Effects of Monomeric Methylmethacrylate on Ocular Tissues

Effects of Monomeric Methylmethacrylate on Ocular Tissues

E F F E C T S O F M O N O M E R I C METHYLMETHACRYLATE ON OCULAR TISSUES P E T E R R. H O L Y K , M.D., A N D D A V I D E. E I F R I G , Chapel Hill...

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E F F E C T S O F M O N O M E R I C METHYLMETHACRYLATE ON OCULAR TISSUES P E T E R R. H O L Y K , M.D.,

A N D D A V I D E. E I F R I G ,

Chapel Hill, North

Polymethylmethacrylate has been shown to be nontoxic when implanted into a wide variety of tissues in experi­ mental animals. 1 - 7 Its use within the eyes of humans and laboratory animals has supported the concept that polymeth­ ylmethacrylate intraocular lenses are chemically safe. Whether the degradation or leaching of monomer from this poly­ mer occurs in sufficient degree to cause chemically related problems is unknown, though recent investigations suggest that it does not. 2 Processing methylmethacrylate in the manufacture of intraocular lenses does depolymerize it to some degree. The amount of monomeric methylmethacry­ late released has not been shown to cause damage to isolated tissues, 1 although ocu­ lar tissues have not been studied intense­ ly after exposure to high concentrations. 2 We designed this study to ascertain what type of damage occurs in eyes in the presence of various concentrations of monomer. If there is a "disease" pro­ duced by the slow leaching of monomeric methylmethacrylate, the recognition of its signs and pathologic characteristics is important in the clinical evaluation of long-term implanted lenses. We stud­ ied the sequence of events in monomer overdose in rabbit eyes to determine what damage occurs, the concentrations at which it occurs, and the clinical From the Department of Ophthalmology, Univer­ sity of North Carolina School of Medicine, Chapel Hill, North Carolina. This study was supported by Precision Cosmet Co., Minneapolis, Minnesota, and the Southern Medical Association. Reprint requests to David E. Eifrig, M.D., Depart­ ment of Ophthalmology, University of North Caroli­ na School of Medicine, Chapel Hill, NC 27514.

M.D.

Carolina

and pathologic characteristics of these changes. M A T E R I A L AND M E T H O D S

Unpolymerized methylmethacrylate containing hydroquinone inhibitor was washed with three successive washings in equal volumes of 2% sodium hydroxide. The monomer was then washed twice with equal volumes of distilled water, and allowed to dry in contact with anhy­ drous calcium chloride for 20 hours at 4CC to remove the inhibitor. 8 The monomer was analyzed by a gasliquid chromatograph with a treated silicone column. No detectable impurity was found. The monomer was stored in a multidose vial wrapped in aluminum foil at -10°C for the duration of the study. Sixty New Zealand white rabbits weighing approximately 3 kg each were divided into four groups of 15 each, and entered into the study at approximately one-month intervals. Each group was further divided into three subgroups cor­ responding to the three concentrations of methylmethacrylate under investigation: 0.05%, 0.5%, 5.0% by volume. In preparation for surgery, the rab­ bits were given ketamine HC1 (Ketalar), 30 mg/kg of body weight and 2 mg of acepromazine maleate, both intramuscu­ larly, followed after ten minutes by pentobarbital sodium (Nembutal), 15 mg/kg of body weight, intravenously. Each eye was examined before surgery with a sur­ gical microscope. The volume of the anterior chamber in the rabbit eye was estimated to be 0.20 ml. 9 The volumes of methylmeth­ acrylate needed to achieve the three ex­ perimental concentrations were calcu-

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lated to be: 0.1 JAI for 500 ppm, 1.0 |ud for 5,000 ppm, and 10.0 jxl for 50,000 ppm. Eyes were randomly selected for injec­ tion with methylmethacrylate; the other eye served as control. A 2-mm incision was made at the super­ ior corneoscleral limbus with a No. 11 Bard-Parker blade, and the anterior cham­ ber was entered. Because loss of aqueous was minimal, the anterior chamber re­ mained formed. The appropriate quantity of methylmethacrylate was injected into the aqueous, with a l-(xl Hamilton sy­ ringe for the 500 ppm groups and a 50-(JL1 Hamilton syringe for both the 5,000 ppm and the 50,000 ppm groups, and the nee­ dle was withdrawn. Closure of the inci­ sion was by slight pressure at the incision site for 30 to 60 seconds. The same procedure was done in the control eye, except that balanced salt so­ lution was used in place of the methyl­ methacrylate. The rabbits were examined with a sur­ gical microscope with a slit lamp attach­ ment. Examinations were carried out daily for one week, and then weekly until the animals were killed. Rabbits received ketamine for all examinations. Both the treated and the control eyes were examined at each sitting. The factors observed were: corneal edema, corneal neovascularization, protein, fibrin, or blood in the anterior chamber, iris en­ gorgement, cataract formation, limbal in­ jection, iris atrophy, and presence of visi­ bly detectable methylmethacrylate. The presence of these findings was quantitated as 0, Tr, 1+, 2 + , 3 + , 4 + when compared to preoperative appearance. 4 Two rabbits from each concentration group were arbitrarily assigned at the beginning of the study for killing at each of the following postoperative days: day 4, 7, 14, 28, 42, 56, 70, and 91. Rabbits were killed with an injection of pentobarbitol sodium. The eyes were then enucleated, and the

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central cornea removed, leaving a 1- to 2-mm limbal fringe of cornea on the globe. The 12 o'clock position of both globe and corneal button were marked with a suture, and stored separately in 4% paraformaldehyde at 4°C. The globes were processed with a tis­ sue processor after fixation in 4% parafor­ maldehyde for a minimum of one week. The eyes were embedded in paraffin, and 8-(x sections made. The tissue was stained with hematoxylin and eosin. The slides were examined and photographed. After storage in 4% paraformaldehyde, selected corneas were washed with diphosphate buffer. Samples 3 mm 2 were cut from the 12 o'clock, central, and 6 o'clock positions of both the treated and control corneas. The corneas were fixed in 2% osmium tetroxide for 90 minutes, and then progressively dehydrated with ethanol. Critical point drying was carried out under Freon; the sample was mount­ ed, coated with gold-paladium alloy, and the corneal endothelium was examined and photographed with a scanning elec­ tron microscope, operating at 20 Kv. 10 One additional experiment was per­ formed in an attempt to determine wheth­ er methylmethacrylate monomer could be found under polarized light. Methylmethacrylate monomer was pur­ posely injected into the corneal stroma, iris stroma, and the superior rectus mus­ cle. A small bubble equivalent to a 5% by volume dose was injected into the anteri­ or chamber as well. The rabbit eye was observed for two weeks, at which time the animal was killed, and the eye was prepared for fro­ zen section. It was then studied under the polarizing microscope. Although pathologic findings were sim­ ilar to the 50,000 ppm group microscopi­ cally, no evidence of methylmethacrylate monomer could be identified. The data generated by this study were manipulated in several ways to determine

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the degree of significance. Initially, the values generated from each observation of all three concentrations were equated and grouped as treatment eye and control eye. These data were then subjected to the paired comparison f-test. By using this analysis, each factor studied—corneal edema, corneal neovascularization, fibrin in the anterior chamber, iris engorgement, limbal injection, cataract, iris atrophy, and methylmethacrylate bubble—was significantly different to a level P < . 0 1 . Analysis of the data in this manner makes no allowance for the concentration dependence of the various factors. To take this into account the data for the treatment eyes were compared to the con­ trol eyes for each factor at each concentra­ tion. The data were analyzed b y using both the least square difference analysis and the more conservative Scheffe proce­ dure. In both analyses, the degree of difference between treatment eyes and control eyes in the 50,000 ppm group (5% by volume) was significantly greater than that between the treatment and the con­ trol eyes of the 5,000 ppm and 500 ppm groups. The degree of difference between the treatment eyes and the control eyes for the 5,000 ppm group was not significant­ ly greater than that of the 500 ppm group for any factor except limbal hyperemia. RESULTS

Postoperatively, the most striking ini­ tial clinical finding was the presence and severity of corneal edema. Our findings show that the severity of corneal edema as well as its duration are correlated to the amount of monomer in­ jected. In the 50,000 ppm group the treat­ ment eye would typically show 2 + to 3+ edema on the first postoperative day su­ periorly, diminishing in severity distal to the upper pole. The edema would lessen over a period of approximately seven days, and was only rarely present at 14 days.

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Fewer rabbits showed corneal edema in the 5,000 ppm groups, and those that did typically cleared in four to five days. The 500 ppm group only occasionally (10%) showed trace corneal edema which cleared rapidly. A few of 48 control eyes showed trace corneal edema which cleared rapidly and was in every case less severe than its companion treatment eye. Invasive vascularization of the cornea appeared superiorly as an extension of the limbal vasculature in a frequency and a severity that were both related to the amount of monomer injected. In the 50,000 ppm group, all but one treatment eye (rabbit killed day 5) showed corneal neovascularization, ranging from Tr to 3 + . Corneal neovascularization was seen as early as postoperative day 1, but typi­ cally began on postoperative day 3 or later. Although the incidence of corneal neovascularization was similar in the 5,000 ppm group, it was unusual to have more than trace vascularization. In the 500 ppm group the incidence was lower, the onset later, and the severity milder. Although corneal neovascularization did occur in the control eye (20/48 cases), the vessels were almost always limited to the surgical wound at the corneoscleral limbus. The treated eyes also had cases where the vessels were limited to the area of the surgical wound, but these were exceptional. Generally, the vascular inva­ sion of the cornea was more widespread in the treated eye. In contrast to corneal neovasculariza­ tion, "limbal injection" was an estimate of the degree of engorgement of the normal vasculature at the corneoscleral limbus. This factor, too, appeared to correlate in severity to the amount of methylmeth­ acrylate injected, but only in the immedi­ ate postoperative period (first week). Thereafter, this factor seemed to vary a great deal. Reactions of the anterior chamber were limited to formation of fibrin (Fig. 1).

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Fig. 1 (Holyk and Eifrig). The rabbit iris and anterior chamber taken one day after injection. Note the vascular engorgement of the surface of the iris and the fibrin clot that overlies the anterior surface of the lens.

There was no generalized bleeding in the anterior chamber. In cases where fibrin was seen in the 500 ppm group or in control eyes it would always be in the area where the surgical incision had pen­ etrated the corneal endothelium. This was also true of the majority of the fi­ brin reactions in the 5,000 ppm group, although several showed reactions of the type described in the 50,000 ppm group. In the 50,000 ppm group the fibrin would form primarily around droplets of methylmethacrylate. On the first few postoperative days the fibrinous reaction could be seen surrounding the area where the remaining methylmethacrylate bub­ ble was, or had been. Most frequently the formation would be at the superior pupil­ lary margin, often involving the iris and anterior lens capsule (Fig. 2). Engorgement of the iris vessels was also proportional to the amount of meth­ ylmethacrylate injected (Fig. 1). Although it was not at all unusual for both treat­ ment and control eyes to show engorge­ ment of the iris, the severity of the en­ gorgement was markedly more pro­ nounced among 50,000 ppm treatment eyes than among the other groups. The duration of pronounced iris engorgement

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also increased with increased monomer dosage. One characteristic of iris engorgement that was true of both treatment and con­ trol eyes was that the last place for the engorgement to disappear was almost in­ variably superiorly, near the 12 o'clock position (Fig. 1). One could speculate that this is related to the surgical procedure, although the reason for this is not clear, since great care was taken not to touch iris or lens with the needle at injection. Perhaps the most significant finding clinically was the presence of two types of iris lesions. One lesion appeared as a thinning of the iris at the pupillary mar­ gin, the other as a scar deforming the normal architecture of the iris. These le­ sions were seen in 12 of 16 treated eyes at 50,000 ppm, invariably in the area where a fibrin clot had been originally, or at the superior pupillary margin where a methylmethacrylate bubble had settled (Fig. 2). The lesions were seen as early as postoperative day 3, but more usually developed by postoperative day 7. The lesions were seen in only three eyes at 5,000 ppm of methylmethacrylate mono­ mer and were always mild in these cases. There was no evidence of iris atrophy in the 500 ppm or control eyes (Fig. 3). Methylmethacrylate monomer also pro­ duced cataracts. Although it is difficult to ascertain exactly how early they form postoperatively because of corneal edema and fibrin in the anterior chamber, there are large anterior subcapsular cataracts formed by postoperative day 2 in the 50,000 ppm group. Both the incidence and size of cataracts increase with in­ creasing monomer dosage. Thirteen of 16 rabbits in the 50,000 ppm group had anterior subcapsular cataracts, many of them obscuring at least 50% of the pupil­ lary aperture. In the 5,000 ppm group, only three treated eyes developed cata­ racts, all of them small. There were no cataracts in the 500 ppm or the control eyes.

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Fig. 2 (Hdlyk and Eifrig). The iris and pupil in a rabbit eye 49 days after injection of 50,000 ppm methylmethacrylate monomer. Within the pupil there is an anterior subcapsular cataract, a dark area of organized fibrin and, at the 1 o'clock position in the pupil an area of iris atrophy. This is the same area as sliown in Figure 6.

At surgery, when the injections were made, the methylmethacrylate could be seen as bubbles of varying size depend­ ing on dosage that would float to the center of the corneal endothelium. In the control eye^ there was a slight turbidity on injection of the balanced salt solution. Seven of 16 eyes receiving 10 pj boli of methylmethacrylate (50,000 ppm) showed traces of the plastic material on postoperative inspection. In most cases the monomer was seen as tiny droplets surrounded by fibrin on the iris at the pupillary margin. Alternately, the mono­ mer could be seen until postoperative day 2 encapsulated in the dense fibrin in the anterior chamber, and then would no longer be detectable. Only three eyes re­ ceiving 1 u.1 boli (5,000 ppm) showed methylmethacrylate bubbles on postoper­ ative examination. In all cases, none was present beyond postoperative day 2. None of the 0.1 (xl bolus (500 ppm) droplets could be seen on postoperative exam­ ination. At killing, every effort was made to

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Fig. 3 (Holyk and Eifrig). Comparative photo­ graph of the iris and pupil of the control eye from the same rabbit as in Figure 2. Note that the iris sphincter is regular and that the iris appears normal.

transfer the tissues to paraformaldehyde as rapidly as possible to preserve them in a fresh state. The globes were exam­ ined and cut for sectioning to maximize the yield of sections showing areas of iris pathology. The control eye counter­ part of each rabbit treated eye studied was sectioned as well. Microscopic exam­ inations concentrated on the anterior seg­ ment. Examination of multiple sets of serial sections of each eye were necessary in most cases to demonstrate the lesions, which were usually small. In most cases the sections at 500 ppm were indistin­ guishable from control. At 5,000 ppm this was true for most slides. Examination of the eyes receiving 50,000 ppm invariably showed corne­ al edema diminishing as postoperative course lengthened. At the corneoscleral junction the number of vessels running in the corneal stroma subepithelially in­ creased, as did the distance they en­ croached on the cornea. In many cases, inflammatory cells could be seen sur-

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Fig. 4 (Holyk and Eifrig). Chamber angle in rab­ bit injected with 5,000 ppm monomer. There is hypercellularity of the trabecular meshwork and iris root (hematoxylin and eosin, X125).

rounding the vessels. The chamber angles were hypercellular in many cases with some slides showing inflammatory in­ filtrates (Fig. 4). Many sections of the ciliary body showed it to be engorged when compared to the control. Sec­ tions of the lens showed anterior subcapsular cataracts. The subepithelial vacuolization seen in both treatment and control lenses appeared to be more pro­ nounced in the treated eye. There were also synechiae to the posterior surface of the iris. The iris showed numerous changes. Milder changes included inflammatory

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Fig. 5 (Holyk and Eifrig). Early iris lesion show­ ing thickened stroma, marked vascular engorgement and a few inflammatory cells (hematoxylin and eosin, X115).

cell infiltrates with edema and vascu­ lar engorgement (Fig. 5). In more severe cases the damage took on several forms. In some, the stroma was markedly dimin­ ished or completely absent anteriorly at the pupillary margin (Figs. 6 and 7). In others marked dropout of sphincter mus­ cle was observed with few other patho­ logic findings (Fig. 6). In still others a scarred fibrinous area was seen anteriorly with surrounding vascular engorgement and inflammatory cells (Figs. 8 and 9). Often in these cases the remaining iris would appear edematous and markedly vascularized. These cases would also

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Fig. 6 (Holyk and Eifrig). Atrophic iris lesion seen in Figure 2. There has been marked thinning of the anterior stroma of this iris, vacuolization of the epithelium, and almost total lack of structure anteri­ or to the iris sphincter (hematoxylin and eosin, x!35).

Fig. 7 (Holyk and Eifrig). The atrophic iris le­ sions seen after monomeric exposure. Note the cel­ lularity of the stroma anterior to the iris sphincter, the engorgement of the stromal vessels, and the cellularity of the epithelium behind the sphincter muscle. Despite the engorgement and cellularity, the thickness of the iris is greatly diminished, and the staining qualities of the sphincter muscle cells are definitely abnormal (hematoxylin and eosin, xl!5).

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Fig. 8 (Holyk and Eifrig). An iris lesion after injection of monomeric methylmethacrylate. The iris stroma has marked edema, vascular engorge­ ment, and some inflammatory cells. The anterior surface of the iris is cellular, but has not begun to shrink. The iris is thicker than normal (hematoxylin and eosin, xll5). show vacuolization of epithelial cells posterior to the sphincter muscle. The corneal endothelium was exam­ ined with the scanning electron micro­ scope (Fig. 10) and it, too, showed chang­ es consistent with cell injury and destruc­ tion with higher concentrations of polymethylmethacrylate. 1 1 There Were

Fig. 10 (Holyk and Eifrig). Low-power scanning electron micrograph of corneal endothelium in con­ trol eye. Note the regularity of cells and appearance of normal microvilli (x900).

Fig. 9 (Holyk and Eifrig). Another "thick" iris lesion showing marked vascular engorgement of the midiris with an increase in thickness and a definite scar within the anterior stroma. The anterior surface of the iris shows a palisading of fibrous cells which appear to be shrinking and causing the dense anteri­ or stromal scar typical of this lesion. This lesion was seen seven days after injection of 50,000 ppm mono­ meric methylmethacrylate (hematoxylin and eosin, X85). areas of total cell loss resulting in bare Descemet's membrane (Fig. 11). Other areas showed large, globular microvilli on

Fig. 11 (Holyk and Eifrig). Area in central cornea showing dropout of many cells with early attempts to fill in bare Descemet's membrane. Pseudo-pod­ like extensions of cells rimming this area imply first efforts at sliding into bare space (50,000 ppm inject­ ed 42 days before killing, x400).

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the posterior endothelial cell surfaces, rupture of plasma membranes with mito­ chondria exposed to aqueous, and areas of foldings in plasma membranes (Fig. 12). All these findings imply that something was wrong with the endothelial cells and, in frequent specimens there was a grada­ tion between severely diseased cells, mildly affected cells, and normal cells. There was a suggestion that high concen­

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trations of polymethylmethacrylate caused higher degrees of cell alteration, but further work is necessary to establish this as a clinical fact. DISCUSSION

The results of this study leave little room for doubt that methylmethacrylate monomer is toxic to the tissues of the anterior segment in rabbit eyes, or that the

Fig. 12 (Holyk and Eifrig). Scan of endothelium of cornea in polymethylmethacrylate-injected eye. Upper left shows normal endothelium with graded cell damage as lower right is reached. The first changes closest to normal cells show enlarged microvilli and some exposed mitochondria. In the lower right bare Descemet's membrane is seen where a cell has dropped out (50,000 ppm injected 42 days before killing, x 1,200).

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toxicity is dose related. Clinically, corneal edema, corneal neovascularization as well as engorgement of iris and limbal vessels, iris atrophy, and cataract formation all occur more frequently and more severely with increasing dosage of monomer. Although there is evidence of a surgical component to the postoperative findings, notably trace corneal edema, and some limbal and iris engorgement, the lesser degree of these findings when compared to the treatment eyes leaves little question that the surgical contribution was small, and that this procedure was relatively benign. The typical course for an eye receiving a 10-(JL1 bolus of monomer would be to show marked corneal edema superiorly with marked (3 to 4+) limbal vessel en­ gorgement. Through the edematous cor­ nea one would see an engorged iris and a fibrin mass obscuring the pupil. By the second or third postoperative day the cor­ neal edema would have diminished suffi­ ciently to see the iris and anterior cham­ ber more clearly. The iris would still be engorged superiorly where the fibrin mass would adhere to it. In cases where there was contact between the fibrin mass and the anterior capsule of the lens, a cataract would later form. During the first week the corneal edema, limbal injection, corneal neovascularization, iris engorge­ ment, and size of fibrin mass would all diminish. Usually a cataract would be evident, and iris atrophy would begin to be discernable. The iris atrophy was the only lesion that would continue to pro­ gress. In the control eye the trace corneal edema, limbal injection, and iris engorge­ ment would all clear rapidly. Pathologically there was a correlation in the severity of a variety of lesions involving cornea, iris, trabecular meshwork, ciliary body and lens, and the amount of monomer injected into the an­ terior chamber. The cornea showed neovascularization

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with vessels extending into the corneal stroma with inflammatory cells around them. The corneal endothelium was dis­ rupted, with cell death and cell dropout noted. These changes were worse superi­ orly where one expects free monomer bubbles to float in the immediate postop­ erative period. The trabecular meshwork was fre­ quently found to be hypercellular or infil­ trated by inflammatory cells, or both. The ciliary body seemed to respond with engorgement on exposure to the methylmethacrylate monomer, a reflec­ tion of the uveitis component throughout the anterior segment. The iris responded in a graded fashion depending on the degree of exposure. Early, mild responses included edema and inflammatory infiltrates, and en­ gorgement. Later frank stromal scars de­ veloped, or there was a dropout of ei­ ther stroma or muscle tissue, or both. At times the pigment epithelium was also af­ fected, showing vacuolization of cells. The atrophic iris lesions were seen in eyes concurrently with the scarred stro­ mal lesions. The lens responded by anterior subcapsular cataract formation which appeared to be dependent on direct contact with concentrated monomer or the inflammatory-fibrinous response around it. Recent work suggests that intraocular lenses can contain up to 5% monomer. 1 In this study we have considered injections of monomer up to 5% of the volume of the anterior chamber. It may be tempting at the outset to compare these values, and conclude that they are equivalent. They are not. Although there may be up to 5% mono­ mer in intraocular lenses, work by Lee and Wrighton 1 2 studying methylmeth­ acrylate for orthopedic use showed that most monomer is released during mixing and during the exothermic phase of poly­ merization, and little is lost once poly­ merization is completed. Also, only the

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small fraction of monomer at the surface is available for leaching. The lens also represents but a small percent of the an­ terior chamber volume. The 5% monomer by volume of the anterior chamber is a different system. According to Ridley, 6 the monomer is soluble in aqueous solution up to 1%. Thus, one would expect a concentrated solution to form in the anterior chamber with the remaining hydrophobic mono­ mer to remain as a droplet. In a static solution this would describe a supersatur­ ated solution of methylmethacrylate in aqueous. However, even this is not an accurate model. First, the aqueous in the anterior chamber is not static, but flows constant­ ly. Also, there is a fibrinous response which isolates the monomer droplet from the remainder of the aqueous. Last, it is not known whether the monomer is ab­ sorbed and excreted by iris, trabecular meshwork, or both. 1 3 One conclusion is clear: the greater the bolus of monomer, the greater the lesions. If one examines the pathologic findings more closely, one finds clues that suggest they are not in response to the aqueous containing monomer, but rather to the droplets of 100% monomer. Lesions of both cornea and iris appear to be locally severe with milder generalized reaction in the remainder of the tissue. This is con­ sistent with a local irritant. In the final analysis, then, one can say that concentrated methylmethacrylate monomer is highly toxic to tissues of the anterior segment in the rabbit eye. Infor­ mation regarding the kinetics of monomer release from intraocular lenses and clear­ ance of monomer from the anterior cham­ ber must be learned, however, before any intelligent correlation can be made be­ tween the information obtained in this study and the question of toxicity due to monomer in intraocular lenses. Such studies are now in progress.

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Intraocular lenses currently in use have little free monomer available for leaching. The long history of lens implantation and examination of eyes obtained for patho­ logic study after intraocular lens implan­ tation suggest that most clinical compli­ cations are related to surgical technique and lens position. 6 * 7,11 ' 14 " 18 Laboratory studies appear to bear out this impression. 4,19,20 This study emphasizes the need for great care in the manufacture and machining of intraocular lenses to avoid the inadvertent production of mon­ omer, since high monomer levels have definite toxic effects on ocular tissues. SUMMARY

Toxic effects of high doses of monomeric methylmethacrylate were demon­ strated in rabbit eyes. These effects were not related to surgical manipulation. Monomeric methylmethacrylate caused limbal hyperemia, corneal edema, corneal neovascularization, iris engorgement, an­ terior chamber inflammation, iris atrophy, and cataract. The doses of monomeric methylmethacrylate needed to produce these lesions were much higher than the amount of monomer available for leach­ ing out of implanted intraocular lenses. REFERENCES 1. Galin, M. A., Turkish, L., and Chowchuvech, E.: Detection, removal and effect of unpolymerized methylmethacrylate in intraocular lenses. Am. J. Ophthalmol. 84:153, 1977. 2. Galin, M. A., Chowchuvech, E., and Turkish, L.: Uveitis and intraocular lenses. Trans. Ophthal­ mol. Soc. U.K. 96:166, 1976. 3. Stinson, N. E.: The tissue reaction induced in rats and guinea-pigs by polymethylmethacrylate (acrylic) and stainless steel. Br. J. Exp. Pathol. 45:21, 1974. 4. Eifrig, D. E., and Doughman, D. J.: Intracapsular plastic lens loop fixation in the rabbit. Arch. Ophthalmol. 94:1167, 1976. 5. Stinson, N. E.: Tissue reaction induced in guinea-pigs by particulate polymethylmeth­ acrylate, polythene, and nylon of the same size range. Br. J. Exp. Pathol. 46:135, 1965. 6. Ridley, F.: Safety requirements for acrylic im­ plants. Br. J. Ophthalmol. 41:359, 1957.

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7. Lieb, W. A., Geeraets, W. J., Guerry, D., I l l , and Dickerson, T.: Tissue tolerance of plastic resins. Eye, Ear, Nose, Throat Mon. 38:210, 1959. 8. Information Bulletin. No. X-28C, Plastics De­ partment, E.I. DuPont de Nemours and Company, Inc., Wilmington, Delaware. 9. Prince, J. H.: The Rabbit in Eye Research. Springfield, III., Charles C Thomas Publishers, 1964, p . 955. 10. Cohen, A. L.: Critical point drying. In Hayat (ed.): Principles and Techniques of Scanning Elec­ tron Microscopy, vol. 1. New York, Van Nostrand, 1974, p p . 44-112. 11. Forstot, S. L., Blackwell, W. L., Jaffe, N. S., and Kaufman, H. E.: The effect of intraocular lens implantation on corneal endothelium. Trans Am. Ophthalmol. Otolaryngol. 83:195, 1977. 12. Lee, A. J. C , and Wrighton, J. D.: Some prop­ erties of polymethylmethacrylate with reference to its use in orthopedic surgery. Clin. Orthop. Rel. Res. 95:281, 1973. 13. Rijke, A. M. and Johnson, R. A.: On the fate of

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methylmethacrylate in blood. J. Biorned. Mater. Res. 11:211, 1977. 14. Epstein, E.: The Ridley lens implant. Br. J. Ophthalmol. 41:368, 1957. 15. Smith, R.: Histopathological studies of eye enucleated after failure of intraocular acrylic lens operations. Br. J. Ophthalmol. 40:473, 1956. 16. Guerry, D., I l l : Present status of the anterior chamber lens. Am. J. Ophthalmol. 50:250, 1960. 17. Bresnick, G. H.: Eyes containing anterior chamber acrylic implant. Arch. Ophthalmol. 82:726, 1969. 18. Guerry, D., I l l , and Geeraets, W. J.: Compli­ cations of anterior-chamber lenses. Am. J. Oph­ thalmol. 54:229, 1962. 19. Sugar, J., Burnett, J., and Forstot, S. L.: Scan­ ning electron microscopy of intraocular lens and endothelial cell interaction. Am. J. Ophthalmol. 86:157, 1978. 20. Eifrig, D. E., and Doughman, D. J.: Intrao­ cular lenses in laboratory animals. Ophthalmic Surg. 8:149, 1977.