Screening for drug-induced spoliation of the hydrogel optic of the AlphaCor™ artificial cornea

Contact Lens & Anterior Eye 29 (2006) 93–100 www.elsevier.com/locate/clae

Screening for drug-induced spoliation of the hydrogel optic of the AlphaCorTM artificial cornea David A. Morrison a, Zoya Gridneva a, Traian V. Chirila b,c, Celia R. Hicks a,* a

Lions Eye Institute and Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, WA, Australia b Queensland Eye Institute, Brisbane, Qld, Australia c School of Physical and Chemical Sciences, Queensland University of Technology, Brisbane, Qld, Australia

Abstract Clinical experience and in vitro investigations demonstrated that AlphaCorTM, a hydrogel keratoprosthesis, can undergo both surface spoliation and internal depositions/colourations after exposure to certain medications, alone or in combination. While the most commonly used medications have not been associated with spoliation in vivo, many medications are reportedly used due to the complex co-pathologies in many recipients, and regional variations in available medications. We screened a number of drugs used or proposed by surgeons for use in AlphaCor patients to evaluate their potential to cause visually significant optic spoliation (surface or intragel, or colour changes). Poly(2hydroxyethyl methacrylate) discs with an identical composition to AlphaCor’s optic were incubated with each medication and then with simulated aqueous humour (SAH) at 37 8C for 7 days. They were then examined under magnification and by histology (selected samples). Clinical feedback for the test medications was reviewed and compared with the in vitro results. A minority of the drugs caused surface spoliation (TobraDex, Prednefrin Forte, Azopt) or colour staining (including Zymar, Vigamox, Quixin) when tested alone, but SAH appeared to promote hydrogel cloudiness and surface deposits. The in vitro spoliation occurred more frequently than in vivo reports of spoliation in recipients of the same medications. This study is consistent with earlier findings in demonstrating involvement of topical medications in hydrogel spoliation, although a much lower incidence of spoliation is reported for AlphaCor in human recipients than indicated by the laboratory findings. The interactions of biological fluids and drugs require further study. # 2006 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved. Keywords: Hydrogels; AlphaCorTM artificial cornea; Topical medication; Deposits; Spoliation

1. Introduction We have previously described [1–3] the in vitro spoliation related to topical medications prescribed during trials of a hydrogel keratoprosthesis (AlphaCorTM, CooperVision Surgical Inc.) and have suggested causative mechanisms. Specifically, we reported that certain medications (such as Betagan (Levobunolol, Allergan, Irvine, USA)) as well as cigarette smoke, were associated with brown optic staining, while a characteristic deposit, a plaque of calcium within the gel rather than on the surface, was associated with coprescription of topical steroids with topical beta-blockers [3]. On in vitro screening of a number of drugs used during * Corresponding author. Tel.: +61 8 9381 0877; fax: +61 8 9381 0759. E-mail address: [email protected] (C.R. Hicks).

AlphaCor clinical trials, a variety of appearances ranging from surface sediments to general material cloudiness, were observed and reported [1], although reports of deposits occurring in vivo were infrequent. Some in vitro deposits were generated by the precipitation of calcium salts from the simulated aqueous humour used as a test medium, a process triggered either by the intrinsic propensity of hydrogels to calcify in media containing calcium ions [4], either abiogenic or biogenic, or by specific interactions between the components of drug formulations and the medium. Other deposits did not contain calcium; they were probably precipitated drugs or their products of degradation. We have also investigated [5] the effects of multipurpose cleaning solutions for contact lens care in attempts to reduce the spoliation. While these cleaning solutions may constitute a valid approach to the

1367-0484/$ – see front matter # 2006 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clae.2006.02.007

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reduction of spoliation, their effect is dependent on the type of spoliation and the medications used. With increased use of the AlphaCor keratoprosthesis in a growing number of countries, the range of topical medications reported to be used has also grown [2,6,7]. This paper describes further studies to evaluate the risk of spoliation associated with additional medication formulations reported by AlphaCor surgeons to be used, or being considered for use, in AlphaCor recipients. These include topical steroids, antibiotics and antiglaucoma medications that differed from those prescribed during earlier trials, as well as other drugs used for the first time in association with AlphaCor, such as Restasis in dry-eyed patients, heparin for reducing fibrin formation, fluorescein agents for evaluating epithelial coverage, and antimitotic drugs reportedly being considered in cases where there is recurrent growth of the anterior tissues over the optic of the implanted device.

2. Materials and methods 2.1. Materials Poly(2-hydroxyethyl methacrylate) (PHEMA) discs were produced as previously described [1,5], ensuring that the material had the same chemical composition as the optic core in the AlphaCor keratoprosthesis. The monomer was supplied by Bimax Chemicals Ltd., Cockeysville, USA. Simulated aqueous humour (SAH) was prepared and used as a test medium in the experiments. Because of paucity of reliable data on the composition of human aqueous, the SAH formulation was based on Gaasterland’s recommendations for primates [8], regarding mainly the major cations and amino acids, as well as on existing available data for the human aqueous [9]. The preparation and processing of SAH was fully detailed in our previous studies [1,5]. High-purity, sterile and nonpyrogenic ‘‘water for injections BP’’ (Viaflex1, Baxter Healthcare, Sydney, Australia), designated henceforth as ‘‘water’’, was used both for preparing SAH and for dissolving one of the drugs. All chemicals were supplied by Sigma–Aldrich, St. Louis, USA. The pH of SAH was between 7.2 and 7.5. Before each use, the required amounts of SAH were filtered through Millex1-GV filters (0.22 mm) supplied by Millipore Corp., Billerica, USA. Sterile sodium chloride 0.9% for irrigation (Baxter Healthcare, Sydney, Australia), designated henceforth as ‘‘saline’’, was used in one series of control samples and for diluting one of the drug solutions. Phosphate buffer required for the histological processing of specimens, was prepared by dissolving tablets (pH 7.2, BDH Gurr, Merck, Poole, UK) in water according to specification. The epoxy resin for embedding was supplied by Fluka AG, St. Gallen, Switzerland, as Durcupan1 ACM.

2.2. Drugs Information on medications used clinically in AlphaCor patients, or being considered for use, is compiled anonymously by surgeons within the device manufacturer’s website CVSConnect (https://secure.coopervisionsurgical.com/) to facilitate review of outcomes by both user surgeons and the device’s Scientific Advisory Board. These data allowed the selection of medications for this study and a subsequent comparison of screening outcomes with clinical outcome reports. Table 1 shows the medications selected for testing in this study, including both drugs/formulations reportedly prescribed in AlphaCor patients that differed from the original study protocol and from those previously screened [1], and those which previously were neither prescribed in AlphaCor patients nor screened, but reported under consideration for clinical use. All drug formulations, except Actilyse were supplied in liquid form and contained water, which is not indicated as an ingredient in Table 1. Actilyse was used as an aqueous solution of 0.25 mg/mL that was prepared according to the supplier’s instructions, by first dissolving 10 mg of the drug in 10 mL water, then allowing it to stand for approximately 10 min, and finally diluting to the required concentration by adding 30 mL saline. 2.3. Experimental procedure PHEMA discs, in their fully hydrated state, were individually placed into 5 mL sterile neutral glass vials (C-32, Contamac, Saffron Walden, UK) and covered with 1 g test solution. The drugs were tested in triplicate (3 discs for each drug). In one series of experiments (‘‘drug only’’), the test solutions were the liquid drug preparations (Table 1) as supplied, or in the case of Actilyse, brought into a liquid form by preparing a solution in saline. The hydrogel specimens were incubated for 7 days in the test solutions and then examined. In another series (‘‘drug/SAH’’), 3 hydrogel discs were incubated individually in each drug for 7 days, and then the drug was removed and replaced by 5 g SAH, where the specimens were postincubated for an additional 7 days before examination. The vials were loaded with specimens and test solutions in a Class II biologic safety cabinet, sealed with silicone bungs (C-35, Contamac, Saffron Walden, UK), and crimped with aluminium top seals (C-33A, Contamac, Saffron Walden, UK). The sealed vials were then placed in an incubating shaker (Unimax 1010, Heidolph Elektro GmbH, Kelheim, Germany), situated in the same safety cabinet. A temperature of 37 8C was established in the incubator and the vials were shaken at 180 cycles/min for the required period. On completion, the hydrogel discs were removed, carefully rinsed with water, and then examined under a magnifying lamp. The aspect of the host solution in each vial was also examined.

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Table 1 Details of medications studied Brand name

Manufacturer

Active ingredient(s)

Other ingredients

Prednisolone Ophthalmic Solution

Bausch & Lomb, Tampa, USA

Prednisolone sodium phosphate

TobraDex

Alcon, Fort Worth, USA

Tobramycin, dexamethasone

Prednefrin Forte

Allergan, Gordon, Australia

Prednisolone acetate, phenylephrine hydrochloride

Pantanol Restasis

Alcon, Fort Worth, USA Allergan, Irvine, USA

Olopatadine Cyclosporine

Zymar

Allergan, Irvine, USA

Gatifloxacin

Vigamox

Alcon, Fort Worth, USA

Quixin

Santen, San Francisco Bay, USA

Moxifloxacin hydrochloride Levofloxacin

Benzalkonium chloride, hydroxypropyl methylcellulose, NaH2PO4, Na2HPO4, NaCl, Na2EDTA, NaOH(?), HCl(?) Benzalkonium chloride, hydroxyethyl cellulose, tyloxapol, Na2EDTA, NaCl, NaOH(?), HCl(?) Benzalkonium chloride, phenazone, Polysorbate 80, boric acid, Na citrate, NaCl, Na2S2O5, Na2EDTA, Hypromellose Benzalkonium chloride, NaCl, Na2HPO4 Glycerin, castor oil, Polysorbate 80, Carbomer 1342, NaOH Benzalkonium chloride, Na2EDTA, NaCl, NaOH(?), HCl(?) Boric acid, NaCl, NaOH(?), HCl(?)

Genticin

Bausch & Lomb, Tampa, USA

Gentamicin sulfate

Timoptol

Timolol

Xalatan Betoptic

Merck Sharpe & Dohme, South Granville, Australia Merck Sharpe & Dohme, South Granville, Australia Merck Sharpe & Dohme, South Granville, Australia Pharmacia/Pfizer, New York, USA Alcon, Fort Worth, USA

Timolol, pilocarpine hydrochloride Latanoprost Betaxolol hydrochloride

Travatan

Alcon, Fort Worth, USA

Travoprost

Azopt

Alcon, Fort Worth, USA

Brinzolamide

Xalacom

Pharmacia/Pfizer, New York, USA

Latanoprost, timolol maleate

Lumigan

Allergan, Irvine, USA

Bimatoprost

Actilyse

Boehringer Ingelheim, Ingelheim, Germany Pharmacia/Pfizer, New York, USA Holles Laboratories, Cohasset, USA Mayne Pharma, Melbourne, Australia Leiter’s Rx Compounding, San Jose, USA

Alteplase

Timoptol XE Timpilo 4

Heparin Injection Fluoresoft-0.35% Fluorouracil Injection Mitomycin

In one control series, hydrogel specimens were incubated for 7 days in 1 g saline and then examined. In another control series, the specimens were incubated for 7 days in 5 g SAH and then examined. The five most severely spoliated samples underwent histological processing for the detection of calcium. The hydrogel discs were fixed in 2.5% glutaraldehyde in phosphate buffer (0.1 M) for 24 h and then processed in a LynxTM EM tissue processor (Australian Biomedical Corporation, Melbourne, Australia), undergoing post-

Timolol

Heparin sodium Fluorexon 5-Fluorouracil Mitomycin

Benzalkonium chloride, NaCl, NaOH(?), HCl(?) Benzalkonium chloride, NaH2PO4, Na2HPO4, NaCl, NaOH(?), HCl(?) Benzalkonium chloride Benzododecinium bromide, gellan gum, mannitol, trometamol Benzalkonium chloride, Na2HPO4 Benzalkonium chloride Benzalkonium chloride, NaCl, Na2EDTA Benzalkonium chloride, castor oil (ethoxylated and hydrogenated), Na2EDTA, boric acid, trometamol, mannitol Benzalkonium chloride, NaCl, Na2EDTA, tyloxapol, mannitol, carbomer Benzalkonium chloride, NaH2PO4, Na2HPO4, NaCl Benzalkonium chloride, NaCl, citric acid, Na2HPO4, NaOH(?), HCl(?) L-Arginine, H3PO4, Polysorb 80, NaOH(?), HCl(?) None NaH2PO4(?), Na2HPO4(?), NaCl(?) NaOH Mannitol, Na2HP04, NaCl, NaOH(?), HCl(?)

fixation in osmium tetroxide, dehydration in graded water–ethanol solutions, and infiltration with epoxy resin. After completion of embedding, 2 mm thick sections of were cut using an LKB 2088 Ultratome V ultramicrotome (LKB-Produkter, Stockholm, Sweden). The sections were deplasticized, stained with 2% alizarin red at pH 4.2, mounted and examined by conventional microscopy. The presence of calcium was indicated by a bright red colouration and visually graded from 0 to ++++.

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3. Results In the first control series, saline did not cause any spoliation of the hydrogel specimens. The samples of the second control series, which were incubated in SAH, showed fine white particles in solution and on the hydrogel surface and the specimens became cloudy. A summary of the results obtained in the two series of experiments (I, drug only and II, drug/SAH) is shown in Table 2. Of the 23 formulations tested in this study, in series I only three drugs (TobraDex, Prednefrin Forte and Azopt) induced surface sedimentation on the hydrogel material. Although devoid of calcium, as there was no source of calcium salts, the deposited layer was strongly attached to the hydrogel surface and could not be removed by washing. Five other agents (Zymar, Vigamox, Quixin, Mitomycin and Fluoresoft-0.35%) caused colouration of the hydrogels in the absence of SAH, but no deposition occurred on the surface. None of the series I hydrogels were noted to have become internally cloudy, although this was difficult to evaluate in those with heavy surface deposits. In the series II experiments, all drugs and agents caused spoliation of the hydrogel when incubated in the presence of SAH. This was manifested by un-washable surface deposits with Prednisolone, Prednefrin Forte (Fig. 1), Zymar, Table 2 Observations of hydrogels and host solutions after in vitro experiments Drug/agent

Drug only series (I)

Drug + SAH series (II)

Prednisolone TobraDex Prednefrin Forte Pantanol Restasis Zymar Vigamox Quixin Genticin Timoptol Timoptol XE Timpilo 4 Xalatan Betoptic Travatan Azopt Xalacom Lumigan Actilyse Heparin Injection Fluoresoft-0.35% Fluorouracil Injection Mitomycin

A E C A G B B B A A A A A A A A A A A A B A B

C E C E D C H C E E C F E C E G E E E E H E H

A: clear and colourless solutions and hydrogel specimens; B: coloured, clear or hazy solutions and hydrogel specimens; C: white particles floating in colourless, clear or hazy solutions; white deposits on hydrogel specimens, not removable by washing; D: as C, but deposits are removable by washing; E: white particles floating in clear solutions, cloudy hydrogel specimens, with or without deposits; F: clear solutions, cloudy hydrogel specimens; G: hazy solutions, clear hydrogel specimens; H: particles present in solutions; solutions and specimens coloured, with or without coloured deposits.

Fig. 1. Spoliation of a hydrogel specimen incubated in Prednefrin Forte and postincubated in simulated aqueous humour: strongly adherent surface deposits.

Vigamox, Quixin, Timoptol XE, Betoptic, Travatan, Fluoresoft and Mitomycin. Loss of transparency was found with Tobradex, Pantanol, Genticin (Fig. 2), Timoptol, Timpilo, Xalatan, Xalacom, Lumigan, Actilyse, Heparin and Fluorouracil; possibly samples with surface deposits were also cloudy, but this was difficult to ascertain. The five agents found to cause colouration in series I, were found in series II additionally to cause surface deposits and/or cloudiness. In most cases, the deposited layer could not be removed by washing. Timoptol XE offered an extreme case of deposit formation (Fig. 3), probably due to the presence of relatively complicated ingredients (Table 1) and the viscous nature of the formulation. Similarly, coloured stains did not wash out. Of the five most strongly spoliated (surface deposit type) samples (Prednisolone, Prednefrin Forte, Zymar, Timoptol

Fig. 2. Spoliation of a hydrogel specimen incubated in Genticin and postincubated in simulated aqueous humour: loss of transparency.

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Table 3 Summary of histological findings of severely spoliated specimens, after exposure to test drug and simulated aqueous humour Drug/agent

Calcium detected histologically (graded 0 to ++++)

Prednisolone Ophthalmic Solution Prednefrin Forte

Stained positive for calcium on the surface (+++) Stained positive for calcium on the surface and, in a localised area only, within the gel (+++) Stained positive for calcium on the surface (+++) but not within the gel (Fig. 4) Stained positive for calcium both on the surface and deeply within the gel (++++) (Fig. 5) Equivocal stain for calcium on the surface and within the gel (+/ )

Zymar

Timoptol XE

Betoptic

Fig. 3. Spoliation of a hydrogel specimen incubated in Timoptol XE and postincubated in simulated aqueous humour: adherent viscous residue.

For comparison with these in vitro screening results, a summary of spoliation data entered in the AlphaCor CVSConnect database in cases where the medications in this study had been prescribed, is provided in Table 4.

4. Discussion

Fig. 4. Histological findings (alizarin red) of specimen after incubation in Zymar and simulated aqueous humour.

XE, Betoptic, all after SAH) that were evaluated histologically, four gave a strongly positive response to calcium (Figs. 4 and 5), mainly near the sample surface, and one (Betoptic) was equivocal (Table 3).

Fig. 5. Histological findings (alizarin red) of specimen after incubation in Timoptol XE and simulated aqueous humour.

AlphaCor is implanted in a staged procedure within the corneal stroma [2,6,7]. In the first stage, the device is placed within an intrastromal pocket that is opened to the anterior chamber by a 3.5 mm trephination posterior to the centre of the device optic, while the anterior surface remains covered by the anterior corneal tissue. After a period of approximately 3 months, the central 3.0 mm of the anterior tissue is removed, exposing the device to the external environment and establishing the device optic as a full-thickness corneal replacement. From the current database in CVSConnect of over 250 devices implanted with a mean follow-up in situ of over 14 months (Stulting RD, Crawford, GJ Dart J et al. AlphaCor: The clinical results to date. ASCRS ASOA Symposium and Congress, April 2005, Washington, DC), none to date has been reported affected by any variety of optic deposition that was detected when stage II surgery was performed. All cases of spoliation or discolouration have occurred subsequent to this step, suggesting a role for exogenous factors such as topical medications in their development. Further, we have previously reported a statistically significant correlation between certain forms of spoliation and topical medications administered shortly prior to their development [3]. As seen in Table 4, prescription of medications additional to the original trial post-stage II protocol [2] (topical medroxyprogesterone 1% and a topical chloramphenicol 1%), is common, increasing the risk for medications to play a role in optic spoliation. This in vitro study was designed to screen topical medications clinically relevant to AlphaCor, in the presence of simulated biological fluid. Although an implanted

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Table 4 Clinical feedback concerning medications tested in this studya Drug/agent

Reported used in AlphaCor patients? (number cases) b

In vivo spoliation reported?

Prednisolone Ophthalmic Solution

Yes (12)

TobraDex

Yes (8)

Prednefrin Forte Pantanol Restasis Zymar

Yes (1) No Yes (2) Yes (8)

Vigamox

Yes (5)

Quixin

Yes (5)

Genticin

Yes (1)

Timoptol or Timoptol XE

Yes (26)

Timpilo 4 Xalatan

No Yes (17)

Betoptic Travatan Azopt Xalacom Lumigan Actilyse

Yes Yes Yes Yes Yes Yes

Heparin Injection (in anterior chamber) Fluoresoft-0.35% Fluorouracil Injection Mitomycin

Yes (27)

Three cases brown deposits. One case white intraoptic deposits.c Two cases surface spoliation One case white intraoptic deposit.c No cases surface spoliation No reports deposits/spoliation Not applicable No reports deposits/spoliation One case surface spoliation (protein). One case brown intragel deposit (patient a smoker) One case white intraoptic deposit.c No cases surface spoliation No cases surface spoliation. One case white intraoptic deposits c One case white intraoptic deposit.c No cases surface spoliation No surface spoliation. three cases brown intraoptic deposits. Eight cases white intraoptic depositsd Not applicable Two cases surface spoliation. Two cases brown deposits. Four cases white intraoptic depositse No No No Case had surface spoliation No No surface spoliation. Case developed white intraoptic depositc No surface spoliation. One white intraoptic deposit No Not applicable Not applicable

a b c d e

(2) (2) (1) (1) (2) (1)

Yes (1) No No

Possible confounding factors such as contact lens wear and dry eye status not included in this table. Clinical data from anonymous feedback into CVSConnect by end August 2005, including all 265 devices implanted to that time. Patient recorded to have received concurrent topical steroids and beta-blockers. Seven of these eight known to have received concurrent topical steroid and beta-blockers. All were reported to have received concurrent topical steroids and beta-blockers.

AlphaCor is in contact both with aqueous humour and with tears after the second stage of surgery, we chose the former as the test medium for these experiments because the concentration of calcium is two times higher than in tears and as such represents a higher risk of inducing calcification. The experiments involved extended exposure times to the test solutions in a static system, while in vivo the drugs are administered intermittently as drops. When administered topically in the eye, the drugs become part of a dynamic system where they can undergo flow, dilution, pharmacologic activity leading to chemical changes, biodegradation and eventual dissipation through specific ocular pathways, and where natural biomolecules with an inhibitory effect on calcium deposition are present. Against this background, this study was designed to over-estimate the probability of in

vivo spoliation that may actually occur on (or within) the implanted device and to minimise the risk of false negative results. Nevertheless, our findings indicate that certain therapeutic agents should be avoided or used with caution in AlphaCor patients. As found in our previous study [1] the results of the present study clearly suggest that topical medications used after implantation of AlphaCor are actively involved in the spoliation of the hydrogel material of the device through formation of deposits and/or colouration. With certain drugs, severe surface spoliation occurred even in the absence of SAH as a source of calcium, the usual culprit in the spoliation of hydrogels when used as contact lenses [10–12] or as IOLs [13–16]. In such cases, the spoliation must be the result of interactions between the components of the

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commercial drug formulations and the polymer network, possibly leading to the precipitation of certain substances present in the formulations. The sediments generated on the hydrogel surface by Azopt in the absence of SAH disappear upon postincubation in SAH (Table 2); this finding is an indication of the complexity of such interactions. Other formulations (Zymar, Vigamox, Quixin, Mitomycin and Fluoresoft-0.35%) induced colouration of the hydrogel in the absence of SAH, but no precipitated matter could be noticed. Again, this must be related to the chemistry of the drugs and various components of the commercial formulations and to their specific interactions with the hydrogel network. Most of the formulations tested in this study did not cause the spoliation of hydrogel specimens unless postincubated in SAH, and it is also notable that the control specimens incubated in SAH without prior drug exposure all developed cloudiness and deposits. The formation of sediments and deposits is probably triggered in the SAH medium by local microscopic defects on the surface of polymer specimens, which may function as nucleation centres for the precipitation of calcium phosphate present in the medium. It may also be induced by local supersaturation due to solute effects [4], or by complicated physicochemical interactions between the molecules of drugs and/or ingredients and the structural moieties of the polymer. The current clinical evidence of a much lower incidence of deposition in vivo than that implied by these in vitro studies, suggests that other factors moderate the chance of depositions occurring in vivo. The experimental SAH used in this study could be unduly provocative of both calciumcontaining surface deposits and a general reduction in clarity. Along with our previous studies [1,3–5], the present study indicates the complexity of interactions between biological fluids and medications, particularly combinations of medications with complex formulations. Colouration, such as the yellow tint seen with fluoroquinolones such as Zymar, seem from these screening results to be associated with a class of drug rather than subsequent interactions with SAH, and to be associated with the drug rather than the preservative. The interesting previously reported finding of a plaque of calcium developing within, rather than on the surface, of the optic, was not found in the present study and appears to be associated strongly with the specific co-administration of topical steroids with topical beta-blockers [3]. Factors that could further influence the risk of significant discolouration, calcium deposition or other spoliation in vivo, include environmental factors, smoking habits, tear film quality and quantity, blink rate and contact lens wear over the device. An analysis of AlphaCor data with respect to the effects of these variables on optic deposition has also been undertaken (submitted). The present laboratory data, correlated with known cases of spoliation in vivo, suggest that in vitro screening over-estimates the chance of significant drug-related surface spoliation in patients, which

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when observed, appears most commonly to be muco-protein rather than drug-related. Screening may help raise awareness of colouration related to some drugs, although again in vitro screening over-estimates the clinical staining reported: to date just one fluoroquinolone recipient was noted to develop brownish optic staining, and this patient was a smoker. It further appears from our results that the SAH used has a high probability of generating hydrogel cloudiness, of which clinical significance is uncertain. Overall it appears likely that the risk of visually significant drug-related spoliation in AlphaCor recipients is low provided that the known specific risk factors such as Betagan, and steroid-beta-blocker co-administration, are avoided. From the present results it appears that Fluoresoft and Mitomycin directly over the optic should also be avoided or used with extreme care. General precautions that optimise tear volume and quality or provide a bandage-lens barrier, along with avoidance of smoking, should further reduce the clinical risk; these precautions probably account for the low incidence of spoliation actually reported to date. Both in vitro screening – arguably without the SAH step – and continued clinical vigilance is necessary to establish with confidence the optimal medications for use in AlphaCor recipients.

Acknowledgements The Biomaterials & Polymer Research group at the Lions Eye Institute receives research subsidies from CooperVision Surgical Inc., the manufacturer of AlphaCorTM. The authors gratefully acknowledge assistance from Ms Joanna Gregg in the preparation of this manuscript.

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