear and stellate corneal lacerations.
Methods A keratome knife was used to create 4.1-mm full-thickness linear incisions (n = 36) and 3 x 4-mm full-thickness stellate incisions (n = 25) in the central cornea of enucleated human eyes. The incisions were sealed with either a suture or the biodendrimer adhesive. The globes were inflated with balanced salt solution, and the increase in intraocular pressure was monitored via a cardiac transducer until fluid leaked from each eye. This intraocular pressure reading from the transducer was recorded at the sight of any leakage through the wound (leakage pressure). By using the Wilcoxon rank sum test, the median leakage pressure was compared for each closure method, separately for each wound group. By using the 1-sided 1-sample t test, each mean leakage pressure value was compared with 34 mm Hg, which is the intraocular pressure under certain stressful physiologic conditions (eg, coughing and the Valsalva maneuver).
Results For globes that underwent a linear incision, the mean leakage pressure was 78.7 mm Hg for the sutured group and 109.6 mm Hg for the adhesive group. Globes that underwent a stellate incision had a mean leakage pressure of 57.8 mm Hg for the sutured group and 78.7 mm Hg for the adhesive group. All of these pressures showed a statistical significance from 34 mm Hg via a 1-sided 1-sample t test.
Conclusions The difference in leakage pressures for all 4 groups was statistically significant relative to 34 mm Hg. This suggests that either method of closure, adhesive or suture, can withstand physiologic increases in intraocular pressure postoperatively and that biodendrimer adhesives are able to seal large corneal lacerations.
Clinical Relevance The use of biodendrimer adhesives to repair a corneal wound constitutes a viable alternative clinical procedure to conventional sutures.
INTRODUCTION
In human patients, corneal perforations are repaired with sutures. However, the use of sutures has limitations and drawbacks. First, suture placement itself inflicts trauma to corneal tissues, especially when multiple passes are necessary. Second, sutures such as 10-0 nylon are not without problems. Suture material may incite infection, inflammation, and vascularization; corneal scarring is more prone to develop with inflammation and vascularization present.1 Third, because of uneven tension on the sutures, asymmetric healing and irregular astigmatism may arise.2 The postoperative integrity of the sutures may also be problematic, with suture loosening or breaking requiring timely removal. Last, a prolonged operative time and technical skill are needed for effective suture placement.
Tissue adhesives are an attractive alternative to sutures. Cyanoacrylate adhesives were first used in the 1960s by Webster et al3 in the repair of corneal perforations. These adhesives are an effective therapeutic option in certain ophthalmic settings. These settings include emergency treatment of small corneal perforations and prophylactic treatment of progressive corneal thinning disorders.4 The goal of tissue adhesive therapy frequently is to provide immediate restoration of structural integrity and occasionally to prevent further corneal thinning. In either case, corneal adhesives can lead to permanent corneal healing or at least offer temporary closure for the anticipation of further surgical intervention that may be necessary (eg, corneal patch grafting, lamellar keratoplasty, and therapeutic penetrating keratoplasty).5
However, corneal adhesives such as cyanoacrylate also have limitations with regard to their ease of applicability and effectiveness.6-9 The methods of application vary and can be cumbersome. The technique requires adept and delicate application of a precise amount of adhesive in a dry environment to facilitate wound closure. Therapeutic effectiveness is often restricted to small corneal perforations of usually less than 1 to 2 mm because of the inability to close larger perforations. Cyanoacrylates polymerize quickly into a hard and brittle material. Patients can experience discomfort from this material in the eye and, thus, a bandage contact lens is often used. Cyanoacrylate adhesives also become opaque when they polymerize, thus obscuring the view of the underlying structures. Furthermore, complications with corneal cyanoacrylate adhesives include cataract formation, corneal infiltrations, granulomatous keratitis, glaucoma, and even a toxic reaction in the retina.10-13
Recently, a photo–cross-linkable tissue adhesive composed of hyaluronic acid was reported for the repair of corneal lacerations. This adhesive formulation was applied to 38 experimental corneal linear and stellate wounds (size, 3 mm) in rabbits and subsequently irradiated with a low-intensity argon laser beam to produce a clear flexible polysaccharide hydrogel patch that sealed the wound. The corneal perforations were completely sealed and the anterior chambers had reformed by 6 hours in hyaluronic acid adhesive–treated eyes. There was no evidence of leakage at this or later times in 37 of the 38 eyes. The intraocular pressure (IOP) had increased to near normal levels by day 7 in all treated eyes. The clinical examination results showed minimal inflammation, and this observation was consistent with the histological findings.14 However, this adhesive is best for repairing full-thickness wounds, and is not effective for other ophthalmic surgical procedures.
Dendrimers offer innovative solutions to address tissue-engineering challenges such as the design of novel tissue adhesives. Unlike linear polymers, like cyanoacrylate or hyaluronic acid, dendrimers are composed of a specific number of branched repeat units that emanate from a central core (Figure 1A and B).15-17 The highly branched framework provides many peripheral functional groups that can be modified based on the desired application. In fact, through the proper selection of core and branched repeat composition and number of branched repeat units, dendrimers can be tailored for specific applications.18-22
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Figure 1. A, A fourth-generation dendrimer composed of glycerol and succinic acid. B, A first-generation dendritic polymer, derivatized with methacrylate moieties, composed of polyethylene glycol, succinic acid, and glycerol.
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We are interested in the design of biodendrimers (dendrimers that are composed of natural metabolites or materials known to be biocompatible) for medical applications.23-24 Recently, the synthesis of zero- to fourth-generation dendritic polymers composed of polyethylene glycol, succinic acid, and glycerol was reported.25 These dendrimers were derivatized with methacrylate moieties and tested as corneal adhesives. Based on mechanical properties and photo–cross-linking rates, the ([G1]-PGLSA-MA)2-PEG dendritic macromolecule (Figure 1B) was identified as a viable candidate for use as a corneal adhesive.
This study evaluates this new argon ion laser–activated biodendrimer adhesive for the repair of corneal lacerations in enucleated human eyes.
METHODS
Each enucleated human eye was held under the operating microscope so that the cornea was oriented upwards, facing the microscope. A 4.1-mm metal keratome knife (Alcon Laboratories, Inc, Ft Worth, Tex) was then used to make a full-thickness 4.1-mm linear incision in the central cornea in 36 eyes (Figure 2A). Of these eyes, 27 were repaired with our biodendrimer adhesive and 9 were repaired with 10-0 monofilament nylon (Ethicon, Inc, Somerville, NJ). A 3 x 4-mm full-thickness stellate incision was made in an additional 25 eyes. Of these eyes, 12 were repaired using the biodendrimer adhesive and 13 were repaired using 10-0 nylon. All wounds were positive for the Seidel sign and were not self-sealing incisions.
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Figure 2. A, Incision using a 4.1-mm keratome knife. B, Application of the adhesive. C, Application of the argon ion laser via a handheld probe.
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For the linear and stellate incision adhesive groups, approximately 15 to 20 µL of the biodendrimer was applied to the dried wound using a 30-gauge needle (Becton Dickinson & Co, Rutherford, NJ) attached to a 1-mL syringe (Becton Dickinson & Co). Attention was given to ensure that the adhesive was applied to the inner borders of the laceration and the surface of the corneal laceration. Dried wounds resulted in better control of the biodendrimer, whereas a wet surface resulted in dilution of the biodendrimer and difficult polymerization. By using a handheld probe, the argon ion laser (a diffuse beam; 200 mW; pulse duration, 1 second) (Coherent, Inc, Santa Clara, Calif) was used to polymerize the biodendrimer and form a semitransparent cross-linked gel, closing the wound (Figure 2B and C). A photoinitiator dye present in the biodendrimer solution was used to start the cross-linking reaction and to monitor the course of the photolysis reaction. After approximately 20 to 30 seconds, the solution turned from pink to clear, indicating that the reaction was complete and that the adhesive had formed a gel; therefore, polymerization was complete (Figure 3A). For the sutured group, 3 interrupted 10-0 nylon sutures were used to close the 4.1-mm linear incision using a needle holder and 0.12 forceps (Figure 3B). The stellate incisions were repaired using 4 interrupted 10-0 nylon sutures (1 suture on each branch of the incision).
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Figure 3. A, Appearance of the globe after the application of glue and laser. B, Appearance of the globe after suture placement.
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A cardiac transducer (Hewlett Packard, Palo Alto, Calif) was used to monitor the IOP of the repaired eyes, as done in similar experiments described in the literature.26 A cardiac transducer was primed and a 20-gauge needle (Sherwood Medical, St Louis, Mo) was attached to the end of the tubing leading from the bottle of balanced salt solution (Figure 4). The needle was then inserted into the optic nerve approximately 1 cm into the globe. The needle remained in the globe, and no movement was noted. It was not necessary to tie the needle and optic nerve together to secure the needle. The cardiac monitor was placed on an arterial pressure setting and adjusted to 0 mm Hg. A 30-gauge needle on a balanced salt solution–filled 5-mL syringe (Becton Dickinson & Co) was inserted through the sclera at the pars plana (ie, approximately 4 mm from the limbus). Balanced salt solution was slowly injected into the eye via a syringe pump (Hewlett Packard) to slowly increase the IOP as measured by the transducer. A handheld IOP-measuring device (Tono-Pen; Medtronic Solan, Jacksonville, Fla) was used to confirm the concordance of the transducer readings. Surgical eye spear sponges (Opticel; Wilson Ophthalmic Corp, Mustang, Okla) were used to wipe the laceration site to check for signs of leakage through the corneal wound. The IOP reading from the transducer was recorded when leakage through the wound (the leakage pressure) was observed.
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Figure 4. Arrangement of the experiment using a cardiac transducer to monitor the intraocular pressure of the repaired eyes. BSS indicates balanced salt solution.
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RESULTS
Linear sutured wounds were compared with linear wounds that received the biodendrimer adhesive. The mean, standard deviation, and median leakage pressures were compared for the 2 groups. The P value was calculated using the Wilcoxon rank sum test to determine whether the leakage pressures were statistically different between the 2 groups. This was similarly done for the globes that underwent a stellate incision.
The linear wounds that received sutures (n = 9) had a mean leakage pressure of 78.7 mm Hg (SD, 27.8 mm Hg). The median leakage pressure was 76.0 mm Hg. The minimum and maximum values were 20 and 117 mm Hg, respectively. Examination of the linear wounds that received the adhesive (n = 27) revealed a mean leakage pressure of 109.6 mm Hg (SD, 82.7 mm Hg). The median leakage pressure was 96.0 mm Hg. The minimum and maximum values were 16 and 360 mm Hg, respectively. The calculated P value for the median leakage pressure between these 2 groups was .39 by the Wilcoxon rank sum test.
The stellate wounds that received sutures (n = 13) had a mean leakage pressure of 57.8 mm Hg (SD, 28.9 mm Hg). The median leakage pressure was 51.0 mm Hg. The minimum and maximum values were 25 and 125 mm Hg, respectively. Analysis of the stellate wounds that received a polymer (n = 12) showed a mean leakage pressure of 78.7 mm Hg (SD, 59.6 mm Hg). The median value was 68.5 mm Hg. The minimum and maximum leakage pressures were 10 and 220 mm Hg, respectively. By using the Wilcoxon rank sum test, P = .43 was calculated using the median leakage pressure between these 2 groups.
By using a 1-sided 1-sample t test, we compared the mean leakage pressure for all 4 experimental groups with 34 mm Hg. We chose this IOP because it has been reported that the IOP increases up to 60% under physiologic functions such as coughing, the Valsalva maneuver, and exercising.27 There was a statistically significant difference in the mean leakage pressure for all 4 groups compared with 34 mm Hg: for stellate wounds that received an adhesive, P = .01; for stellate wounds that received a suture, P = .006; for linear wounds that received an adhesive, P<.001; and for linear wounds that received a suture, P = .001.
COMMENT
The mean leakage pressure was higher for the stellate and linear wounds that received the biodendrimer sealant compared with a suture. However, this difference in mean leakage pressure for both types of wounds was not statistically significant when the sutured corneas were compared with the corneas that received the adhesive. The linear and stellate wounds that received a polymer also had a higher standard deviation compared with globes that received sutures. Whether the incision was sutured or sealed, the wounds were secure. The repaired wounds were sufficiently strong to withstand leakage pressures measured in reference to an IOP of 34 mm Hg, which corresponds to normal physiologic stresses such as coughing, the Valsalva maneuver, and exercising.
With each use of the biodendrimer adhesive, our technique improves and we observe better outcomes. This adhesive is more user friendly and requires less technical expertise. The globes that received the dendritic adhesive had a higher mean leakage pressure, although this was not statistically significant. In addition, this sealant is elastic, which will reduce the likelihood for astigmatism, and is degradable because it possesses ester linkages, suggesting that cell migration into the wound can occur during healing. Other advantages of this biodendrimer adhesive over suture or cyanoacrylate adhesives include its control of polymerization, its transparency and elasticity, and its smooth rubbery texture when gelled. Possible future applications of our polymer may include its use in securing corneal transplants and dislocated laser-assisted in situ keratomileusis flaps or its use as a drug delivery vehicle. We are conducting in vivo studies on white leghorn chickens (Gallus domestica) with similarly constructed linear wounds that are either sealed with the photo–cross-linkable biodendrimer adhesive or sutured. In summary, this sealant holds promise as a replacement or supplement to standard sutures used in the repair of small and large corneal lacerations.
AUTHOR INFORMATION
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Corresponding author and reprints: Terry Kim, MD, Duke University Eye Center, Campus Box 3802, Erwin Road, Durham, NC 27710 (e-mail: terry.kim{at}duke.edu).
Submitted for publication July 9, 2003; final revision received October 22, 2003; accepted November 21, 2003.
This study was supported by grant R01 EY13881-01 from the National Eye Institute, National Institutes of Health, Bethesda, Md; the Pew Foundation, Philadelphia, Pa; and the Johnson & Johnson Focused Giving Program, New Brunswick, NJ.
Dr Velazquez had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
From the Departments of Ophthalmology (Drs Velazquez, Kristinsson, Stinnett, Grinstaff, and Kim) and Chemistry (Mr Carnahan), Duke University, Durham, NC. Dr Grinstaff is now with the Department of Biomedical Engineering and Chemistry, Boston University, Boston, Mass. The authors have no relevant financial interest in this article.
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