Ординатура / Офтальмология / Английские материалы / Biomaterials and regenerative medicine in ophthalmology_Chirila_2010

experimentationisnecessarytodetermineifanyoftheseproposedmechanisms for the formation of a snowflake lesion are probable.

Our initial belief when first looking at the spherical lesions was that fluid permeates into the cavitated lesions, forming vacuoles or ‘glistenings’. Further examination of the lesions however, suggested that they are dry, rather than fluid-filled lesions. We have recently analyzed a PMMA lens explanted because of snowflake degeneration in the dry and hydrated states.4 The lesions characteristic of the condition were restricted to the central 2 mm of the lens optic in the dry state. This is the smallest area ever observed, and may be related to the fact that the patient’s pupils were relatively constricted as noted on the exam before and after dilation. Upon hydration of the explanted lens, an unusual amount of water was collected within the central 4 mm of the lens optic, where multiple linear cracks were present. These cracks were not evident under light microscopy in the dry state. They may represent the initial injury before the typical snowflake lesions are seen, or they may be secondary to the initial presence of the more central snowflake lesions. In any case, the clinical significance of snowflake degeneration may depend on the amount of water collected within the area of cracks. The emergence of this complication could have represented a more significant problem, except for the fact that many of the patients implanted with these IOLs are now deceased. However, surgeons must be aware that there are probably still a number of patients living with varying stages of snowflake degeneration.

3.3Opacification and degradation of silicone intraocular lenses

3.3.1Early opacification

We reported on the laboratory analyses of six IOLs explanted from patients who had visual disturbances caused by early postoperative opacification of the lens optic.5,6 Six patients with three-piece silicone lenses presented with optic cloudiness, as early as a few hours after implantation. The lenses were implanted in four different locations in Brazil, and in France. The lenses in Brazil were stored at the same location before implantation. Gross and microscopic analyses were performed (dry and hydrated states). One-half of each specimen underwent gas chromatography–mass spectrometry (GC–MS) analysis and/or extraction by isopropyl alcohol or acetonitrile. One lens also underwent SEM with EDS. The IOLs were examined for the presence of contaminants and/or deposits that could cause fast optic opacification. The lenses showed whitish optic discoloration in the hydrated state, but became transparent upon complete dehydration (Fig. 3.2). Suspect exogenous chemical compounds were identified in GC–MS analyses; general classes included terpenes and ketones, typically found in industrial cleaning agents and

3.2 Early opacification of silicone lenses.

(a) and (b) Gross photographs of a three-piece silicone lens explanted because of optic opacification occurring within 24 hours of implantation, related to influx of water within the optic. The lens is white while hydrated (a) and the degree of opacity decreases as the lens dries (b). (c) and (d) Photomicrographs showing the same phenomenon under light microscopy.

ophthalmology in medicine regenerative and Biomaterials 40

fumigants. Surface analyses (SEM and EDS) did not show any significant deposits on the external surfaces and sagittal cut of one of the specimens. Later, we reported on two other similar cases, from the United Kingdom and Hong Kong.7

Tanaka et al.8 observed a phenomenon similar to our eight cases, in an 83-year-old Japanese patient implanted with an SI40 NB. In his report, the IOL presented with a ‘brown haze’ on the first postoperative day. The haze did not decrease until day 15 postoperatively, when the IOL was then explanted. Light microscopic evaluation of the explanted lens showed the presence of numerous spheroid structures in the central region of the optic, similar to glistenings. The authors suggested that the haze was secondary to influx of water within the lens, but no analyses to determine possible causative factors were carried out.

A thorough review of the history of the lenses evaluated in this study was carried out by the manufacturer (AMO, Santa Ana, CA, USA), according to their serial numbers. Although all the implantations in Brazil were carried out in different locations, and the lenses were from different manufacturing lots, it was determined that they had all been stored in the same area in Brazil, preoperatively. Spraying of the storage area with cleaning and insecticide agents was reportedly performed. Taking this fact into account, as well as the presence of exogenous chemical compounds in GC-MS analyses of these lenses, we hypothesized that chemical contamination of the lenses might have occurred preoperatively. This might have caused surface changes, rendering the relatively hydrophobic silicone surfaces more hydrophilic, allowing influx of water and therefore opacification of the IOL optic. It was noteworthy that after complete lens extraction of the lenses in some cases (i.e. removal of all adsorbed molecules), re-immersion of the lenses in solution did not cause any degree of optic opacification. Of particular interest was the presence of terpenes in some cases, and cyclohexanone in one case, which are not expected to be found in an IOL as they are not used in the lens manufacturing process, but are used in the manufacture of cleaning and insecticide agents. However, no clear history of preoperative contamination could be determined in some cases.

Three-piece silicone IOLs with PMMA haptics require sterilization by techniques using low temperature and pressure. Therefore, ethylene oxide gas sterilization is used.9 For effective sterilization with ethylene oxide, selection of packaging material is very important, and permeability is one of the most important criteria. The packaging material must be permeable enough for ethylene oxide and moisture to enter the package (and air escape) and sterilize the contents within the desired cycle time. The packaging material must also have sufficient breathability to permit release of toxic residues (e.g. ethylene oxide residual gas). At the same time, the packaging material must be impermeable to bacteria and other contaminants. If this

42 Biomaterials and regenerative medicine in ophthalmology

kind of packaging allows sterilization by ethylene oxide, one must assume that other chemical vapors may also penetrate the package and contaminate the lenses.

3.3.2Late opacification

There have been reports of brownish discoloration and central haze of silicone lenses in the early 1990s.10–15 In 1991, Milauskas reported 15 cases

of brownish discoloration with IOLs manufactured by Staar and Iolab, observed from 15 to 60 months after implantation.12 A decrease in the contrast sensitivity of the patients affected was observed in the more severe cases.

Later, Milauskas identified 9 other cases, with the same kind of lenses.13 Watt has also reported a case of central brownish discoloration of another silicone lens (AMO SI18 NGB), observed 6 weeks after implantation.14 Koch and Heit reported on two other similar cases, with the same lens design.11 In general this complication was considered clinically insignificant; IOL explantation has rarely been performed. These reports have suggested that the brown haze was due to light scatter from water vapor that may diffuse into the silicone when immersed in an aqueous medium. This may be caused by some anomaly of the curing process during the manufacture of those lenses or by incomplete extraction of large polymers. UV blocking agents did not seem to be an issue with lens discoloration since the phenomenon was also observed with silicone IOL models not containing these agents. Additional filtration steps in the manufacturing process of silicone lenses seemed to solve the problem.

More recently, we reported on 12 cases of late-postoperative opacification of silicone lenses (4 weeks to 2 years); all lenses were explanted in the United States (Werner L, Mamalis N, Olson RJ. Postoperative optic opacification of silicone IOLs: Analyses of 20 explants. Best-Paper-of-Session Award, Free Papers, Cataract Session, at the American Academy of Ophthalmology – AAO meeting, New Orleans, LA, USA, November 11, 2007). The degree of optic opacification was not as marked as for the lenses that showed earlier-onset opacification. GC-MS analyses of the lenses also showed components not matching chemicals used in AMO’s silicone material synthesis, or components used while manufacturing the lenses. Of particular interest, is the presence of benzophenone in 7 out of 12 lenses. Although this compound may also be used as a UV blocker, the one used by the manufacturer on the corresponding designs is a modified benzotriazole compound.

AMO have reviewed the lot of history files for all lenses with known serial numbers, and no deviations regarding procedures used at the time of their manufacture were found. These lenses and the one without a serial number but with information on implant/explant dates were all manufactured at the Pharmacia facility in Groningen, before improvements in AMO’s synthesis

process (refinement of raw materials used during synthesis) were introduced. To date, to the best of their knowledge, no similar cases of opacification of silicone lenses manufactured after the improvements in the synthesis process were observed. According to the manufacturer, the incidents/complaints reported in this study represent a very low fraction of the total lenses sold and no relationship to manufacturing batches and components used – among other factors considered – was found. AMO currently performs several chemical analyses on their silicone material. These include analyses of the molecular weight of extracts obtained during silicone synthesis and IOL manufacturing, as residual monomers and short polymer chains may cause opacification when lenses are kept in water for some time at 37 °C.

3.3.3Discoloration associated with dyes

Although experimental studies demonstrated that silicone lenses do not significantly interact with commonly used capsular dyes, we reported one case of blue discoloration of a silicone IOL.16 The patient was a 52-year- old man who underwent uneventful phacoemulsification with implantation of an SI40 NB (AMO) in the right eye. A ‘blue dye’ was used to enhance visualization during capsulorhexis. Postoperatively, the patient presented with corneal edema and a discolored IOL (Fig. 3.3(a). The lens was therefore explanted and exchanged. The corneal edema resolved within 1 month of the initial surgical procedure. After explantation, gross and microscopic analyses of the explanted silicone lens revealed that its surface and internal substance had been permanently stained blue. It was then determined in this case that methylene blue had been inadvertently used instead of trypan blue to stain the anterior capsule. Of course, the most significant problem in this case was not the discoloration of the IOL itself, but the use of a solution that was not appropriate for the intraocular environment, raising concerns about toxic anterior segment syndrome (TASS).17

3.3.4Discoloration associated with systemic medication

Silicone IOL opacification/discoloration has also been associated with the long-term use of systemic medications. Katai et al. reported on a patient who was treated with amiodarone for 3 years and developed brown discoloration of the silicone lenses in both eyes.18 Jones and Irwin described the case of a patient who developed a rose discoloration of the silicone lenses in both

eyes after receiving rifabutin for 10 months.19 Recently, there have been reports from South India of green discoloration of silicone IOLs.20,21 The

phenomenon was noted at 6 months postoperatively, but as the patients were asymptomatic, the lenses were not explanted. To date, careful scrutiny of the medical and surgical history of the patients failed to reveal factors that

3.3 Other causes of explantation of silicone lenses. (a) Light photomicrograph of

a three-piece silicone lens explanted because of inadvertent use of methylene blue as a capsular dye instead of trypan blue, with blue discoloration of the lens.

(b) Clinical photograph showing adhesion of silicone oil used in retinal surgery to the implanted silicone lens. (c) Light photomicrograph of

a three-piece silicone lens explanted because of coating of the

optic component with ophthalmic ointment used by the surgeon after the implantation procedure.

(d) Gross photograph of a silicone plate lens,

explanted because of optic calcification in an eye with asteroid hyalosis.

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might have predisposed the IOLs to green discoloration. A previous report from Pakistan had also described a similar complication.21

3.3.5Coating with silicone oil

Opacification/discoloration of silicone lenses in the late-postoperative period was also observed in relation to deposition of material on the lens surfaces. The interaction of silicone oil, used in vitreoretinal surgery, with standard silicone IOLs in a given patient is a well-documented clinical complication (Fig. 3.3(b).22,23 Patients with vitreoretinal problems that may require use of silicone oil should not be implanted with silicone lenses, as the oil will attach to the lens surfaces, causing optical irregularities. This irreversible adherence of silicone oil to the IOL optic may lead to different sequelae, including visual disturbances and visual loss for the patient, as well as obstruction of the vitreoretinal surgeon’s view into the eye. This is a complication not generally seen by the implanting cataract surgeon but, rather, at a later stage in a patient’s postoperative course, by a vitreoretinal surgeon. Experimental studies showed that, although silicone IOLs show maximal adherence to silicone oil, other lens biomaterials are not immune to this complication. Silicone oil coverage was related to the dispersive energy component of the surface charge of the IOL biomaterial. Low dispersive energy materials had less silicone oil coverage, while those with higher dispersive energy had more oil coverage. Regardless of the degree of oil-induced cloudiness of the IOL, visual loss is often severe by the time most patients develop severe vitreoretinal disease that requires radical treatment with silicone oil. Therefore the clinical importance of this complication actually relates most significantly to patients who may be deemed to have a high propensity for severe vitreoretinal disease that may require silicone oil treatment at a later date. Common conditions that may fall into this category include: rhegmatogenous retinal degeneration, previous retinal tears or detachment in the same or fellow eye, family history of hereditary retinal detachment, high risk of ocular trauma, high myopia or ocular developmental abnormalities, congenital cataract and proliferative diabetic retinopathy. Patients that fall in any of the above categories should proactively receive an appropriate IOL with the future complications borne in mind.

3.3.6Coating with ophthalmic ointment

We have recently reported eight cases of TASS related to an oily material within the anterior chamber of the patients’ eyes.24 The eight patients had undergone uneventful phacoemulsification by the same surgeon via clear corneal incisions, with implantation of three-piece silicone lens designs. Postoperative medications included antibiotic/steroid ointment, and pilocarpine

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gel; each eye was firmly patched at the end of the procedure. On the first postoperative day, some patients presented with diffuse corneal edema, increased intraocular pressure (IOP), and an oily, film-like material within the anterior chamber, coating the corneal endothelium. The others presented with an oily bubble floating inside the anterior chamber, which was later seen coating the IOL. Additional surgical procedures required included penetrating keratoplasty (N = 4), IOL explantation (N = 6), and trabeculectomy (N = 1). Two corneal buttons were analyzed histopathologically, two explanted IOLs underwent gross and light microscopic analyses (as well as surface analyses on one of them), and four other explanted IOLs underwent GC-MS.

Pathological examination of the corneas showed variable thinning of the epithelium, with edema. The stroma was diffusely thickened, and the endothelial cell layer was absent. Evaluation of the explanted IOLs confirmed the presence of an oily substance coating large areas of their anterior and posterior optic surfaces (Fig. 3.3(c). GC-MS of the lens extracts identified a mixed chain hydrocarbon compound, which was also found in the GCMS analyses of the ointment used postoperatively. Therefore, the results indicated that the ointment gained access to the eye, causing the postoperative complications described. These cases highlight the importance of appropriate wound construction and integrity, as well as the risks of tight eye patching following placement of ointment. McDonnell et al. evaluated the dynamic morphology of clear corneal cataract incisions by creating clear corneal incisions in human and rabbit eyes obtained postmortem.25 They found that, at low pressures, wound edges tended to gape, starting at the internal aspect of the wound. In a retrospective study, Shingleton et al. demonstrated that a significant percentage of eyes having clear corneal phacoemulsification had an IOP of 5 mm Hg or less 30 minutes after surgery.26

Intraocular penetration of ointments has already been described in the literature. In 1973, Fraunfelder and Hanna, published a report on a survey sent to 400 randomly selected ophthalmologists from the Fellows in the American Academy of Ophthalmology and Otolaryngology.27 Of the 327 surveys returned, 65 (20%) reported having seen ointment entrapped in the anterior chamber postoperatively in a total of 95 patients. Garzozi et al. reported the case of a patient who presented with a bubble floating in the anterior chamber after radial keratotomy.28 Aralikatti et al. reported the case of a patient who underwent uneventful phacoemulsification through an oblique, self-sealing clear corneal incision, and presented with a white lump of a substance in the anterior chamber, overlying the pupil, on the first postoperative day.29 More recently, Riedl et al. described ointment entering the anterior chamber after cataract surgery through a temporal corneal incision.30 Therefore, the possibility of intraocular penetration of any kind of ointment used postoperatively, not only in cataract surgery, but in different types of penetrating procedures, should therefore be anticipated.

Ophthalmic ointment may also gain intraocular access after surgery, but only coat the IOL implanted later postoperatively. We have recently evaluated the case of a patient who underwent uneventful phacoemulsification with implantation of a three-piece silicone IOL (SI30 NB, AMO) via a 3.0 mm scleral tunnel incision.31 Postoperative medications included antibiotic/steroid drops and ointments. Eight months postoperatively, the patient started having recurrent episodes of anterior-chamber inflammatory reaction. The suspicion that lens instability was causing the reactions led to two repositioning procedures, including performance of McCannel sutures. Finally, 18 months postoperatively, the IOL presented with a ‘greasy’ film and it was later exchanged. GC-MS analysis of the ointment used after each surgical procedure showed several compounds that had mass spectra characteristic of hydrocarbons similar to those detected in the extract prepared from the explanted IOL. In this case, it is possible that the ointment entered the anterior chamber after the IOL repositioning procedures, perhaps through clear corneal paracentesis usually required for the placement of McCannel iris-suture fixation. The first observation of globules on the IOL was only noted 5 months after the last procedure. The reasons for this late onset remain unclear to us. Chen et al. have also recently reported a case where an oily-like material was only observed inside the anterior chamber in the late-postoperative period after cataract surgery.32 The material was identified as ointment by Fourier transform infrared and confocal Raman microspectroscopies.

3.3.7Calcification in asteroid hyalosis

Calcified deposits leading to significant opacification requiring explantation were observed on the surface of silicone IOLs in eyes with asteroid hyalosis. Four cases were initially reported in the literature, all with silicone-plate lenses in patients with unilateral asteroid hyalosis (Fig. 3.3(d)).33,34 Whitish deposits appeared only on the posterior optic surface of the lens late postoperatively. Two out of the four reported patients had diabetes. In two of the cases, the deposits were noted before Nd:YAG laser capsulotomy was performed. Fast re-accumulation of the deposits on the posterior surface of the lenses was described after the procedure. In the other two cases, it is not clear whether or not the deposits were present before the Nd:YAG procedure. While in the three cases reported by us, the deposits were observed mostly within the area of the Nd:YAG capsulotomy,33 in the case reported by Wackernagel et al., the deposits also appeared on the periphery of the optic, covered by the posterior capsule.34

Later we described the first similar case related to a three-piece silicone lens, in a patient with bilateral asteroid hyalosis.35 The 76-year-old diabetic woman underwent uneventful cataract surgery in 1994 with implantation of an SI30 NB (AMO) IOL in the left eye. An Nd:YAG laser posterior

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capsulotomy was performed 2 years after cataract surgery, but persistent whitish deposits were observed on the posterior optic surface of the lens. Over the next 3 years, the opacification increased in the region corresponding to the capsulotomy. The IOL was explanted/exchanged. The right eye had cataract surgery in 1995. The acrylic lens implanted in this eye developed no opacities after 6 years.

There are only a few cases in the recent literature describing the association between dystrophic calcification of silicone lenses and asteroid hyalosis. Calcification of silicone lenses in the absence of this vitreous condition has not been reported. Indeed, in the absence of asteroid hyalosis, long-term calcified deposits were previously observed only on the surface or within the substance of some hydrophilic acrylic IOL designs. There is, therefore, increasing evidence that the material opacifying the silicone lenses is derived from the asteroid bodies, or derived from a similar process that results in this vitreous condition, as its composition was found to be similar to that of hydroxyapatite (calcium and phosphate). The latter is more likely the case because the asteroid calcium is already ‘out of solution’. It is, however, still unclear why only a few cases have been observed, while there have probably been many implantations of silicone lenses of various designs in patients with asteroid hyalosis. Careful clinical examination of pseudophakic patients with asteroid hyalosis will confirm if this phenomenon is more widespread, but only significant enough to require IOL explantation in a few cases. This will also confirm if the phenomenon is restricted to silicone lenses. Without such knowledge, it is difficult to proscribe silicone IOL implantation in the presence of asteroid hyalosis.

3.4Opacification and degradation of hydrophilic acrylic intraocular lenses

3.4.1Discoloration

Capsular dyes such as fluorescein sodium, indocyanine green (ICG), and trypan blue have been successfully used for staining the anterior capsule (injection under an air bubble or intracameral subcapsular injection), for performing capsulorhexis in advanced/white, intumescent, or hypermature cataracts. We described for the first time the occurrence of blue discoloration of an IOL by a capsular dye (Fig. 3.4).36 The lens was an hydrophilic acrylic design (Acqua, Mediphacos). The patient was a 79-year-old Caucasian male patient, who underwent cataract surgery with implantation of this hydrophilic acrylic design. Trypan blue 0.1% was injected under an air bubble to stain the anterior capsule before capsulorhexis. Seven days after surgery, the patient presented with ‘dark and double’ vision (monocular diplopia). The IOL was decentered superiorly and appeared dark blue. The lens was explanted